Search Results (77)

Neuropathic pain is a chronic and debilitating disorder of the somatosensory system that affects a significant proportion of the population and is characterized by abnormal responses such as hyperalgesia and allodynia. Voltage-gated ion channels, including sodium (Na_V), calcium (Ca_V), and potassium (K_V) channels, play a pivotal role in modulating neuronal excitability and pain signal transmission following nerve injury. This review intends to provide a comprehensive analysis of the molecular and cellular mechanisms by which dysregulation in the expression, localization, and function of specific Na_V channel subtypes (mainly Na_V1.7 and Na_V1.8) and their auxiliary subunits contributes to aberrant neuronal activation, the generation of ectopic discharges, and sensitization in neuropathic pain. Likewise, special emphasis is placed on the crucial role of Ca_V channels, particularly Ca_V2.2 and the auxiliary subunit Ca_Vα₂δ, whose overexpression increases calcium influx, neurotransmitter release, and neuronal hyperexcitability, thus maintaining persistent pain states. Furthermore, K_V channels (particularly K_V7 channels) function as brakes on neuronal excitability, and their dysregulation facilitates the development and maintenance of neuropathic pain. Therefore, targeting specific K_V channel subtypes to restore their function is also a promising therapeutic strategy for alleviating neuropathic pain symptoms. On the other hand, recent advances in the development of small molecules as selective modulators or inhibitors targeting voltage-gated ion channels are also discussed. These agents have improved efficacy and safety profiles in preclinical and clinical studies by attenuating pathophysiological channel activity and restoring neuronal function. This review seeks to contribute to guiding future research and drug development toward more effective mechanism-based treatments by discussing the molecular mechanisms underlying neuropathic pain and highlighting translational therapeutic opportunities. Full article

Background: A large number of patients suffer from neuropathic pain, and systemic therapy often remains ineffective while inducing severe side effects. Topical therapy with the TRPV1-agonist capsaicin is an established alternative, and the identification of co-therapeutics that modulate TRPV1 may be a promising approach to reduce the dose of capsaicin while maintaining efficacy. Here, we aimed to determine if the antidepressant amitriptyline displays properties rendering it a potential co-therapeutic agent. Methods: We performed patch clamp and calcium imaging experiments on HEK293T cells expressing human (h) TRPV1 as well as on dorsal root ganglion (DRG) neurons from adult mice. Results: Amitriptyline induced an increase in intracellular calcium in both HEK293T and mouse DRG neurons expressing TRPV1. Patch clamp experiments revealed a concentration-dependent activation of hTRPV1 by amitriptyline that was also evident in cell-free inside-out patches. When hTRPV1 was fully activated by capsaicin, amitriptyline induced concentration-dependent and partly reversible current inhibition. In contrast, amitriptyline potentiated small responses to capsaicin, heat and protons. We also found that amitriptyline desensitized hTRPV1 to capsaicin. This effect was reduced by the intracellular application of the strong calcium chelator BAPTA. Furthermore, the non-desensitizing mutant hTRPV1-Y672K displayed a reduced amitriptyline-induced desensitization. Conclusions: Our data showed that amitriptyline can activate, sensitize, desensitize and even inhibit TRPV1. Together with its property as a strong local anesthetic, our data suggest that amitriptyline may be a promising adjunct to topical capsaicin. Full article

Background: Peripheral nerves have a certain regenerative ability, but their repair and regeneration after injury is a complex process, usually involving a large number of genes and proteins. In a previous study, we analyzed the gene expression profile in rats after sciatic nerve injury and found significant changes in transforming growth factor-beta 1 (TGF-β1) expression, suggesting that TGF-β1 may be involved in the process of nerve regeneration after injury. Methods: In this study, we first detected the time-course expression and localization of TGF-β1 in dorsal root ganglion (DRG) tissues in a rat sciatic nerve transection model via RT-qPCR. Secondly, we investigated the bioactive roles of TGF-β1 in primary cultured DRG neuron cells through a CCK8 assay, TUNEL assay, and immunofluorescence staining. Thirdly, we explored the neuroprotective roles of TGF-β1 in an in vivo model of sciatic nerve regeneration through morphological observation, behavioral, and electrophysiological tests, and a molecular biological measure. Results: We found that TGF-β1 expression was increased after injury and mainly located in the cytoplasm and nuclei of neuron cells in the DRG. TGF-β1 may regulate the viability, apoptosis, and neurite outgrowth of primary DRG neuron cells. In our in vivo model of sciatic nerve regeneration, TGF-β1 improved nerve regeneration and neuronal function recovery after sciatic nerve injury, alleviated the inflammatory response, and relieved neuropathic pain via the TGF-β1/smad2 pathway. Conclusions: This study provides an experimental and theoretical basis for using TGF-β1 as a neuroprotective agent after peripheral nerve injury in clinical practice in the future. Full article

Background: Botulinum toxin (BoNT), produced by Clostridium botulinum, has transitioned from being a lethal neurotoxin to a versatile therapeutic agent. Its ability to inhibit neurotransmitter release by targeting Soluble N-ethylmaleimide-sensitive factor Attachment Protein Receptor (SNARE) proteins underpins its applications in treating conditions such as spasticity, dystonia, chronic pain, and overactive bladder. The clinical and pharmacological properties of BoNT have been extensively studied, with significant advancements in its therapeutic use, safety profile, and understanding of associated adverse effects. Objective: This comprehensive review aims to consolidate historical developments, molecular mechanisms, clinical applications, and challenges associated with BoNT, with a focus on expanding its therapeutic scope while ensuring safety and efficacy. Method: A narrative approach was used to analyze and synthesize insights from 155 references spanning experimental studies, clinical trials, and reviews. Key topics included BoNT’s historical milestones, mechanisms of action, therapeutic applications, and adverse events. Findings: BoNT demonstrates remarkable efficacy in a wide range of medical and cosmetic applications. In movement disorders such as dystonia and spasticity, it reduces muscle overactivity and improves functional outcomes. In chronic pain management, including migraines and neuropathic pain, BoNT significantly alleviates symptoms by modulating neurotransmitter activity. Cosmetic use for conditions like glabellar lines and hyperhidrosis highlights its precision and safety when administered appropriately. For conditions like strabismus and blepharospasm, BoNT effectively restores muscle control, reducing involuntary contractions. In urological applications, BoNT has proven to be an effective therapy for overactive bladder, offering significant symptom relief in refractory cases. However, concerns about long-distance effects, where the toxin may spread beyond the injection site to affect distant muscles or systems, have been reported in certain high-dose or sensitive populations. These findings emphasize the importance of dose optimization and patient-specific approaches. Adverse effects such as localized pain, hematoma, dysphagia, and systemic effects, particularly in high-risk groups, underscore the need for careful monitoring. The development of immunogenicity, leading to neutralizing antibodies, remains a challenge that impacts long-term therapeutic efficacy. Emerging research on novel serotypes, including BoNT/X, and innovations in delivery mechanisms, offer promising avenues to address current limitations. Advances in optimizing dosing regimens and refining injection techniques have also contributed to minimizing complications and improving outcomes across diverse patient populations. Conclusions: BoNT remains a cornerstone in neurology and cosmetic medicine, with its therapeutic potential still expanding. The balance between efficacy and safety, driven by innovations in formulation and application, underscores the importance of continued research. Future directions should focus on minimizing adverse effects, reducing immunogenicity, and exploring novel indications to further enhance its clinical utility. Full article

Background/Objectives: Neuropathic pain associated with neuromas is a complex clinical problem to treat. Targeted Muscle Reinnervation (TMR) has been demonstrated to treat pain both as a prophylactic procedure in amputated patients and in patients affected by painful neuromas. It is not clear what its role could be in chronic situations: the literature reports amazing results but also unsuccessful pain relief. Methods: A retrospective analysis was conducted on patients treated with TMR for long-lasting painful neuromas in the upper and lower limbs. Following a clinical and instrumental diagnosis, all patients responded positively to a local anesthetic block. During follow-up visits, the NRS and DN4 questionnaires were used to assess improvement in pain. Results: Three patients were included in this study. TMR was performed 45 months after trauma. Two TMRs involved nerves of the upper extremity, in one case, the tibial nerve. The recipient muscles were the second lumbricalis, pronator quadratus, and flexor digitorum longus of the foot. After surgery, pain decreased for 3 months, but patients experienced a relapse that returned to levels close to the pre-operative period. The types of pain, as reported in DN4 questionnaire, changed slightly compared to those in the pre-surgical period. Follow-up ranged between 12 and 19 months. Conclusions: This small series collected the results of TMR in patients affected by long-lasting symptomatic neuromas in the upper and lower extremities. Despite what is published in other series, this procedure reduced pain for up to 6 months. At final follow-up, the type of pain changed slightly as reported in the DN4 questionnaire, and pain scores reduced by just one point as shown by the NRS. Our experience suggests that TMR might have a slight effect on long-lasting painful neuromas and in these cases, only short-term pain relief could be expected. This suggests using TMR as close as possible to the trauma in order to increase the chances of relieving pain. Full article

Background: Low back pain (LBP) is a leading cause of disability worldwide, often driven by distinct pain mechanisms: nociceptive, neuropathic, and central sensitization. Accurate classification of these mechanisms is critical for guiding effective, targeted treatments. Methods: A scoping review was conducted following the Joanna Briggs Institute methodology and reported according to PRISMA-ScR guidelines. A comprehensive literature search was performed in MEDLINE, Cochrane CENTRAL, Scopus, PEDro, and Web of Science. Eligible studies included adults with LBP and focused on clinical criteria for classifying pain mechanisms. Data on study methods, population characteristics, and outcomes were extracted and synthesized. Results: Nine studies met the inclusion criteria. Nociceptive pain was characterized by localized symptoms proportional to mechanical triggers, with no neurological signs. Neuropathic pain was associated with burning sensations, dysaesthesia, and a positive neurodynamic straight leg raise (SLR) test. Central sensitization featured widespread pain, hyperalgesia, and disproportionate symptoms. Tools such as painDETECT, DN4, and the Central Sensitisation Inventory (CSI) were validated for neuropathic and central sensitization pain. Central sensitization and neuropathic pain were linked to greater disability and psychological distress compared to nociceptive pain. Conclusions: This review aims to provide a historical perspective on pain mechanism classifications and to explore how previous frameworks have influenced current diagnostic concepts in physiotherapy practice. By synthesizing key clinical criteria used to differentiate between nociceptive, neuropathic, and central sensitization pain, this review proposes a practical framework to improve the accuracy of pain classification in clinical settings. Full article

Background: Posterior fossa syndrome (PFS), also known as cerebellar mutism syndrome, occurs in about 25% of pediatric patients undergoing resection of a posterior cranial fossa medulloblastoma. It is characterized primarily by mutism or reduced/impaired speech and may include variable symptoms such as motor dysfunction (apraxia, ataxia, hypotonia), supranuclear cranial nerve palsies, neurocognitive changes, and emotional lability. Long-term multidisciplinary rehabilitation is typically required, with recovery taking approximately six months, though many children experience long-term residual deficits. Neuropathic pain associated with PFS is rarely reported in pediatric patients, and evidence for its management is limited. Methods: This case report describes a 10-year-old boy who developed PFS following incomplete resection of a medulloblastoma. Clinical presentation included mutism, irritability, emotional lability, sleep disturbances, and neuropathic pain localized at the C5 level. The patient was treated with a combination of gabapentin, diazepam, and baclofen. Results: The combined pharmacological approach resulted in successful management of the patient’s neuropathic pain and other symptoms associated with PFS, improving his overall condition. Conclusions: This case highlights the potential effectiveness of a multimodal pharmacological regimen for treating neuropathic pain and associated symptoms in pediatric patients with PFS. Further research is needed to explore optimal treatment strategies for this rare but challenging complication. Full article

Background: Diabetes ranks high among worldwide global health problems, and diabetic foot ulcer syndrome (DFU) is considered as one of its most serious complications. The purpose of this study was to evaluate the impact of local ozone therapy procedures on the wound healing process in patients with two DFU types: neuropathic and ischemic. Material and Methods: In the retrospective study reported here, the treatment outcomes of 90 patients were analyzed: 44 males (48.8%) and 46 females (51.2%), in the age range between 38 and 87 years of age, with neuropathic (group 1) and ischemic (group 2) diabetic foot ulcers treated by means of local ozone therapy. The assessment of therapeutic effects in both groups of patients included an analysis of the rate of ulcer healing using planimetry and an analysis of the intensity of pain associated with ulcers performed using the VAS scale. Results: After the application of ozone therapy procedures, a statistically significant decrease in the surface area of the ulcers was obtained in both groups of patients, respectively: in group 1 from 7 (6–7.5) cm² to 3 (2–3.5) cm² and in group 2 from 7.5 (6.5–8) cm² to 5 (4.5–5.5) cm² (p < 0.001), with a complete healing of ulcers not observed in any patients from groups 1 and 2. After treatment, the surface area of the assessed ulcers was smaller in the neuropathic group. The intensity of pain experienced after treatment also decreased with statistical significance in both groups (p < 0.001). Conclusions: Short-term local ozone therapy was effective in promoting wound healing and alleviating pain in patients with DFUs of both neuropathic and ischemic etiology. The effectiveness of therapy in the neuropathic type of DFUs was significantly higher than in the ischemic type, in which patients had a higher incidence of risk factors and more advanced lesions, characterized by a larger initial ulcer area and greater intensity of pain. Full article

This study provides an updated overview of the clinical characteristics of post-traumatic trigeminal neuropathic pain (PTNP) resulting from dental procedures or facial trauma, addressing its etiology, prevalence, evaluation, management, and prognosis. PTNP arises from injury to the trigeminal nerve, which governs sensory and motor functions in the maxillofacial region. The prevalence and characteristics of PTNP vary considerably across studies, with a reported prevalence ranging from 1.55% to 13%. The predominant causative factors are dental procedures, particularly third molar removal and implant placement. While gender distribution varies, a trend towards higher incidence in females is observed, particularly within the 40–60-year age group. Anatomically, the mandibular nerve is frequently involved. PTNP presents with a spectrum of symptoms ranging from tingling sensations to severe pain. Diagnostic challenges arise due to the lack of standardized criteria and potential overlap with focal neuralgia, necessitating comprehensive evaluation. Misdiagnosis can lead to prolonged patient suffering and unnecessary interventions. Successful management hinges on prompt diagnosis and interdisciplinary collaboration, with early intervention crucial in mitigating progression to chronic pain. Although nerve recovery post-trauma is challenging, preventive measures through accurate evaluation and treatment are paramount. Management strategies for PTNP include non-invasive and surgical interventions, with non-invasive approaches encompassing systemic and local pharmacological management. This narrative review aims to enhance uniformity in PTNP evaluation and treatment approaches, ultimately improving patient care and outcomes. Full article

Complex regional pain syndrome (CRPS) is a multifaceted condition characterized by chronic neuropathic pain, allodynia, and hyperalgesia. The incidence of CRPS postoperatively is alarmingly high, particularly following carpal tunnel surgeries, Dupuytren’s fasciectomy, and repairs of wrist and hand fractures, with recurrence rates soaring in individuals with a history of CRPS. Despite extensive research, the management of CRPS remains complicated, highlighting the urgent need for effective prevention strategies. This scoping review aimed to consolidate current evidence surrounding the efficacy of perioperative anesthetic techniques in preventing new-onset or recurrent CRPS, focusing on the application of various anesthetic interventions. Through a comprehensive literature search, eight articles were identified, discussing a spectrum of techniques, including wide awake local anesthesia no tourniquet (WALANT) and various regional blockade methods. This review revealed that the WALANT technique, with its simplicity and lower costs, exhibited promising results in preventing CRPS. Conversely, techniques involving intravenous regional and axillary plexus blocks showed variable efficacy, necessitating further investigation. The scarcity of high-quality evidence underscores the critical need for meticulously designed, large-scale randomized controlled trials to validate these findings and explore the potential of stellate ganglion block in the prevention of recurrent CRPS. Full article

Background/Objectives: Different analgesic techniques have been used in the clinical management of chronic post-hernioplasty pain (CPHP), with variable results. This study aimed to investigate clinical factors associated with long-term outcome of the transversus abdominal plane (TAP) block for CPHP. Methods: We retrospectively analyzed 26 patients with CPHP who were treated with single or multiple TAP blocks with local anesthetic and steroid. Patients were evaluated for pain and neuropathic pain intensity by a Numerical Rating Scale (NRS) and the painDETECT questionnaire (PDQ), for anxiety and depression by the Hospital Anxiety and Depression Scale, and for quality of life by the 12-item Short Form Health Survey (SF12). Results: At 6 months post-treatment, 20 patients (77%) presented substantial (>50%) or moderate (30–50%) CPHP relief and were considered responders. In responders, the 24-h average and maximum NRS pain significantly declined (p < 0.01) from 7.3 ± 1.3 to 2.6 ± 2.1 and from 8.8 ± 1.5 to 5.1 ± 2.0, and the neuropathic PDQ score from 9.1 ± 3.2 to 6.1 ± 1.3; the physical SF12 score improved from 36.5 ± 5.8 to 44.3 ± 7.5 (p < 0.01). Six patients failed to achieve a significant CPHP improvement and were considered non-responders. Non-responders presented a significantly (p < 0.05) longer CPHP, higher body mass index and neuropathic symptoms, and more frequent anxiety, depression, diabetes, and fibromyalgia. Conclusions: The TAP block with local anesthetic and steroid should be considered as a therapeutic option for CPHP. However, medical and psychiatric comorbidities negatively impact the TAP block effectiveness for CPHP. Full article

The nucleus accumbens shell (NAcSh) is a major structure associated with distinct aspects of reward and mnemonic information encoding, relying on spatial data to define optimal behavioral strategies. Chronic pain-derived striatal plasticity is considered one underpinning cause of working memory (WM) impairments. However, it is unclear how the NAcSh is involved in these spatial deficits. To address this, we evaluated the impact of unilateral local NAcSh electrical lesions during the execution of a food-reinforced eight-shaped spatial alternation WM task. Behavioral performance was assessed in rats after the onset of the neuropathic pain model—spared nerve injury (SNI). Our findings indicate that the induction of SNI and/or NAcSh lesions did not significantly impact the animals’ performance accuracy or motor activity during the execution of the behavioral task, but altered their response latency patterns. In addition, these manipulations did not induce significant antinociceptive effects. Collectively, these results suggest that the NAcSh may participate in specific aspects of spatial information integration and processing under neuropathic pain conditions. Full article

In this study, we focused on innovative approaches to improve drug administration in oral pathology, especially by transmucosal and transdermal pathways. These improvements refer to the type of microneedles used (proposing needles in the saw), to the use of certain enhancers such as essential oils (which, besides the amplifier action, also have intrinsic actions on oral health), to associations of active substances with synergistic action, as well as the use of copolymeric membranes, cemented directly on the tooth. We also propose a review of the principles of release at the level of the oral mucosa and of the main release systems used in oral pathology. Controlled failure systems applicable in oral pathology include the following: fast dissolving films, mucoadhesive tablets, hydrogels, intraoral mucoadhesive films, composite wafers, and smart drugs. The novelty elements brought by this paper refer to the possibilities of optimizing the localized drug delivery system in osteoarthritis of the temporomandibular joint, neuropathic pain, oral cancer, periodontitis, and pericoronitis, as well as in maintaining oral health. We would like to mention the possibility of incorporating natural products into the controlled failure systems used in oral pathology, paying special attention to essential oils. Full article

Novel antiepileptic drugs have been developed at an unparalleled rate during the past 15 years. Gabapentin (GBP), which was approved for the treatment of refractory localization-related epilepsies in the U.K. and Europe in 1993, was one of the first drugs to come out of this era. Since then, GBP has become well-known across the world, not only for its antiepileptic qualities but also for its effectiveness in the treatment of chronic pain disorders, particularly neuropathic pain. In this review, the crystal structures of GBP and GBP-related compounds have been analyzed and compared. Particular attention has been paid to the polymorphism of GBP and its hydrates, their thermodynamic stability, and conformational differences. In addition, the puckering parameters for the cyclohexane ring of a total of 118 molecules of GBP found in the analyzed crystal structures have been calculated and analyzed. The results of recent high-pressure crystallization studies and quantum chemical calculations indicate that the entire landscape of GBP has not been revealed yet. Full article

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. Full article