Reduced circ_lrrc49 in trigeminal ganglion contributes to neuropathic pain in mice by downregulating Ist1 and impairing autophagy.

Orofacial neuropathic pain is a common symptom induced by orofacial nerve injury caused by a range of trauma or dental and maxillofacial procedures but lacks effective treatment. Circular RNAs (circRNAs) participate in the regulatory processes of neuropathic pain. Nevertheless, the biological roles of circRNAs in orofacial neuropathic pain remain unexplored. In this study, circRNA sequencing and Real-time quantitative polymerase chain reaction (RT-qPCR) were carried out. Notably, a novel circRNA named circ_lrrc49 was identified to be downregulated following chronic constriction injury of the infraorbital nerve (CCI-ION) in mice on day 14. Subsequent RNA Antisense Purification (RAP)-mass spectrometry and RNA immunoprecipitation found a direct interaction between circ_lrrc49 and increased sodium tolerance 1 homolog (Ist1). Western blot (WB) identified decreased expression of Ist1 on day 14 post-CCI-ION. Considering the known relationship between Ist1 and autophagy, LC3-II and p62 were detected to be upregulated, and an accumulation of autophagosomes were observed at the same time point. Besides, the knockdown of circ_lrrc49 by small interfering RNA (siRNA) reduced Ist1 expression, increased LC3-II, p62 levels and autophagosomes amount, and evoked orofacial mechanical hypersensitivity, which could be counteracted by the Ist1 overexpression. Similarly, the knockdown of Ist1 by siRNA also increased LC3-II and p62 levels and evoked orofacial mechanical hypersensitivity without influence on circ_lrrc49. Moreover, autophagy activation by rapamycin alleviated orofacial mechanical hypersensitivity evoked by CCI-ION or circ_lrrc49 knockdown. In conclusion, our data revealed the existence of a circ_lrrc49/Ist1/autophagy signaling axis contributing to the progression of orofacial neuropathic pain. These discoveries reveal the intricate molecular processes that drive orofacial neuropathic pain and identify circ_lrrc49 as a promising target for potential therapeutic interventions.

Hyperexcitability of muscle spindle afferents in jaw-closing muscles in experimental myalgia: Evidence for large primary afferents involvement in chronic pain.

The goals of this review are to improve understanding of the aetiology of chronic muscle pain and identify new targets for treatments. Muscle pain is usually associated with trigger points in syndromes such as fibromyalgia and myofascial syndrome, and with small spots associated with spontaneous electrical activity that seems to emanate from fibers inside muscle spindles in EMG studies. These observations, added to the reports that large-diameter primary afferents, such as those innervating muscle spindles, become hyperexcitable and develop spontaneous ectopic firing in conditions leading to neuropathic pain, suggest that changes in excitability of these afferents might make an important contribution to the development of pathological pain. Here, we review evidence that the muscle spindle afferents (MSAs) of the jaw-closing muscles become hyperexcitable in a model of chronic orofacial myalgia. In these afferents, as in other large-diameter primary afferents in dorsal root ganglia, firing emerges from fast membrane potential oscillations that are supported by a persistent sodium current (INaP ) mediated by Na+ channels containing the α-subunit NaV 1.6. The current flowing through NaV 1.6 channels increases when the extracellular Ca2+ concentration decreases, and studies have shown that INaP -driven firing is increased by S100ß, an astrocytic protein that chelates Ca2+ when released in the extracellular space. We review evidence of how astrocytes, which are known to be activated in pain conditions, might, through their regulation of extracellular Ca2+ , contribute to the generation of ectopic firing in MSAs. To explain how ectopic firing in MSAs might cause pain, we review evidence supporting the hypothesis that cross-talk between proprioceptive and nociceptive pathways might occur in the periphery, within the spindle capsule.

Clinical insights into traumatic injury of the inferior alveolar and lingual nerves: a comprehensive approach from diagnosis to therapeutic interventions.

OBJECTIVES: This scoping review explores the risk and management of traumatic injuries to the inferior alveolar and lingual nerves during mandibular dental procedures. Emphasizing the significance of diagnostic tools, the review amalgamates existing knowledge to offer a comprehensive overview. MATERIALS AND METHODS: A literature search across PubMed, Embase, and Cochrane Library informed the analysis. RESULTS: Traumatic injuries often lead to hypo-/anesthesia and neuropathic pain, impacting individuals psychologically and socially. Diagnosis involves thorough anamnesis, clinical-neurological evaluations, and radiographic imaging. Severity varies, allowing for conservative or surgical interventions. Immediate action is recommended for reversible causes, while surgical therapies like decompression, readaptation, or reconstruction yield favorable outcomes. Conservative management, utilizing topical anesthesia, capsaicin, and systemic medications (tricyclic antidepressants, antipsychotics, and serotonin-norepinephrine-reuptake-inhibitors), proves effective for neuropathic pain. CONCLUSIONS: Traumatic nerve injuries, though common in dental surgery, often go unrecorded. Despite lacking a definitive diagnostic gold standard, a meticulous examination of the injury and subsequent impairments is crucial. CLINICAL RELEVANCE: Tailoring treatment to each case's characteristics is essential, recognizing the absence of a universal solution. This approach aims to optimize outcomes, restore functionality, and improve the quality of life for affected individuals.

Charcot-Marie-Tooth Disease with Myelin Protein Zero Mutation Presenting as Painful, Predominant Small-Fiber Neuropathy.

Charcot-Marie-Tooth disease (CMT) rarely presents with painful symptoms, which mainly occur in association with myelin protein zero (MPZ) gene mutations. We aimed to further characterize the features of painful neuropathic phenotypes in MPZ-related CMT. We report on a 58-year-old woman with a longstanding history of intermittent migrant pain and dysesthesias. Examination showed minimal clinical signs of neuropathy along with mild changes upon electroneurographic examination, consistent with an intermediate pattern, and small-fiber loss upon skin biopsy. Genetic testing identified the heterozygous variant p.Trp101Ter in MPZ. We identified another 20 CMT patients in the literature who presented with neuropathic pain as a main feature in association with MPZ mutations, mostly in the extracellular MPZ domain; the majority of these patients showed late onset (14/20), with motor-nerve-conduction velocities predominantly in the intermediate range (12/20). It is hypothesized that some MPZ mutations could manifest with, or predispose to, neuropathic pain. However, the mechanisms linking MPZ mutations and pain-generating nerve changes are unclear, as are the possible role of modifier factors. This peculiar CMT presentation may be diagnostically misleading, as it is suggestive of an acquired pain syndrome rather than of an inherited neuropathy.

Progress in study on animal models of trigeminal neuralgia. / ä¸‰å‰ç¥žç»ç—›åŠ¨ç‰©æ¨¡åž‹çš„ç ”ç©¶è¿›å±•.

Trigeminal neuralgia is a manifestation of orofacial neuropathic pain disorder, always deemed to be an insurmountable peak in the field of pain research and treatment. The pain is recurrent, abrupt in onset and termination similar to an electric shock or described as shooting. A poor quality of life has been attributed to trigeminal neuralgia, as the paroxysms of pain may be triggered by innocuous stimuli on the face or inside the oral cavity, such as talking, washing face, chewing and brushing teeth in daily life. The pathogenesis of trigeminal neuralgia has not been fully elucidated, although the microvascular compression in the trigeminal root entry zone is generally considered to be involved in the emergence and progression of the pain disorder. In addition, orofacial neuropathic pain restricted to one or more divisions of the trigeminal nerve might be secondary to peripheral nerve injury. Based on current hypotheses regarding the potential causes, a variety of animal models have been designed to simulate the pathogenesis of trigeminal neuralgia, including models of compression applied to the trigeminal nerve root or trigeminal ganglion, chronic peripheral nerve injury, peripheral inflammatory pain and center-induced pain. However, it has not yet been possible to determine which model can be perfectly employed to explain the mechanisms. The selection of appropriate animal models is of great significance for the study of trigeminal neuralgia. Therefore, it is necessary to discuss the characteristics of the animal models in terms of animal strains, materials, operation methods and behavior observation, in order to gain insight into the research progress in animal models of trigeminal neuralgia. In the future, animal models that closely resemble the features of human trigeminal neuralgia pathogenesis need to be developed, with the aim of making valuable contributions to the relevant basic and translational medical research.

[Diagnosing neuropathic orofacial pain in the general dental practice]. / Diagnosticeren van neuropathische orofaciale pijn in de algemene tandartspraktijk.

Dental pain is a common reason for patients to visit the dentist. This type of pain is usually easy to diagnose and treat. However, diagnosing and treating other forms of orofacial pain remains complicated. One of the most challenging types of orofacial pain to diagnose and treat is neuropathic orofacial pain: pain resulting from damage to nerve tissue. Recognizing this type of pain in a timely manner can prevent unnecessary invasive dental treatments and disappointment for patients who seek help for this type of pain. There are relatively simple tools for dentists to distinguish neuropathic pain from other types of orofacial pain. The treatment of neuropathic pain is primarily focused on symptom relief through medication.

The rs216009 single-nucleotide polymorphism of the CACNA1C gene is associated with phantom tooth pain.

Phantom tooth pain (PTP) is a rare and specific neuropathic pain that occurs after pulpectomy and tooth extraction, but its cause is not understood. We hypothesized that there is a genetic contribution to PTP. The present study focused on the CACNA1C gene, which encodes the α1C subunit of the Cav1.2 L-type Ca2+ channel (LTCC) that has been reported to be associated with neuropathic pain in previous studies. We investigated genetic polymorphisms that contribute to PTP. We statistically examined the association between genetic polymorphisms and PTP vulnerability in 33 patients with PTP and 118 patients without PTP but with pain or dysesthesia in the orofacial region. From within and around the CACNA1C gene, 155 polymorphisms were selected and analyzed for associations with clinical data. We found that the rs216009 single-nucleotide polymorphism (SNP) of the CACNA1C gene in the recessive model was significantly associated with the vulnerability to PTP. Homozygote carriers of the minor C allele of rs216009 had a higher rate of PTP. Nociceptive transmission in neuropathic pain has been reported to involve Ca2+ influx from LTCCs, and the rs216009 polymorphism may be involved in CACNA1C expression, which regulates intracellular Ca2+ levels, leading to the vulnerability to PTP. Furthermore, psychological factors may lead to the development of PTP by modulating the descending pain inhibitory system. Altogether, homozygous C-allele carriers of the rs216009 SNP were more likely to be vulnerable to PTP, possibly through the regulation of intracellular Ca2+ levels and affective pain systems, such as those that mediate fear memory recall.

Comparison of amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline, and duloxetine supplemented with pregabalin for the treatment of diabetic peripheral neuropathic pain (OPTION-DM): a multicentre, double-blind, randomised crossover trial.

BACKGROUND: Diabetic peripheral neuropathic pain (DPNP) is common and often distressing. Most guidelines recommend amitriptyline, duloxetine, pregabalin, or gabapentin as initial analgesic treatment for DPNP, but there is little comparative evidence on which one is best or whether they should be combined. We aimed to assess the efficacy and tolerability of different combinations of first-line drugs for treatment of DPNP. METHODS: OPTION-DM was a multicentre, randomised, double-blind, crossover trial in patients with DPNP with mean daily pain numerical rating scale (NRS) of 4 or higher (scale is 0-10) from 13 UK centres. Participants were randomly assigned (1:1:1:1:1:1), with a predetermined randomisation schedule stratified by site using permuted blocks of size six or 12, to receive one of six ordered sequences of the three treatment pathways: amitriptyline supplemented with pregabalin (A-P), pregabalin supplemented with amitriptyline (P-A), and duloxetine supplemented with pregabalin (D-P), each pathway lasting 16 weeks. Monotherapy was given for 6 weeks and was supplemented with the combination medication if there was suboptimal pain relief (NRS >3), reflecting current clinical practice. Both treatments were titrated towards maximum tolerated dose (75 mg per day for amitriptyline, 120 mg per day for duloxetine, and 600 mg per day for pregabalin). The primary outcome was the difference in 7-day average daily pain during the final week of each pathway. This trial is registered with ISRCTN, ISRCTN17545443. FINDINGS: Between Nov 14, 2017, and July 29, 2019, 252 patients were screened, 140 patients were randomly assigned, and 130 started a treatment pathway (with 84 completing at least two pathways) and were analysed for the primary outcome. The 7-day average NRS scores at week 16 decreased from a mean 6·6 (SD 1·5) at baseline to 3·3 (1·8) at week 16 in all three pathways. The mean difference was -0·1 (98·3% CI -0·5 to 0·3) for D-P versus A-P, -0·1 (-0·5 to 0·3) for P-A versus A-P, and 0·0 (-0·4 to 0·4) for P-A versus D-P, and thus not significant. Mean NRS reduction in patients on combination therapy was greater than in those who remained on monotherapy (1·0 [SD 1·3] vs 0·2 [1·5]). Adverse events were predictable for the monotherapies: we observed a significant increase in dizziness in the P-A pathway, nausea in the D-P pathway, and dry mouth in the A-P pathway. INTERPRETATION: To our knowledge, this was the largest and longest ever, head-to-head, crossover neuropathic pain trial. We showed that all three treatment pathways and monotherapies had similar analgesic efficacy. Combination treatment was well tolerated and led to improved pain relief in patients with suboptimal pain control with a monotherapy. FUNDING: National Institute for Health Research (NIHR) Health Technology Assessment programme.

Orofacial pain for clinicians: A review of constant and attack-like facial pain syndromes.

BACKGROUND: Primary headache syndromes such as migraine are among the most common neurological syndromes. Chronic facial pain syndromes of non-odontogenic cause are less well known to neurologists despite being highly disabling. Given the pain localization, these patients often consult dentists first who may conduct unnecessary dental interventions even if a dental cause is not identified. Once it becomes clear that dental modalities have no effect on the pain, patients may be referred to another dentist or orofacial pain specialist, and later to a neurologist. Unfortunately, neurologists are also often not familiar with chronic orofacial pain syndromes although they share the neural system, i.e., trigeminal nerve and central processing areas for headache disorders. CONCLUSION: In essence, three broad groups of orofacial pain patients are important for clinicians: (i) Attack-like orofacial pain conditions, which encompass neuralgias of the cranial nerves and less well-known facial variants of primary headache syndromes; (ii) persistent orofacial pain disorders, including neuropathic pain and persistent idiopathic facial/dentoalveolar pain; and (iii) other differential diagnostically relevant orofacial pain conditions encountered by clinicians such as painful temporomandibular disorders, bruxism, sinus pain, dental pain, and others which may interfere (trigger) and overlap with headache. It is rewarding to know and recognize the clinical picture of these facial pain syndromes, given that, just like for headache, an internationally accepted classification system has been published and many of these syndromes can be treated with medications generally used by neurologists for other pain syndromes.

Evaluated periodontal tissues and oxidative stress in rats with neuropathic pain-like behavior.

BACKGROUND: Oxidative stress has a critical effect on both persistent pain states and periodontal disease. Voltage-gated sodium NaV1.7 (SCN9A), and transient receptor potential ankyrin 1 (TRPA1) are pain genes. The goal of this study was to investigate oxidative stress markers, periodontal status, SCN9A, and TRPA1 channel expression in periodontal tissues of rats with paclitaxel-induced neuropathic pain-like behavior (NPLB). METHODS AND RESULTS: Totally 16 male Sprague Dawley rats were used: control (n = 8) and paclitaxel-induced pain (PTX) (n = 8). The alveolar bone loss and 8-hydroxy-2-deoxyguanosine (8-OHdG) levels were analyzed histometrically and immunohistochemically. Gingival superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities (spectrophotometric assay) were measured. The relative TRPA1 and SCN9A genes expression levels were evaluated using quantitative real-time PCR (qPCR) in the tissues of gingiva and brain. The PTX group had significantly higher alveolar bone loss and 8-OHdG compared to the control. The PTX group had significantly lower gingival SOD, GPx and CAT activity than the control groups. The PTX group had significantly higher relative gene expression of SCN9A (p = 0.0002) and TRPA1 (p = 0.0002) than the control in gingival tissues. Increased nociceptive susceptibility may affect the increase in oxidative stress and periodontal destruction. CONCLUSIONS: Chronic pain conditions may increase TRPA1 and SCN9A gene expression in the periodontium. The data of the current study may help develop novel approaches both to maintain periodontal health and alleviate pain in patients suffering from orofacial pain.

Exercise induced myelin protein zero improvement in neuropathic pain rats.

PURPOSE: Aerobic exercise including swimming plays a suitable role in improving somatosensory injuries. Neuropathic pain is a debilitating condition that occurs following injury or diseases of somatosensory system. In the present study, we tried to investigate the effect of exercise on myelin protein zero of sciatic nerve injured rats. MATERIALS AND METHODS: Forty male rats (180-220 g) were divided into five groups (intact, sham, sham + exercise, neuropathy, and neuropathy + exercise). Right Sciatic nerve of anesthetized rats was exposed and loosely ligated (four ligations with 1 mm apart) using catgut chromic sutures to induce neuropathy. After 3 days of recovery, swimming exercise began (20 min/day/5 days a week/4 weeks). Mechanical allodynia and thermal hyperalgesia were detected using Von Frey filaments and plantar test, respectively. Sciatic nerve at the place of injury was dissected out to measure the myelin protein zero by western blot analysis. In the intact and sham groups, sciatic nerve removed at the place similar to injured group. RESULTS: We found that neuropathy significantly (p < 0.05) reduced paw withdrawal mechanical and thermal thresholds and swimming exercise significantly (p < 0.05) increased paw withdrawal mechanical and thermal thresholds compared to the neuropathy group. Moreover, we found that MPZ level significantly (p < 0.01) decreased in neuropathy group against that in sham group, and exercise prominently (p < 0.05) reversed MPZ level towards control level. CONCLUSIONS: Swimming exercise improves myelin protein zero level in neuropathic rats along with attenuating neuropathic pain. This is a promising approach in improving neuropathological disorders including Charcot-Marie-Tooth and Dejerine-Sottas disease.

Does Immediate Long-Span Nerve Allograft Reconstruction Affect the Incidence of Chronic Postsurgical and Neuropathic Pain in the Reconstructed Mandible Following Resection for Benign and Malignant Disease.

BACKGROUND: Peripheral nerve injury can lead to chronic postsurgical pain (CPSP) and neuropathic pain following major surgery. PURPOSE: Determine in patients undergoing ablative mandibular operations with transection of the trigeminal nerve: do those who undergo immediate repair, when compared to those whose nerves are not repaired, have a decreased or increased risk for CPSP or post-traumatic trigeminal neuropathic pain (PTTNp)? STUDY DESIGN, SETTING, SAMPLE: A multisite, retrospective cohort of patients who underwent resection of the mandible for benign or malignant disease with either no repair or immediate repair of the intentionally transected trigeminal nerve with a long-span nerve allograft were analyzed for the presence or absence of CPSP and PTTNp at 6 months. PREDICTOR VARIABLE: The primary predictor was the immediate repair or no repair of the trigeminal nerve. MAIN OUTCOME VARIABLE: The primary outcome was the presence or absence of CPSP and PTTNp at 6 months postsurgery. COVARIATES: There were 13 covariate variables, including age, sex, ethnicity, nerve injury, type of PTTNp, malignant or benign pathology and subtypes of each, use of radiation or chemotherapy, treatment of transected nerve end, longest follow-up time, pain scale, and onset of pain. ANALYSES: Two-tailed Student's t test and Welch's t test were performed on mean scores and post hoc logistics and linear regression modeling were performed when indicated. The confidence level for statistical significance was P value <.05. RESULTS: There were 103 and 94 subjects in the immediate and no-repair groups, respectively. The incidence of CPSP in the no-repair group was 22.3% and PTTNp was 2.12%, while there was 3.8% CPSP and 0% PTTNp in the repair group, which was statistically significant (P = <.001). Logistic regression modeling showed a statistically significant inverse relationship between the immediate repair and the incidence of CPSP/PTTNp with an odds ratio of 0.43, 95% confidence interval 0.18 to 1.01, P = .05. Greater age, malignant pathology, and chemo/radiation treatments were covariates found more frequently in the no repair group. CONCLUSION AND RELEVANCE: Immediate repair of an intentionally transected trigeminal nerve with a long-span nerve allograft during resection of the mandible for both benign and malignant disease appears to reduce CPSP and possibly eliminate the development of PTTNp.

Development and evaluation of Hedyotis corymbosa (L.) extract containing phytosomes: a preclinical approach for treatment of neuropathic pain in rodent model.

PURPOSE: The study was aimed to encapsulate Hedyotis corymbosa extract (HCE) into phytosomes to improve its therapeutic efficacy in neuropathic pain by enhancing the bioavailability of chief chemical constituent Hedycoryside -A (HCA). METHODS: For preparing phytosomes complexes (F1, F2, and F3), HCE and phospholipids were reacted in disparate ratio. F2 was chosen to assess its therapeutic efficacy in neuropathic pain induced by partial sciatic nerve ligation. Nociceptive threshold and oral bioavailability were also estimated for F2. RESULTS: Particle size, zeta potential and entrapment efficiency for F2 were analysed as 298.1 ± 1.1 nm, -3.92 ± 0.41 mV and 72.12 ± 0.72% respectively. F2 gave enhanced relative bioavailability (158.92%) of HCA along with a greater neuroprotective potential showing a significant antioxidant effect and augmentation (p < 0.05) in nociceptive threshold with the diminution in damage to nerves. CONCLUSION: F2 is an optimistic formulation for enhancing the HCE delivery for the effective treatment of neuropathic pain.

Neuropathic Pain After Dental Implant Surgery: Literature Review and Proposed Algorithm for Medicosurgical Treatment.

The objective of this study is to establish an algorithm for the medicosurgical treatment of dental implant-induced neuropathic pain. The methodology was based on the good practice guidelines from the French National Authority for Health: the data were searched on the Medline database. A working group has drawn up a first draft of professional recommendations corresponding to a set of qualitative summaries. Consecutive drafts were amended by the members of an interdisciplinary reading committee. A total of 91 publications were screened, of which 26 were selected to establish the recommendations: 1 randomized clinical trial, 3 controlled cohort studies, 13 case series, and 9 case reports. In the event of the occurrence of post-implant neuropathic pain, a thorough radiological assessment by at least a panoramic radiograph (orthopantomogram) or especially a cone-beam computerized tomography scan is recommended to ensure that the tip of the implant is placed more than 4 mm from the anterior loop of the mental nerve for an anterior implant and 2 mm from the inferior alveolar nerve for a posterior implant. Very early administration of high-dose steroids, possibly associated with partial unscrewing or full removal of the implant preferably within the first 36-48 hours after placement, is recommended. A combined pharmacological therapy (anticonvulsants, antidepressants) could minimize the risk of pain chronicization. If a nerve lesion occurs in the context of dental implant surgery, treatment should be initiated within the first 36-48 hours after implant placement, including partial or full removal of the implant and early pharmacological treatment.

Cryoneurolysis of alveolar nerves for chronic dental pain: A new technique and a case series.

BACKGROUND: Chronic neuropathic dental pain has a poor prognosis with a low chance of significant spontaneous improvement. Local or oral therapies may be efficient, however short in terms of duration with potential side effects. Cryoneurolysis has been described to prevent acute postoperative pain or to treat some chronic pain conditions; however, application to dental orofacial pain has not been reported so far. CASE SERIES: Following a positive diagnostic block on the corresponding alveolar nerve, neuroablation was performed using a cryoprobe on three patients suffering from persistent pain after a dental extraction and 1 after multiple tooth surgeries. The effect of treatment was assessed using a Pain Numeric Rating Scale (NRS) and determined by changes in medication dosage and quality of life at day 7 and 3 months. Two patients experienced more than 50% of pain relief at 3 months, 2 by 50%. One patient was able to wean off pregabalin medication, one decreased amitriptyline by 50%, and one decreased tapentadol by 50%. No direct complications were reported. All of them mentioned improvement in sleep and quality of life. CONCLUSION: Cryoneurolysis on alveolar nerves is a safe and easy-to-use technique allowing prolonged neuropathic pain relief after dental surgery.

Formulation design and evaluation of epalrestat mouth dissolving tablets comprising superdisintegrant from natural sources manufactured by direct compression method and stability studies of optimized formulation.

Among the oral route, mouth dissolving tablets (MDTs) offer a benefit for drugs with slow dissolution and having low oral bioavailability. Epalrestat is one of the best effective diabetic neuropathy medication used for treating nerve pain. The problem associated with this drug is high first pass metabolism and low solubility in acidic media as well in basic media leads to short half-life, delayed dissolution and side effects. Therefore, the goal of the current work is to developed an epalrestat MDTs tablet that will provide quick drug dissolution and a quick onset of action for the treatment of nerve pain. MDTs of epalrestat were formulated by direct compression using natural superdis integrants obtained from the various sources such as fenugreek, gum karaya and banana powder. All of the pre- and post-compression parameter results were shown to be in accordance with established specifications. In comparison to other formulations of MDTs, formulation F3 with 15 mg (7.5%) of banana powder displayed a higher rate of dissolution. It was determined that epalrestat MDTs containing natural superdisintegrant were successfully formulated with acceptable physical and chemical properties, quick oral cavity disintegration, a quick onset of action and improved patient compliance.

Single-nucleotide polymorphisms of the SLC17A9 and P2RY12 genes are significantly associated with phantom tooth pain.

Phantom tooth pain (PTP) is a rare and specific neuropathic pain that occurs after pulpectomy and tooth extraction, but its cause is not understood. We hypothesized that there is a genetic contribution to PTP. We focused on solute carrier family 17 member 9 (SLC17A9)/vesicular nucleotide transporter (VNUT) and purinergic receptor P2Y12 (P2RY12), both of which have been associated with neuropathic pain and pain transduction signaling in the trigeminal ganglion in rodents. We sought to corroborate these associations in humans. We investigated gene polymorphisms that contribute to PTP. We statistically examined the association between genetic polymorphisms and PTP vulnerability in 150 patients with orofacial pain, including PTP, and 500 healthy subjects. We found that the rs735055 polymorphism of the SLC17A9 gene and rs3732759 polymorphism of the P2RY12 gene were associated with the development of PTP. Carriers of the minor allele of rs735055 and individuals who were homozygous for the major allele of rs3732759 had a higher rate of PTP. Carriers of the minor allele of rs735055 reportedly had high SLC17A9 mRNA expression in the spinal cord, which may increase the storage and release of adenosine triphosphate. Individuals who were homozygous for the major allele of rs3732759 may have higher P2RY12 expression that is more active in microglia. Therefore, these carriers may be more susceptible to PTP. These results suggest that specific genetic polymorphisms of the SLC17A9 and P2RY12 genes are involved in PTP. This is the first report on genes that are associated with PTP in humans.

Evaluation of the analgesic effect of ɑ-lipoic acid in treating pain disorders: A systematic review and meta-analysis of randomized controlled trials.

Neuropathic pain is the most prevalent form of chronic pain caused by a disease of the nervous system, such as diabetic polyneuropathy. ɑ-Lipoic acid (ALA) is an antioxidant that has been widely studied for the treatment of pain symptoms in diverse conditions. Therefore, this study aimed to investigate the efficacy of ALA in the treatment of different types of pain through a systematic review and meta-analysis of randomized clinical trials. The study protocol was registered in the International Prospective Registry of Systematic Reviews (CRD42021261971). A search of the databases resulted in 1154 articles, 16 of which were included in the review (9 studies with diabetic polyneuropathy and 7 studies with other painful conditions). Most of the included studies had a low risk of bias. ALA showed efficacy for the treatment of headache, carpal tunnel syndrome and burning mouth syndrome. Meta-analysis was conducted only with the studies using diabetic polyneuropathy. Compared to placebo, ALA treatment decreased the total symptom score (TSS). The subgroup meta-analysis indicated a decrease of stabbing pain, burning, paraesthesia, and numbness in ALA-treated patients compared to placebo. In addition, both routes of administration, intravenous and oral, demonstrated the efficacy to reduce TSS. Therefore, ALA should be used to treat diabetic polyneuropathy pain symptoms. However, the standardization of treatment time and the dose may advance for the approval of ALA for clinical use in diabetic polyneuroneuropathy.

Pharmacovigilance in hospice/palliative care: Net effect of amitriptyline or nortriptyline on neuropathic pain: UTS/IMPACCT Rapid programme international consecutive cohort.

BACKGROUND: Real-world effectiveness of interventions in palliative care need to be systematically quantified to inform patient/clinical decisions. Neuropathic pain is prevalent and difficult to palliate. Tricyclic antidepressants have an established role for some neuropathic pain aetiologies, but this is less clear in palliative care. AIM: To describe the real-world use and outcomes from amitriptyline or nortriptyline for neuropathic pain in palliative care. DESIGN: An international, prospective, consecutive cohort post-marketing/phase IV/pharmacovigilance/quality improvement study of palliative care patients with neuropathic pain where the treating clinician had already made the decision to use a tricyclic antidepressant. Data were entered at set times: baseline, and days 7 and 14. Likert scales graded benefits and harms. SETTING/PARTICIPANTS: Twenty-one sites (inpatient, outpatient, community) participated in six countries between June 2016 and March 2019. Patients had clinician-diagnosed neuropathic pain. RESULTS: One hundred and fifty patients were prescribed amitriptyline (110) or nortriptyline (40) of whom: 85% had cancer; mean age 73.2 years (SD 12.3); mean 0-4 scores for neuropathic pain at baseline were 1.8 (SD 1.0). By day 14, doses of amitriptyline were 57 mg (SD 21) and nortriptyline (48 mg (SD 21). Fifty-two (34.7%) patients had pain improvement by day 14 (amitriptyline (45/110 (43.3%); nortriptyline (7/40 (18.9%)). Thirty-nine (27.7%) had new harms; (amitriptyline 29/104 (27.9%); nortriptyline 10/37 (27.0%); dizziness (n = 23), dry mouth (n = 20), constipation (n = 14), urinary retention (n = 10)). Benefits without harms occurred (amitriptyline (26/104 (25.0%); nortriptyline (4/37 (10.8%)). CONCLUSIONS: Benefits favoured amitriptyline while harms were similar for both medications.

Trigeminal Traumatic Neuroma: a Comprehensive Review of the Literature Based On a Rare Case.

PURPOSE OF REVIEW: Traumatic neuromas in general, and trigeminal traumatic neuromas in particular, are relatively rare entities originating from a damage to a corresponding nerve or its branches. This manuscript is a comprehensive review of the literature on trigeminal traumatic neuromas based on an interesting and challenging case of bilateral intraoral lesions. RECENT FINDINGS: The diagnosis for this patient was bilateral trigeminal traumatic neuromas. It is possible that these patients have a genetic predisposition to the development of these lesions. It is a neuropathic pain condition and may mimic dental and other trigeminal pain entities. Topical treatment with lidocaine gel, utilizing a custom-made neurosensory stent, rendered the patient significant and sustained pain relief. Trigeminal traumatic neuromas present a diagnostic challenge even to a seasoned clinician, due to the complex clinical features that may mimic other entities. Topical medications such as local anesthetics may be a good viable alternative to systemic medications to manage the pain associated with the condition. Early identification of the lesion and the associated pain helps in the succinct management of symptomatic trigeminal traumatic neuromas.