There remains a substantial unmet need for effective and safe treatments for neuropathic pain. The Neuropathic Pain Special Interest Group aimed to update treatment recommendations, published in 2015, on the basis of new evidence from randomised controlled trials, emerging neuromodulation techniques, and advances in evidence synthesis.

For this systematic review and meta-analysis, we searched Embase, PubMed, the International Clinical Trials Registry, and ClinicalTrials.gov from data inception for neuromodulation trials and from Jan 1, 2013, for pharmacological interventions until Feb 12, 2024. We included double-blind, randomised, placebo-controlled trials that evaluated pharmacological and neuromodulation treatments administered for at least 3 weeks, or if there was at least 3 weeks of follow-up, and which included at least ten participants per group. Trials included participants of any age with neuropathic pain, defined by the International Association for the Study of Pain. We excluded trials with enriched enrolment randomised withdrawal designs and those with participants with mixed aetiologies (ie, neuropathic and non-neuropathic pain) and conditions such as complex regional pain syndrome, low back pain without radicular pain, fibromyalgia, and idiopathic orofacial pain. We extracted summary data in duplicate from published reports, with discrepancies reconciled by a third independent reviewer on the platform Covidence. The primary efficacy outcome was the proportion of responders (50% or 30% reduction in baseline pain intensity or moderate pain relief). The primary safety outcome was the number of participants who withdrew from the treatment owing to adverse events. We calculated a risk difference for each comparison and did a random-effects meta-analysis. Risk differences were used to calculate the number needed to treat (NNT) and the number needed to harm (NNH) for each treatment. Risk of bias was assessed by use of the Cochrane risk of bias tool 2 and certainty of evidence assessed by use of GRADE. Recommendations were based on evidence of efficacy, adverse events, accessibility, and cost, and feedback from engaged lived experience partners. This study is registered on PROSPERO, CRD42023389375.

We identified 313 trials (284 pharmacological and 29 neuromodulation studies) for inclusion in the meta-analysis. Across all studies, 48 789 adult participants were randomly assigned to trial groups (20 611 female and 25 078 male participants, where sex was reported). Estimates for the primary efficacy and safety outcomes were tricyclic antidepressants (TCAs) NNT=4·6 (95% CI 3·2-7·7), NNH=17·1 (11·4-33·6; moderate certainty of evidence), α2δ-ligands NNT=8·9 (7·4-11·10), NNH=26·2 (20·4-36·5; moderate certainty of evidence), serotonin and norepinephrine reuptake inhibitors (SNRIs) NNT=7·4 (5·6-10·9), NNH=13·9 (10·9-19·0; moderate certainty of evidence), botulinum toxin (BTX-A) NNT=2·7 (1·8-9·61), NNH=216·3 (23·5-∞; moderate certainty of evidence), capsaicin 8% patches NNT=13·2 (7·6-50·8), NNH=1129·3 (135·7-∞; moderate certainty of evidence), opioids NNT=5·9 (4·1-10·7), NNH=15·4 (10·8-24·0; low certainty of evidence), repetitive transcranial magnetic stimulation (rTMS) NNT=4·2 (2·3-28·3), NNH=651·6 (34·7-∞; low certainty of evidence), capsaicin cream NNT=6·1 (3·1-∞), NNH=18·6 (10·6-77·1; very low certainty of evidence), lidocaine 5% plasters NNT=14·5 (7·8-108·2), NNH=178·0 (23·9-∞; very low certainty of evidence). The findings provided the basis for a strong recommendation for use of TCAs, α2δ-ligands, and SNRIs as first-line treatments; a weak recommendation for capsaicin 8% patches, capsaicin cream, and lidocaine 5% plasters as second-line recommendation; and a weak recommendation for BTX-A, rTMS, and opioids as third-line treatments for neuropathic pain.

Our results support a revision of the Neuropathic Pain Special Interest Group recommendations for the treatment of neuropathic pain. Treatment outcomes are modest and for some treatments uncertainty remains. Further large placebo-controlled or sham-controlled trials done over clinically relevant timeframes are needed.

NeuPSIG and ERA-NET Neuron.

Neuropathic corneal pain (NCP) is a debilitating condition characterized by persistent pain due to corneal nerve damage or dysfunction. Millions of individuals and their families endure the significant impact of chronic pain. Effective management strategies are crucial yet limited, prompting the exploration of innovative treatments such as photobiomodulation (PBM).

In vivo preclinical therapeutics investigation in mice.

Thy1-YFP mice.

This study evaluates the efficacy of PBM in treating NCP across 4 animal models: normal control, sham control, pulled nerve, and full transection (FT). Behavioral assessments, including the von Frey test (VFT) for mechanical sensitivity and the eye-wiping test (EWT) for chemical sensitivity, were employed to evaluate the therapeutic impact of PBM till day 56 (D-1, D1, D3, D5, D7, D14, D28, D42, and D56).

Advances in therapeutic approach for NCP through the potential of PBM.

Photobiomodulation significantly reduced behavioral manifestations of pain in the pulled nerve model (VFT: no PBM [D1 = 0.043 ± 0.044, D56 = 0.05 ± 0.014] and PBM [D1 = 0.050 ± 0.008 {P value = 0.18}, D56 = 0.09 ± 0.014 {P value = 0.02}], EWT: no PBM [D1 = 11.96 ± 0.47, D56 = 12.11 ± 0.15] and PBM [D1 = 11.73 ± 0.18 {P value = 0.2}, D56 = 11.22 ± 0.31] [P value = 0.01]) and FT model (VFT: no PBM [D1 = 0.022 ± 0.0028, D56 = 0.023 ± 0.0047] and PBM [D1 = 0.024 ± 0.0028 {P value = 0.2}, D56 = 0.073 ± 0.0094] [P value = 0.02]), EWT: no PBM [D1 = 13.1 ± 0.14, D56 = 13.36 ± 0.30] and PBM [D1 = 12.86 ± 0.41, {P value = 0.2}, D56 = 12.53 ± 0.41] [P value = 0.04]}, suggesting an effective reduction of pain sensitivity and an increase in corneal nerve function. The temporal patterns also suggest that early intervention with PBM, initiated shortly after nerve injury, may be crucial for preventing the chronic progression of NCP.

These outcomes support PBM as a promising nonpharmacologic intervention for NCP; this not only reinforces the potential of PBM in NCP treatment but also provides a foundation for future clinical applications in managing corneal neuropathy.

The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Epidural spinal cord stimulation (SCS) or dorsal root ganglion stimulation (DRG-S) is a neuromodulatory, reversible interventional procedure for patients with pain who cannot be adequately treated with conservative and less invasive means. This review provides the recently updated German recommendations for SCS and DRG-S, followed by a standardized diagnostic and therapeutic procedure.

The purpose of this work is to present the current evidence-based results of SCS, including DRG-S, for various neuropathic and nonneuropathic pain conditions. Moreover, it aims to optimize the treatment of patients with chronic pain for whom neuromodulation can be a component in the treatment concept of multimodal pain therapy.

A systematic literature search was conducted based on a Cochrane analysis, followed by search strategies in the common data bases (PubMed, Medline, and Embase). The relevant literature was reviewed and discussed within working groups. Finally, evaluation of evidence and identification of recommendations was performed by members of the guideline commission comprising representatives of relevant medical societies in Germany.

The first German guideline on SCS was published in April 2013. Any guideline has only limited validity (eg, in Germany, guidelines are valid for a maximum of five years). Owing to the numerous publications in this field, an update had become mandatory. On the basis of literature from 2013 to 2018, indications were newly identified or reevaluated. In addition, new methods were discussed, and predictors for treatment success were defined as part of the psychologic assessment.

Neuromodulation, especially SCS, is based on the systematic study of treatment data. Real-world data are indispensable. Particularly in the current situation, in which fundamental questions about the value of SCS are being publicly discussed, sometimes in nonscientific media, it is essential to publish systematic guidelines, on both a national and international level.

Chronic neuropathic pain and depression are common and debilitating conditions in cancer patients, significantly impacting their quality of life. Pregabalin, an anticonvulsant medication, is used for neuropathic pain and may also influence depressive symptoms. This study evaluates the efficacy and safety of pregabalin on pain intensity, depression severity, and side effects in cancer patients with chronic neuropathic pain and depression.

To evaluate the impact of pregabalin on pain intensity, depression severity, and the safety profile in cancer patients with chronic neuropathic pain and depression.

This observational case series included 10 cancer patients experiencing chronic neuropathic pain and depression. Pregabalin was administered at a starting dose of 150 mg twice daily, with adjustments based on patient tolerance and pain response up to 300 mg twice daily. Pain intensity and depression severity were assessed using the brief pain inventory (BPI) and the Hamilton depression rating scale (HDRS) at baseline, 4 weeks, and 8 weeks. Side effects were monitored using a self-reported side effect questionnaire.

Pregabalin led to a significant reduction in pain intensity and depression severity. The mean BPI score decreased from 7.8 (SD = 1.2) at baseline to 5.2 (SD = 1.4) at 4 weeks and 4.1 (SD = 1.5) at 8 weeks, representing reductions of 33.3% and 47.4%, respectively. The mean HDRS score decreased from 18.5 (SD = 4.0) at baseline to 13.2 (SD = 4.1) at 4 weeks and 9.8 (SD = 3.6) at 8 weeks, showing reductions of 28.4% and 47.0%, respectively. Side effects included dizziness (50%), drowsiness (40%), weight gain (30%), and dry mouth (20%). No severe adverse effects were reported. All patients completed the study, with 30% requiring dose adjustments.

Pregabalin significantly alleviates both chronic neuropathic pain and depression in cancer patients with a manageable safety profile. These findings support the use of pregabalin in this patient population, though further research with larger samples and controlled designs is warranted.

Neuropathic pain is a chronic condition resulting from injury or dysfunction in the somatosensory nervous system, which leads to persistent pain and a significant impairment of quality of life. Research has highlighted the complex molecular mechanisms that underlie neuropathic pain and has begun to delineate the roles of microRNAs (miRNAs) in modulating pain pathways. miRNAs, which are small non-coding RNAs that regulate gene expression post-transcriptionally, have been shown to influence key cellular processes, including neuroinflammation, neuronal excitability, and synaptic plasticity. These processes contribute to the persistence of neuropathic pain, and miRNAs have emerged as critical regulators of pain behaviors by modulating signaling pathways that control pain sensitivity. miRNAs can influence neuropathic pain by targeting genes that encode protein kinases involved in pain signaling. This review focuses on miRNAs that have been demonstrated to modulate neuropathic pain behavior through their effects on protein kinases or their immediate upstream regulators. The relationship between miRNAs and neuropathic pain behaviors is characterized as either an upregulation or a downregulation of miRNA levels that leads to a reduction in neuropathic pain. In the case of miRNA upregulation resulting in an alleviation of neuropathic pain behaviors, protein kinases exhibit a positive correlation with neuropathic pain, whereas decreased protein kinase levels correlate with diminished neuropathic pain behaviors. The only exception is GRK2, which shows an inverse correlation with neuropathic pain. In the case of miRNA downregulation resulting in a reduction in neuropathic pain behaviors, protein kinases display mixed relationships to neuropathic pain, with some kinases exhibiting positive correlation, while others exhibit negative correlation. By exploring how protein kinases mediate miRNA modulation of neuropathic pain, valuable insight may be gained into the pathophysiology of neuropathic pain, offering potential therapeutic targets for developing more effective strategies for pain management.

Herpes zoster is an acute condition caused by the reactivation of varicella zoster virus, often affecting the skin and mucosa. When varicella zoster virus invades the trigeminal ganglion, it can lead to trigeminal herpes zoster, with postherpetic neuralgia as the most common complication. Postherpetic neuralgia, characterized by persistent pain for over 3 months after skin lesions heal, significantly impacts quality of life, including sleep, mood, and social interactions. Current treatments, including antiviral drugs, analgesics, and neurotrophic agents, are often insufficient, and many patients still suffer from refractory postherpetic neuralgia. This highlights the need for alternative treatments. Trigeminal ganglion electrical stimulation has shown potential in managing refractory trigeminal herpes zoster and preventing postherpetic neuralgia. However, reports on its effectiveness remain scarce. This article presents two rare cases where trigeminal ganglion electrical stimulation was successfully used to treat refractory trigeminal herpes zoster and prevent postherpetic neuralgia.

This study reports two cases of trigeminal herpes zoster that were refractory to pharmacological treatment and successfully alleviated using trigeminal ganglion electrical stimulation, which also effectively prevented postherpetic neuralgia. Both patients, a 62-year-old Chinese female and a 65-year-old Chinese male, presented with severe pain, itching, sensory disturbances, and extensive vesicular lesions on the left side of the face, involving the ophthalmic (V1) and maxillary (V2) branches. Despite receiving antiviral drugs, analgesics, and neurotrophic agents, their symptoms remained inadequately controlled, with pain scores ranging from 8 to 10. After undergoing trigeminal ganglion electrical stimulation, the pain score of both patients dropped to 2-3 on the first day post-treatment, with significant improvement in the herpes zoster blisters and pain. During follow-up, the pain continued to improve, with marked reduction in the pain and itching in the affected areas, and sleep quality also improved. At 1, 3, and 6 months of follow-up, neither patient had developed postherpetic neuralgia. These cases suggest that trigeminal ganglion electrical stimulation may be an effective method for treating refractory trigeminal herpes zoster and preventing postherpetic neuralgia, significantly improving herpes symptoms and alleviating pain.

These cases demonstrate that trigeminal ganglion electrical stimulation can provide rapid and sustained pain relief while preventing postherpetic neuralgia in refractory trigeminal herpes zoster patients. This highlights the potential of trigeminal ganglion electrical stimulation as a novel therapeutic approach, particularly for patients who do not respond to conventional treatments. Its success in these cases suggests a promising direction for further research and clinical application.

This study aimed to compare the effects of pregabalin, gabapentin, and duloxetine on diabetic peripheral neuropathy (DPN) to guide tailored treatment.

In this retrospective study, 180 patients with type 2 diabetes and DPN were matched 1:1:1 across three groups based on HbA1c and age, resulting in 60 patients per group. Clinical data were collected, and the painDETECT score was used to evaluate treatment response over six weeks.

After six weeks, the gabapentin group had significantly higher pain scores than the pregabalin (P = 0.002) and duloxetine groups (P < 0.001). The pregabalin group's scores were higher than the duloxetine group's, but not significantly (P = 0.62). Side effects were more frequent with duloxetine (23.3 %) compared to gabapentin (1.7 %) and pregabalin (6.7 %) (P = 0.001). Among those with over 50 % improvement, mean HbA1c levels were 9.42 for gabapentin, 10.43 for pregabalin, and 7.72 for duloxetine. Duloxetine significantly lowered HbA1c compared to gabapentin (P = 0.001) and pregabalin (P = 0.001), with no significant difference between gabapentin and pregabalin (P = 0.45).

Duloxetine and pregabalin effectively treat DPN. Gabapentin and pregabalin are suitable for patients with HbA1c over 8.7, while duloxetine is better for those with well-controlled HbA1c. Treatment should consider side effects, adherence, costs, and response time.

Level III retrospective cohort study.

Neuropathic pain is a complex and challenging condition that arises from abnormal processing of somatosensory information, often following nerve injury or dysfunction. Its diagnosis involves a detailed clinical history, sensory examination, and diagnostic tests such as electromyography, nerve conduction studies, and MRI to identify nerve damage or structural causes. In athletes, neuropathic pain can result from nerve entrapment syndromes, post-surgical complications, or peripheral nerve injuries, with unique challenges in pain assessment due to psychological factors and exercise-induced changes. Pharmacological management primarily includes anticonvulsants (e.g., gabapentin, pregabalin) and antidepressants (e.g., tricyclics, SNRIs), tailored to minimize side effects that could impair athletic performance. Effective treatment requires a careful balance to manage pain while maintaining physical capabilities. When treating athletes for neuropathic pain, healthcare providers must ensure prescribed medications comply with World Anti-Doping Agency (WADA) regulations. Narcotics (opioids) and cannabinoids are prohibited in-competition. Glucocorticoids are also banned in-competition if administered via injection, orally, or rectally, and elevated levels in urine may lead to sanctions.

Neuropathic pain is a prevalent issue that often arises following injuries to the peripheral or central nervous system. Unfortunately, there is currently no definitive and flawless treatment available to alleviate this type of pain. However, exercise has emerged as a promising nonpharmacological and adjunctive approach, demonstrating a significant impact in reducing pain intensity. This is why physical therapy is considered a beneficial approach for diminishing pain and promoting functional recovery following nerve injuries. Regular physical activity exerts its hypoalgesic effects through a diverse array of mechanisms. These include inhibiting oxidative stress, suppressing inflammation, and modulating neurotransmitter levels, among others. It is possible that multiple activated mechanisms may coexist within an individual. However, the priming mechanism does not need to be the same across all subjects. Each person's response to physical activity and pain modulation may vary depending on their unique physiological and genetic factors. In this review, we aimed to provide a concise overview of the mechanisms underlying the beneficial effects of regular exercise on neuropathic pain. We have discussed several key mechanisms that contribute to the improvement of neuropathic pain through exercise. However, it is important to note that this is not an exhaustive analysis, and there may be other mechanisms at play. Our goal was to provide a brief yet informative exploration of the topic.

Background/Objectives: Chronic pain remains a pervasive and challenging public health issue, often resistant to conventional treatments such as opioids, which carry substantial risks of dependency and adverse effects. Cannabinoids, bioactive compounds derived from the Cannabis sativa plant and their synthetic analogs, have emerged as a potential alternative for pain management, leveraging their interaction with the endocannabinoid system to modulate pain and inflammation. Methods: The current, evolving literature regarding the history, efficacy, applications, and safety of cannabinoids in the treatment of chronic pain was reviewed and summarized to provide the most current review of cannabinoids. Results: Evidence suggests that cannabinoids provide moderate efficacy in managing neuropathic pain, fibromyalgia, cancer-related pain, and multiple sclerosis-related spasticity. Patient-reported outcomes further indicate widespread perceptions of cannabinoids as a safer alternative to opioids, with potential opioid-sparing effects. However, the quality of existing evidence is limited by small sample sizes and methodological inconsistencies. Regulatory barriers, including the classification of cannabis as a Schedule I substance in the United States, continue to hinder robust research and clinical integration. Moreover, the risks associated with cannabinoids, such as psychiatric effects, addiction potential, and drug interactions, necessitate cautious application. Conclusions: Cannabinoids represent a promising, albeit complex, alternative for chronic pain management, particularly given the limitations and risks of traditional therapies such as opioids. However, significant deficiencies remain in the research. While smaller trials and systematic reviews indicate therapeutic potential, the quality of evidence is often low due to limited sample sizes, short study durations, and methodological inconsistencies. Large-scale, randomized controlled trials with long-term follow-up are urgently needed to confirm efficacy and safety across diverse patient populations and pain etiologies.

Neurological and psychiatric manifestations occur in patients with primary Sjogren's disease (SjD) with a wide-ranging clinical presentation, affecting quality of life, social participation, and prognosis. Despite this, neither central nor peripheral neurological symptoms are systematically evaluated in the context of autoimmunity or identified as manifestations of SjD. The EULAR Sjogren's Syndrome Disease Activity Index (ESSDAI) covers only part of them in the neurological domain.

We performed a systematic review of the diagnosis and prevalence of central, peripheral, and autonomic nervous system manifestations in primary SjD, following the recommendations proposed by the Cochrane Collaboration Handbook. Observational studies were included when their main issue was the diagnosis and the prevalence of the manifestations individually. We employed a generalized linear mixed model (GLMM) method with a random-effects model, and the results were computed using logit transformation, implemented through the 'meta' and 'metafor' packages in the R software (version 3.6.1). To present these recommendations, agreement among experts was investigated using the Delphi method in in-person meetings.

We propose ten recommendations regarding the investigation and management of neurological involvement in SjD that had 100% agreement among participants.

These recommendations add to the literature on the clinical care of patients with SjD.

Crisugabalin (HSK16149), a novel VGCC α2δ ligand, has been approved for the treatment of adult diabetic peripheral neuropathic pain (DPNP) and postherpetic neuralgia (PHN). In this study, an LC-MS/MS method was developed for the determination of crisugabalin in rat plasma and tissues homogenate. Samples were extracted by protein precipitation and separated on a Hypersil GOLD aQ column with methanol and 2 mM ammonium acetate in water containing 0.1 % formic acid as mobile phase. Crisugabalin and its internal standard HSK7891 were ionized by electrospray ionization source and detected by multiple reaction monitoring with transitions of m/z 210.9 → 134.4 and m/z 246.0 → 129.3. Over the range of 0.0100-10.0 μg/mL, the selectivity, linearity, precision and accuracy, matrix effect, stability, recovery and dilution integrity of crisugabalin were validated in rat plasma. Validation was also performed in rat liver homogenate at concentrations ranging from 0.0200-20.0 μg/g. The method was then successfully applied to determine the pharmacokinetics and tissue distribution of crisugabalin. In rats, orally administered crisugabalin was completely and rapidly absorbed with a peak time of about 0.57 h, and was mainly distributed to kidney, bladder and liver tissues. Crisugabalin exhibited linear pharmacokinetics over the oral dose range of 3-30 mg/kg.

Patients with neuropathic pain (NP) have significantly lower quality of life. Because the pathophysiology of NP is not fully understood, there is a lack of effective treatment for it in clinic. This study set out to investigate the precise mechanism by which pulsed radiofrequency (PRF) alleviated NP.

The rat models of chronic constriction injury of the sciatic nerve (CCI) were established to simulate the occurrence of NP, following with measuring MWT and TWL to evaluate the pain of the rats. HE staining was utilized to observe the rat spinal cord tissue pathology. The expression of MG53, ATF4 and CHOP was evaluated by qRT-PCR and WB, while the expression of inflammatory factors was measured by ELISA. In addition, immunofluorescence assay was used to detect the expression of MG53 and Iba-1.

PRF treatment alleviated NP in CCI rats, as well as upregulating the expression of MG53 and inhibiting microglial activation. After MG53 knockdown, the remission of NP by PRF was significantly weakened, but microglial activation and endoplasmic reticulum stress (ERS) exhibited enhancement. Therefore, PRF inhibited microglial activation by upregulating MG53. After injection of ERS inducer in CCI rats, the inhibition effect of overexpressed MG53 on microglial activation and its alleviation effect on NP were reversed. Consequently, MG53 played a role in suppressing microglial activation by mediating the inhibition of ERS.

PRF attenuated microglial activation by upregulating MG53 to inhibit ERS, resulting in the alleviation of NP in CCI rats.

Neuromodulation techniques have emerged as promising strategies for managing chronic pain. These techniques encompass various modalities of nerve stimulation, including Spinal Cord Stimulation (SCS), Dorsal Root Ganglion Stimulation (DRG-S), and Peripheral Nerve Stimulation (PNS). Studies consistently demonstrate significant improvements in pain intensity, quality of life, and reduced opioid usage among patients treated with these modalities. However, neuromodulation presents challenges, such as the need for frequent in-person follow-up visits to ensure proper functionality of the implanted device. Our review explored factors impacting compliance in current neuromodulation users and examined how remote monitoring can mitigate some of these challenges. We also discuss outcomes of recent studies related to remote monitoring of neuromodulation.

While remote monitoring capabilities for neuromodulation devices is an emerging development, there are promising results supporting its role in improving outcomes for chronic pain patients. Higher patient satisfaction, improved pain control, and reduced caretaker burdens have been observed with the use of remote monitoring. This review discusses the current challenges with neuromodulation therapy and highlights the role of remote monitoring. As the field continues to evolve, understanding the importance of remote monitoring for neuromodulation is crucial for optimizing pain management outcomes.

Highly variable pain mechanisms in people with low back pain or spine-related leg pain might contribute to inefficacy of neuropathic pain medication. This meta-analysis aimed to determine how neuropathic pain is identified in clinical trials for people taking neuropathic pain medication for low back pain or spine-related leg pain and whether subgrouping based on the presence of neuropathic pain influences efficacy.

EMBASE, MEDLINE, Cochrane Central, CINAHL [EBSCO], APA PsycINFO, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry were searched from inception to 14 May, 2024. Randomized and crossover trials comparing first-line neuropathic pain medication for people with low back pain or spine-related leg pain to placebo or usual care were included. Two independent authors extracted data. Random-effects meta-analyses of all studies combined, and pre-planned subgroup meta-analyses based on the certainty of neuropathic pain (according to the neuropathic pain Special Interest Group [NeuPSIG] neuropathic pain grading criteria) were completed. Certainty of evidence was judged using the grading of recommendations assessment development and evaluation [GRADE] framework.

Twenty-seven included studies reported on 3619 participants. Overall, 33% of studies were judged unlikely to include people with neuropathic pain, 26% remained unclear. Only 41% identified people with possible, probable, or definite neuropathic pain. For pain, general analyses revealed only small effects at short term (mean difference [MD] - 9.30 [95% confidence interval [CI] - 13.71, - 4.88], I2 = 87%) and medium term (MD - 5.49 [95% CI - 7.24, - 3.74], I2 = 0%). Subgrouping at short term revealed studies including people with definite or probable neuropathic pain showed larger effects on pain (definite; MD - 16.65 [95% CI - 35.95, 2.65], I2 = 84%; probable; MD - 10.45 [95% CI - 14.79, - 6.12], I2 = 20%) than studies including people with possible (MD - 5.50 [95% CI - 20.52, 9.52], I2 = 78%), unlikely (MD - 6.67 [95% CI - 10.58, 2.76], I2 = 0%), or unclear neuropathic pain (MD - 8.93 [95% CI - 20.57, 2.71], I2 = 96%). Similarly, general analyses revealed negligible effects on disability at short term (MD - 3.35 [95% CI - 9.00, 2.29], I2 = 93%) and medium term (MD - 4.06 [95% CI - 5.63, - 2.48], I2 = 0%). Sub-grouping at short term revealed larger effects in studies including people with definite/probable neuropathic pain (MD - 9.25 [95% CI - 12.59, - 5.90], I2 = 2%) compared with those with possible/unclear/unlikely neuropathic pain (MD -1.57 [95% CI - 8.96, 5.82] I2 = 95%). Medium-term outcomes showed a similar trend, but were limited by low numbers of studies. Certainty of evidence was low to very low for all outcomes.

Most studies using neuropathic pain medication for low back pain or spine-related leg pain fail to adequately consider the presence of neuropathic pain. Meta-analyses suggest neuropathic pain medication may be most effective in people with low back pain or spine-related leg pain with a definite/probable neuropathic pain component. However, the low to very low certainty of evidence and poor identification of neuropathic pain in most studies prevent firm recommendations.

This chapter aims to review the current pharmacological options for neuropathic pain treatment, their mechanisms of action, and future directions for clinical practice. Achieving pain relief in neuropathic pain conditions remains a challenge in clinical practice. The field of pharmacotherapy for neuropathic pain has encountered significant difficulties in translating substantial advances in our understanding of the underlying pathophysiological mechanisms into clinically effective therapies. This chapter presents the drugs recommended for the pharmacotherapy of neuropathic pain, based on the widely accepted treatment guidelines formulated by the Neuropathic Pain Special Interest Group of the International Association for the Study of Pain. In addition to discussing how the evidence base is created as part of international consortia, the drugs are also examined in terms of their putative molecular mechanisms as well as pharmacological pleiotropy, i.e., their potential unspecific and multi-target effects resulting in modulation of neuronal hyperexcitability. The chapter closes with a discussion of potential future developments in the field.

China carries a heavy burden of postherpetic neuralgia, with an unmet need for novel drugs with greater efficacy and less prominent neurotoxic effects than existing calcium channel ligands.

To investigate the efficacy and safety of crisugabalin, an oral calcium channel α2δ-1 subunit ligand, for postherpetic neuralgia.

This randomized clinical trial, carried out between November 9, 2021, and January 5, 2023, at 48 tertiary care centers across China had 2 parts. Part 1 was a phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study consisting of a 2-week screening period, a 7-day run-in period, and a 12-week double-blind treatment period. Part 2 was a 14-week open-label extension study. Investigators, statisticians, trial clinicians, and patients were blinded to trial group assignments. Participants included adults with postherpetic neuralgia with an average daily pain score (ADPS) of at least 4 on the 11-point Numeric Pain Rating Scale over the preceding week, with the exclusion of patients with pain not controlled by prior therapy with pregabalin (≥300 mg/d) or gabapentin (≥1200 mg/d).

Patients were randomized 1:1:1 to receive crisugabalin, 20 mg twice daily (ie, 40 mg/d), and crisugabalin, 40 mg twice daily (ie, 80 mg/d), or placebo for 12 weeks. Eligible patients received crisugabalin, 40 mg, twice daily during extension.

The primary efficacy end point was the change from baseline in ADPS at week 12.

The study enrolled 366 patients (121 patients receiving crisugabalin, 40 mg/d; 121 patients receiving crisugabalin, 80 mg/d; 124 patients receiving placebo; median [IQR] age, 63.0 [56.0-69.0] years; 193 men [52.7%]). At week 12, the least squares mean (SD) change from baseline in ADPS was -2.2 (0.2) for crisugabalin, 40 mg/d, and -2.6 (0.2) for crisugabalin, 80 mg/d, vs -1.1 (0.2) for placebo, with a least squares mean difference of -1.1 (95% CI, -1.6 to -0.7; P < .001) and -1.5 (-95% CI, -2.0 to -1.0; P < .001) vs placebo, respectively. No new safety concerns emerged.

Crisugabalin, 40 mg/d, or crisugabalin, 80 mg/d, was well tolerated and demonstrated a statistically significant improvement in ADPS over placebo.

ClinicalTrials.gov Identifier: NCT05140863.

Chronic pain is a constantly recurring and persistent illness, presenting a formidable healthcare challenge for patients and physicians alike. Current first-line analgesics offer only low-modest efficacy when averaged across populations, further contributing to this debilitating disease burden. Moreover, many recent trials for novel analgesics have not met primary efficacy endpoints, which is particularly striking considering the pharmacological advances have provided a range of highly relevant new drug targets. Heterogeneity within chronic pain cohorts is increasingly understood to play a critical role in these failures of treatment and drug discovery, with some patients deriving substantial benefits from a given intervention while it has little-to-no effect on others. As such, current treatment failures may not result from a true lack of efficacy, but rather a failure to target individuals whose pain is driven by mechanisms which it therapeutically modulates. This necessitates a move towards phenotypical stratification of patients to delineate responders and non-responders in a mechanistically driven manner. In this article, we outline a bench-to-bedside roadmap for this transition to mechanistically informed personalised pain medicine. We emphasise how the successful identification of novel analgesics is dependent on rigorous experimental design as well as the validity of models and translatability of outcome measures between the animal model and patients. Subsequently, we discuss general and specific aspects of human trial design to address heterogeneity in patient populations to increase the chance of identifying effective analgesics. Finally, we show how stratification approaches can be brought into clinical routine to the benefit of patients.

Electrospun fibers prepared from water-soluble polymers (PVP, PVA, and HPMC) were loaded with pregabalin, a BCS I drug, to address its fast release and adverse effects. The drug dissolved partially (1.8-2.8 wt%) in the polymers, with excess pregabalin in crystalline form within the fibers. The solubility of the drug varied with the pH of the dissolution medium. Most of the drug encapsulated into the fibers during electrospinning, but some was lost due to technical reasons. PVP showed no impact on drug release, offering no benefit as a carrier. However, PVA-based fibers exhibited considerably slower release than the dissolution rate of the neat drug and also the release rate from fibers prepared from the other polymers. This indicates the potential of PVA for using it with pregabalin in practical drug formulations with improved release properties. The pH of the dissolution medium influenced solubility and release rate for specific polymers. Overall, the study highlights the importance of polymer selection and pH control in optimizing the release profile of pregabalin in enhanced drug delivery.

Gabapentinoids are commonly prescribed to control neuropathic pain of lumbar radiculopathy. Few trials have compared the efficacy of gabapentin (GBP) and pregabalin (PGB). Therefore, the authors conducted a meta-analysis to compare the difference in effect between GBP and PGB in lumbar radiculopathy patients.

Articles which were published between January 1, 1960 and May 31, 2023 were investigated via Cochrane Central Register of Controlled Trials, Embase, Google Scholar, and MEDLINE. This meta-analysis was conducted on patients with lumbar radiculopathy. Gabapentin was used as an intervention, and pregabalin as a comparison. As outcomes, pain rating scales including visual analog scale (VAS) and numeric pain rating scale (NRS), and number of adverse events (dizziness and sedation) were obtained.

PGB showed statistically significant improvement in pain scale (VAS and NRS) in short-term follow-up (6 weeks or less) compared to GBP. (Total mean difference of -0.31) However, in the long-term follow-up (6 weeks to 12 weeks), there was no difference in pain reduction effect between two groups. The incidence of AEs showed no difference between two groups.

Based on this article, the existing evidence suggests that PGB was more effective in reducing pain of lumbar radiculopathy compared to GBP at the short-term follow-up, but there was no difference in the long-term follow-up. Physicians should consider this finding in prescribing medications for patients with lumbar radiculopathy.

To provide optimal care in pancreatic ductal adenocarcinoma, involvement of palliative medicine and nutritional support is recommended. Advances in endoscopy have resulted in robust options for biliary and gastrointestinal stenting for relief of obstruction. Notwithstanding, surgical hepaticojejunostomy and gastrojejunostomy remain incontrovertible considerations for biliary obstruction and gastric outlet obstruction, respectively. For PDAC-associated pain, opioid therapy continues to be the mainstay. However, refractory pain may be treated with interventional procedures such as celiac or splanchnic nerve blocks or neurolysis. In patients with PDAC, enteral nutrition can be further complicated by exocrine pancreatic insufficiency, which should be treated with oral pancreatic enzyme supplementation.

Central post-stroke pain (CPSP) poses a multifaceted challenge in medical practice, necessitating a thorough and multidisciplinary approach for its diagnosis and treatment. This review examines current methods for addressing CPSP, highlighting both pharmacological and non-pharmacological therapies. It covers the mechanisms and clinical effectiveness of these treatments in managing CPSP and emphasizes the importance of personalized treatment plans, given the varied causes of CPSP.

Recent advancements have illuminated diverse treatment modalities for CPSP. Pharmacotherapy spans from conventional analgesics to anticonvulsants and antidepressants, tailored to mitigate the neuropathic characteristics of CPSP. Non-pharmacological interventions, including physical therapy and psychological strategies, are pivotal in managing CPSP's chronic nature. For cases resistant to standard treatments, advanced interventions such as nerve blocks and surgical procedures like deep brain stimulation (DBS) or motor cortex stimulation (MCS) are considered. Additionally, innovative technologies such as neuromodulation techniques and personalized medicine are emerging as promising avenues to enhance therapeutic outcomes and improve quality of life for individuals grappling with CPSP.

Modern approaches in managing CPSP require an interdisciplinary and patient-centric approach. Customizing treatment plans to address the specific etiology and symptoms of CPSP is crucial. Pharmacotherapy remains fundamental, encompassing medications such as anticonvulsants and antidepressants tailored to manage neuropathic pain. Integrating non-pharmacological interventions is crucial for providing comprehensive care. Additionally, investigating innovative technologies and personalized medicine presents promising opportunities to enhance treatment results and elevate the quality of life for those suffering from CPSP. Ultimately, an integrated approach that acknowledges the multifaceted nature of CPSP is essential for effective management and patient well-being.

Botulinum toxin type A (BTX-A), produced by the gram-positive anaerobic bacterium Clostridium botulinum, acts by cleaving synaptosome-associated protein-25 (SNAP-25), an essential component of the presynaptic neuronal membrane that is necessary for fusion with the membrane proteins of neurotransmitter-containing vesicles. Recent studies have highlighted the efficacy of BTX-A in treating chronic pain conditions, including lower back pain, chronic neck pain, neuropathic pain, and trigeminal neuralgia, particularly when patients are unresponsive to traditional painkillers. This review focuses on the analgesic effects of BTX-A in various chronic pain conditions, with a particular emphasis on the orofacial region.

This review focuses on the mechanisms by which BTX-A induces analgesia in patients with inflammatory and temporomandibular joint pain. This review also highlights the fact that BTX-A can effectively manage neuropathic pain and trigeminal neuralgia, which are difficult-to-treat chronic pain conditions. Herein, we present a comprehensive assessment of the central analgesic effects of BTX-A and a discussion of its various applications in clinical dental practice.

BTX-A is an approved treatment option for various chronic pain conditions. Although there is evidence of axonal transport of BTX-A from peripheral to central endings in motor neurons, the precise mechanism underlying its pain-modulating effects remains unclear. This review discusses the evidence supporting the effectiveness of BTX-A in controlling chronic pain conditions in the orofacial region. BTX-A is a promising therapeutic agent for treating pain conditions that do not respond to conventional analgesics.

Diabetic peripheral neuropathy (DPN) is a prevalent disease, and the relevant literature has been increasingly investigated over the past years. Consequently, it is imperative to conduct a scientific and comprehensive DPN research field bibliometric analysis. This study aims to summarize and visualize the literature distribution laws, the research hotspots, and the development trends in DPN using bibliometric methods. We searched all relevant documents published from 2011 to 2023 in the Web of Science Core Collection. Bibliometric analysis and network visualization were performed using VOSviewer, R-bibliometrix, and CiteSpace tools, focusing on countries, institutions, authors, journals, highly cited papers, references, and keywords. This study included a total of 2708 documents. The annual number of publications in the field has notably increased. China, the USA, and the UK take on critical significance in DPN research. The University of Manchester in the UK has the highest number of publications (109). Malik has the most publications (86). Tesfaye literature has been most frequently cited by scholars of DPN research. The Journal of Diabetes and its Complications and Frontiers in Endocrinology have the most publications (45 each). Diabetes Care stands out with the highest impact factor (16.200), number of citations (2516), and H-index (27) among the number of publications top 10 journals. The paper "Colloca, L. et al Neuropathic pain. Nature Reviews Disease Primers. 2017, 3 (1):1-19" has the highest number of citations (1224 times). The most critical co-cited reference is "Tesfaye S, 2010, DIABETES CARE, V33, P2285" (cited 408 times). Keywords like "type 2 diabetes," "diagnosis," "association," "retinopathy," "risk factors," "progression," "corneal confocal microscopy," "nephropathy," "balance," "microvascular complications," "inflammation," "disease," and "insulin resistance" represent the recent research hotspots. The development, research hotspots, and future trends of the global DPN domain from 2011 to 2023 were summarized and visualized in this study. This study can present more insights into the general situation of DPN research and provide a useful reference for clinical decision-making and directions of subsequent research.

This study aims to quantitatively analyse nortriptyline's analgesic potency, safety and tolerability.

Systematic review and meta-analysis.

The systematic search was conducted in Scopus, Web of Science and PubMed in February 2023.

Clinical trials evaluating the efficacy of nortriptyline in reducing pain scores (open-label studies and comparisons of nortriptyline with placebo or other analgesics) in different pain types were included.

The data extraction procedure and the screening phases were carried out based on predetermined eligibility criteria. To pool the data, the standardised mean difference (SMD) and standardised mean change (SMC) methods, along with random-effect and fixed-effect meta-analysis, were used. The risk of bias was assessed using the Cochrane Collaboration method, and the Grading of Recommendations Assessment, Development and Evaluation criteria were used to measure the certainty of the results.

14 of the initial 648 studies were eventually imported. Nortriptyline was reported to significantly reduce pain severity in chronic low back pain, painful symptoms in major depressive disorder, neuropathy, chronic pelvic pain and neuropathic corneal pain. However, it was not superior to placebo in fibromyalgia and knee osteoarthritis. In comparison to placebo and various alternative analgesics, the pooled SMD for lowering pain scores was 0.43 (0.23-0.64) and -0.18 (-0.39 to 0.03), respectively. In the pretreatment and post-treatment analyses, the pooled SMC was -1.20 (-1.48 to -0.93). Although constipation and xerostomia were the most commonly reported side effects, all references indicated that the adverse events were well tolerated at the administered dosages.

While nortriptyline is effective in some chronic pains, such as neuropathies, it lacks efficacy in some other chronic pains, such as fibromyalgia and osteoarthritis. Nortriptyline is well tolerated when administered in doses intended for its analgesic effects. Moreover, several studies suggested that the analgesic effects of nortriptyline are comparable to those of amitriptyline and gabapentin.

Pain is a common complaint, and the consumption of analgesics is prevalent. Community pharmacists, as primary contact points for patients, can play a crucial role in guiding patients toward rational pharmacotherapy or alternative pain management strategies. However, there are no specific educational curricula or standard guidelines to support this role, and the perception of this potential role is not well known. We conducted an anonymous online questionnaire among community pharmacists in Norway to assess their knowledge, perspectives, and willingness to engage in pain care. The survey also explored potential facilitators and barriers, and the use of any current guidelines. Seventy-one community pharmacists participated from various regions in Norway. Findings revealed that community pharmacists felt knowledgeable and willing to engage in pain management but anticipated barriers such as time constraints and a lack of standard guidelines. Participants also highlighted the need for better collaboration with other healthcare professionals and continuous professional development to enhance their role. To optimize the role of community pharmacists in pain management, therefore, integrating them into multidisciplinary healthcare teams, minimizing barriers, and providing continuous education and standard guidelines seem essential. This approach can empower community pharmacists and improve pain management outcomes.

Tricyclic antidepressants (TCAs) are a treatment option for diabetic peripheral neuropathy (DPN). Existing evidence demonstrates the prolonged use of TCA therapy increases the risk of cognitive decline and dementia, likely due to the anticholinergic effects of these medications. Anticholinergic activity is thought to contribute significantly to the observed increase in cognitive decline and dementia risks associated with long-term TCA use. There is little information available to describe the usage patterns of TCAs in DPN, particularly within underserved populations who receive care at federally qualified health centers.

The objective of this study was to characterize (1) prescribing patterns of TCAs as a treatment for DPN and (2) evidence of deprescribing attempts in an FQHC population.

A retrospective chart review of electronic medical record data for patients at 2 different FQHCs was performed. A convenience sample of 100 adults ≥ 18 years of age was stratified into 2 age groups, 18-55 years and 55+ years. All patients had a diagnosis of type 1 or type 2 diabetes mellitus and had been prescribed TCAs in the previous 4 years and had a visit with a primary care provider in the past 12 months.

The study population was comprised of 100 individuals. Seventy-four of 100 were persistent users of TCAs at the time of data collection, and the mean duration of utilization was 54.8 months. In total, 104 TCAs were prescribed across 100 individual patients. Of all 104 prescribed TCAs, 66 (63%) were prescribed at a rate that exceeded thresholds associated with a higher risk of dementia. Black older adults prescribed TCAs were more likely to exceed this dose threshold.

Sixty-five percent of patients used TCAs with a strength, frequency, and duration that exceeded risk thresholds for dementia in an older adult population. Interventions preventing use of or deprescribing TCAs in patients with DPN should be conducted for the potential benefits of preventing or delaying cognitive impairment and promoting equitable care.

Neuropathic pain affects millions of patients, but there are currently few viable therapeutic options available. Microtubule affinity-regulating kinases (MARKs) regulate the dynamics of microtubules and participate in synaptic remodelling. It is unclear whether these changes are involved in the central sensitization of neuropathic pain. This study examined the role of MARK1 or MARK2 in regulating neurosynaptic plasticity induced by neuropathic pain.

A rat spinal nerve ligation (SNL) model was established to induce neuropathic pain. The role of MARKs in nociceptive regulation was assessed by genetically knocking down MARK1 or MARK2 in amygdala and systemic administration of PCC0105003, a novel small molecule MARK inhibitor. Cognitive function, anxiety-like behaviours and motor coordination capability were also examined in SNL rats. Synaptic remodelling-associated signalling changes were detected with electrophysiological recording, Golgi-Cox staining, western blotting and qRT-PCR.

MARK1 and MARK2 expression levels in amygdala and spinal dorsal horn were elevated in SNL rats. MARK1 or MARK2 knockdown in amygdala and PCC0105003 treatment partially attenuated pain-like behaviours along with improving cognitive deficit, anxiogenic-like behaviours and motor coordination in SNL rats. Inhibition of MARKs signalling reversed synaptic plasticity at the functional and structural levels by suppressing NR2B/GluR1 and EB3/Drebrin signalling pathways both in amygdala and spinal dorsal horn.

These results suggest that MARKs-mediated synaptic remodelling plays a key role in the pathogenesis of neuropathic pain and that pharmacological inhibitors of MARKs such as PCC0105003 could represent a novel therapeutic strategy for the management of neuropathic pain.

The rehabilitation of central post-stroke pain (CPSP) is a complex clinical challenge, and repetitive transcranial magnetic stimulation (rTMS) has been widely applied in the research of neurofunctional recovery following stroke. However, there is currently no reliable evidence-based medicine supporting the efficacy of rTMS in central post-stroke pain. This review aims to evaluate the effects of rTMS on central post-stroke pain.

Following the PRISMA guidelines, we conducted searches on PubMed, Cochrane Library, Embase, Web of Science, CNKI, and Wan Fang Data Knowledge Service Platform. We searched for randomized controlled trials (RCTs) investigating the use of rTMS in treating central post-stroke pain, and conducted screening based on inclusion and exclusion criteria. Characteristics of the included RCTs were extracted. The heterogeneity of the trials was assessed using the I2 statistic. Meta-analysis was performed using Stata 17 software. Bias risk and methodological quality were evaluated using the Cochrane RoB 2 tool and the Pedro scale.

A total of six randomized controlled trials involving 288 patients met our inclusion criteria. In our analysis, rTMS was more effective in treating patients with CPSP compared to the placebo group (SMD=-1.15, 95% CI: -1.69, -0.61, P < 0.001). Furthermore, results from subgroup analysis indicated no statistically significant difference in the improvement of pain for durations exceeding 6 months when comparing rTMS to conventional treatment (SMD=-0.80, 95% CI: -1.63, 0.03, P = 0.059).

TMS can alleviate pain in CPSP patients and improve their motor function, but its effects on depression, anxiety, and MEP-latency are not significant.

https://www.crd.york.ac.uk/prospero/, CRD42024497530.

Patients with Lumbar Spinal Stenosis (LSS) typically complain of back pain and leg pain. These symptoms reduce the quality of life (QoL) and also cause sleep disturbances. This study compares pregabalin and limaprost's efficacy in LSS for pain, disability, QoL, and sleep, aiming to offer insights for medication selection.

This study was designed as a prospective, randomized, single-center, single-blinded, clinical superiority trial targeting patients with LSS. For 6 weeks, 111 patients per group were administered medication following a standard regimen, after which patient-reported outcomes were measured. The primary outcome was the Visual Analogue Scale (VAS) for back and leg pain, and the secondary outcomes included the Oswestry Disability Index (ODI), European Quality of Life 5 Dimensions (EQ-5D), and sleep quality.

After 6 weeks of medication, there were significant improvements over time in the primary outcome, VAS for back pain and leg pain, in both groups, but no significant difference between the 2 groups. Similarly, for the secondary outcomes, ODI and EQ-5D, both groups showed significant improvements, yet there was no significant difference between them. In the subgroup analysis targeting poor sleepers (Pittsburgh sleep quality index, PSQI >5), both groups also exhibited significant improvements in sleep quality, but again, there was no significant difference between the groups.

Efficacy of pregabalin, limaprost in back and leg pain, ODI, EQ-5D, and sleep quality, but there was no significant difference between the 2 groups. Thus, it is advisable to prescribe based on individual drug responses and potential complications.

Neuropathic pain is a challenging condition. Despite the immense progress made in the pathophysiology and treatment of such conditions, so much work still has to be done. New frontiers previously unexplored are now objects of study with exciting results, mainly regarding neuromodulation and optogenetics. This review explores the already known pathophysiology and the clinical and surgical treatment in the light of evidence-based medicine. Additionally, new concepts and insights are discussed, presenting the hope for the development of new paradigms in the treatment of neuropathic pain.

Building on previous investigations, structural modifications to the neuronal calcium ion channel blocker MONIRO-1 and related compounds were conducted that included replacement of the amide linker with an aniline and isosteric sulfonamide moiety, and the previously used strategy of substitution of the guanidinium group with less hydrophilic amine functionalities. A comprehensive SAR study revealed a number of phenoxyaniline and sulfonamide compounds that were more potent or had similar potency for the CaV2.2 and CaV3.2 channel compared to MONIRO-1 when evaluated in a FLIPR-based intracellular calcium response assay. Cytotoxicity investigations indicated that the sulfonamide analogues were well tolerated by Cos-7 cells at dosages required to inhibit both calcium ion channels. The sulfonamide derivatives were the most promising CaV2.2 inhibitors developed by us to date due, possessing high stability in plasma, low toxicity (estimated therapeutic index > 10), favourable CNS MPO scores (4.0-4.4) and high potency and selectivity, thereby, making this class of compounds suitable candidates for future in vivo studies.

Kaempferol, a flavonoid compound found in various fruits, vegetables, and medicinal plants, has garnered increasing attention due to its potential neuroprotective effects in neurological diseases. This research examines the existing literature concerning the involvement of kaempferol in neurological diseases, including stroke, Parkinson's disease, Alzheimer's disease, neuroblastoma/glioblastoma, spinal cord injury, neuropathic pain, and epilepsy. Numerous in vitro and in vivo investigations have illustrated that kaempferol possesses antioxidant, anti-inflammatory, and antiapoptotic properties, contributing to its neuroprotective effects. Kaempferol has been shown to modulate key signaling pathways involved in neurodegeneration and neuroinflammation, such as the PI3K/Akt, MAPK/ERK, and NF-κB pathways. Moreover, kaempferol exhibits potential therapeutic benefits by enhancing neuronal survival, attenuating oxidative stress, enhancing mitochondrial calcium channel activity, reducing neuroinflammation, promoting neurogenesis, and improving cognitive function. The evidence suggests that kaempferol holds promise as a natural compound for the prevention and treatment of neurological diseases. Further research is warranted to elucidate the underlying mechanisms of action, optimize dosage regimens, and evaluate the safety and efficacy of this intervention in human clinical trials, thereby contributing to the advancement of scientific knowledge in this field.

Patients suffering lumbosacral radicular pain report radiating pain in one or more lumbar or sacral dermatomes. In the general population, low back pain with leg pain extending below the knee has an annual prevalence that varies from 9.9% to 25%.

The literature on the diagnosis and treatment of lumbosacral radicular pain was reviewed and summarized.

Although a patient's history, the pain distribution pattern, and clinical examination may yield a presumptive diagnosis of lumbosacral radicular pain, additional clinical tests may be required. Medical imaging studies can demonstrate or exclude specific underlying pathologies and identify nerve root irritation, while selective diagnostic nerve root blocks can be used to confirm the affected level(s). In subacute lumbosacral radicular pain, transforaminal corticosteroid administration provides short-term pain relief and improves mobility. In chronic lumbosacral radicular pain, pulsed radiofrequency (PRF) treatment adjacent to the spinal ganglion (DRG) can provide pain relief for a longer period in well-selected patients. In cases of refractory pain, epidural adhesiolysis and spinal cord stimulation can be considered in experienced centers.

The diagnosis of lumbosacral radicular pain is based on a combination of history, clinical examination, and additional investigations. Epidural steroids can be considered for subacute lumbosacral radicular pain. In chronic lumbosacral radicular pain, PRF adjacent to the DRG is recommended. SCS and epidural adhesiolysis can be considered for cases of refractory pain in specialized centers.

SIP30, characterized by a coiled-coil functional domain, plays a key role in regulating synaptic vesicle exocytosis and is implicated in neuropathic pain resulting from peripheral nerve injury. Because neuropathic pain is studied in primates (including human), domesticated animals, and rodents, we conducted a phylogenetic analysis of SIP30 in selected species of these three groups of mammals. SIP30 exhibits a high degree of sequence divergence in comparison to its protein binding partners SNAP25 and ZW10, which show broad sequence conservation. Notably, we observed an increased rate of change in the highly conserved coiled-coil domain in the SIP30 protein, specifically within primates. This observation suggests an accelerated adaptation of this functional domain in primate species.

Background: The efficacy of topical treatments in alleviating neuropathic pain is well-established. However, there is a paucity of research on topical interventions designed specifically for intra-oral application, where the tissue composition differs from that of exposed skin. Methods: This comprehensive review endeavors to assess the extant evidence regarding the efficacy of topical treatments in addressing neuropathic pain within the oral cavity. Utilizing combinations of search terms, we conducted a thorough search across standard electronic bibliographic databases-MEDLINE (via PubMed), Embase, Google Scholar, and Up to Date. The variables under scrutiny encompassed topical treatment, local intervention, chronic oral and orofacial pain, and neuropathic pain. All pertinent studies published in the English language between 1992 and 2022 were included in our analysis. Results: Fourteen relevant manuscripts were identified, primarily consisting of expert opinions and case reports. The comprehensive review suggests that topical treatments, especially when applied under a stent, could be effective in mitigating neuropathic pain in the oral area. However, it is crucial to conduct further studies to confirm these preliminary results. The limitations of the reviewed studies, mainly the reliance on expert opinions, small sample sizes, inconsistent study designs, and a lack of long-term follow-up data, highlight the need for more rigorous research. Conclusions: Although initial findings indicate topical treatments may be effective for oral neuropathic pain, the limitations of current studies call for more thorough research. Further comprehensive studies are essential to validate the efficacy of these treatments, standardize procedures, and determine long-term results. This will provide clearer guidance for treating chronic neuropathic pain in the oral cavity.

The pharmacological management of chronic low back pain (LBP) is complex. The World Health Organisation recommends a laddered approach to pain medication usage. The PainDETECT questionnaire distinguishes between neuropathic pain (NeP), nociceptive pain (NoP), and ambiguous pain. By elucidating the difference in medication efficacy between these groups, clinicians can provide a tailored treatment plan to manage patient's pain. This study aimed to investigate the relationship between pharmacological treatments, pain categorizations, and medication efficacy as reported by patients.

A secondary retrospective analysis of a prospectively collected database was conducted involving 318 consecutively recruited patients, aged 18 years and above, who completed PainDETECT, medication history and patient reported medication efficacy questionnaires. Medication history was categorized into four lines of treatment: first line (paracetamol ± non-prescribed anti-inflammatories), second line (prescribed anti-inflammatories), third line (anticonvulsants/neuromodulators) and fourth line (opioids). Medication efficacy was measured using a three-point Likert scale: effective (+2), somewhat effective (+1), no effect (0).

The study included 120, 50, 54 and 94 patients on first line, second line, third line and fourth line treatment, respectively. The NeP group had higher mean numerical rating scale (NRS) compared to NoP group in all four lines of treatment (8.10 ± 1.59 vs. 5.47± 2.27, p < 0.001, 8.64± 1.43 vs. 5.52± 1.86, p < 0.001, 8.00± 1.07 vs. 6.37± 2.39, p < 0.01, and 8.05± 1.73 vs. 7.2± 1.29, p < 0.05). When confounding for severity of LBP as measured by NRS, the distribution of medication efficacy significantly differed amongst the NeP, ambiguous and NoP groups in patients undergoing fourth line pharmacological treatment (r2 = 8.623, p < 0.05). The NoP group exhibited significantly higher medication efficacy compared to the NeP group (U = 14.038, p < 0.05). There was no significant difference in medication efficacy across the pain classifications for first, second- and third-line treatment.

Opioids was the only line of treatment more effective in targeting NoP, as determined by the PainDETECT questionnaire, compared to NeP. This pioneering study illustrates the complex nature of pharmacological management for chronic LBP. It underscores the importance of tailoring pharmacological treatment plans to fit individual pain profiles and expectations instead of adopting a blanket approach to pain management.

Currently available therapies for neuropathic pain show limited efficacy. This study aimed to investigate the anti-nociceptive effect of the spirocyclopiperazinium salt compound LXM-15 in spinal nerve ligation (SNL) rats and to explore the potential mechanisms.

Mechanical allodynia and thermal hyperalgesia tests were used to evaluate the effects of LXM-15 in SNL rats. The expression of CaMKIIα, CREB, JAK2, STAT3, c-fos and TNF-α was detected by western blotting, ELISA or qRT-PCR analysis. Receptor blocking test was performed to explore possible target.

Administration of LXM-15 (1, 0.5, 0.25 mg/kg, i.g.) dose-dependently attenuated mechanical allodynia and thermal hyperalgesia in rats subjected to SNL (p < 0.01, p < 0.05), and the effects were completely blocked by peripheral α7 nicotinic or M4 muscarinic receptor antagonist (p > 0.05). LXM-15 significantly decreased the overexpression of phosphorylated CaMKIIα, CREB, JAK2 and STAT3 proteins and the mRNA levels of TNF-α and c-fos (p < 0.01, p < 05). All of the effects could be blocked by α7 or M4 receptor antagonist. Furthermore, LXM-15 reduced the protein expression of TNF-α and c-fos (p < 0.01, p < 0.05). No significant acute toxicity or abnormal hepatorenal function was observed.

This is the first study to report that LXM-15 exerts significant anti-nociceptive effect on SNL rats. This effect may occur by activating peripheral α7 nicotinic and M4 muscarinic receptors, further inhibiting the CaMKIIα/CREB and JAK2/STAT3 signalling pathways, and finally inhibiting the expression of TNF-α and c-fos.

Existing treatments for neuropathic pain show limited efficacy with severe adverse reactions. This paper is the first to report that LXM-15, a new spirocyclopiperazinium salt compound, exerts a significant anti-nociception in SNL rats without obvious toxicity. The underlying mechanisms include activating peripheral α7 nicotinic and M4 muscarinic receptors, then inhibiting the signalling pathways of CaMKIIα/CREB and JAK2/STAT3 and the expressions of TNF-α and c-fos. This study sheds new light on the development of novel analgesic drugs with fewer side effects.

Radiation therapy plays a fundamental role in oncological emergencies such as superior vena cava syndrome (SVCS) and metastatic epidural spinal cord compression (MESCC). These are two examples of critical complications of metastatic cancer in terms of pain and functional impact (respiratory and/or neurological). The aim of this review is to explore the current indications, treatment options and outcomes for emergency radiotherapy regarding to these complications.Regarding SVCS, studies are mostly retrospective and unanimously demonstrated a beneficial effect of radiotherapy on symptom relief. Spinal cord compression remains an indication for urgent radiotherapy, and should be combined with surgery when possible. The innovative stereotactic body radiotherapy (SBRT) showed promising results, however this technique requires small volumes and more time preparation and therefore is often unsuitable for SVCS and MESCC emergencies.This review concluded that radiotherapy has a central role to play within a multimodal approach for SVCS and MESCC treatment. Further prospective studies are needed to confirm the effectiveness of radiation and establish the criteria for selecting patients to benefit from this treatment option.

(1) Background: Transcranial direct current stimulation (tDCS) appears to alleviate chronic pain via a brain-down mechanism. Although several review studies have examined the effects of tDCS on patients with chronic pain, no systematic review or meta-analysis has comprehensively analyzed the effects of tDCS on chronic orthopedic joint pain in one study. We aim to evaluate the effectiveness of tDCS for pain reduction in chronic orthopedic patients; (2) Methods: A comprehensive search of five electronic databases (Medline, Embase, Web of Science, CINAHL, and Cochrane) was performed. Only randomized controlled trials that compared tDCS with a control intervention were included. Eighteen studies met our inclusion criteria. We identified four categories of chronic orthopedic pain: knee (k = 8), lower back (k = 7), shoulder (k = 2), and orofacial pain (k = 1). Random effect models were utilized, and a sensitivity analysis was conducted in the presence of significant heterogeneity. Studies within each pain condition were further classified according to the number of treatment sessions: 1-5 sessions, 6-10 sessions, and >10 sessions.; (3) Results: Significant reductions in chronic orthopedic joint pain were observed following tDCS compared to controls for knee (g = 0.59, p = 0.005), lower back (g = 1.14, p = 0.005), and shoulder (g = 1.17, p = 0.020). Subgroup analyses showed pain reductions after 6-10 tDCS sessions for knee pain and after 1-5 and >10 sessions for lower back pain; (4) Conclusions: tDCS could be considered a potential stand-alone or supplemental therapy for chronic knee and lower back pain. The effectiveness of tDCS treatment varies depending on the number of treatment sessions. Our findings suggest the importance of implementing individualized treatment plans when considering tDCS for chronic pain conditions.

Multiple sclerosis is a chronic and progressive neurological disease, with an important socio-economic burden. Over time, an increased incidence of headaches like migraines and tension headaches has been observed among these patients. Headaches have not been considered as multiple sclerosis-related symptoms, even representing a red flag for multiple sclerosis diagnosis. It is uncertain whether the headache-multiple sclerosis association could be explained by the presence of common triggers or a common physiopathological mechanism (involvement of tertiary B-cell follicles). An important differential diagnosis is between multiple sclerosis attacks and migraines with aura, which can also be associated with neurological deficits. Another important aspect is the occurrence or exacerbation of the cephalalgic syndrome after the initiation of therapy for multiple sclerosis (DMTs), or the improvement of headache after the initiation of certain DMT drugs. In addition to headaches, individuals diagnosed with multiple sclerosis often report experiencing diverse pain syndromes, contributing to an additional decline in their overall quality of life. These syndromes are frequently neglected, the focus being on slowing down the progression of neurological deficits. This review aims to evaluate the characteristics of multiple-sclerosis-related headaches (frequency, possible correlation with attacks, and disease-modifying therapies) and the key distinctions in imaging characteristics between demyelinating lesions in multiple sclerosis and those observed in cases of primary headaches.