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1.
J Integr Neurosci ; 22(1): 25, 2023 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-36722242

RESUMO

BACKGROUND: There are no articles that aim to evaluate the specific role of surgical decompression on the recovery of pain and positive sensory symptoms (PSS) in patients with brachial plexus neuropathy (BPN), as well as the relationship between pain and frequency of sensory manifestations. METHODS: A prospective before and after study was performed, considering the pain intensity through the visual analogue scale (VAS), and the frequency of PSS through a proposed new scale: Sensory Frequency of Symptoms Scale (SFSS). To compare the patients before and after the intervention, a paired T-test, a Wilcoxon signed-rank test, and Cohen's D test were made, coupled with a Spearman analysis in order to establish the relationship between pain and PSS. RESULTS: Sixteen patients were included in the study, the clinical evaluation showed changes in pain according with VAS, going from a mean preoperative state of 8.19 to 1.31 after surgery, showing significant changes (84%, p < 0.00006, Δ = 2.776). Within the PSS, a significant decrease was observed in paresthesias (74%, p < 0.0001, Δ = 1.645), dysesthesias (80%, p < 0.002, Δ = 1.453), and allodynia (70%, p = 0.031, Δ = 0.635). Conversely, the preoperative correlation analysis between pain and dysesthesias/allodynia showed a low and non-significant relationship (R < 0.4, p > 0.05). CONCLUSIONS: Surgical decompression is an effective technique for the relief of pain and sensory manifestations in adult patients with BPN of compressive origin. No relationship was observed between pain and dysesthesias/allodynia. Therefore, during clinical evaluation, they should be considered as independent manifestations, highlighting the need to validate new scales.


Assuntos
Neuropatias do Plexo Braquial , Neuralgia , Adulto , Humanos , Hiperalgesia , Parestesia , Estudos Prospectivos , Neuralgia/diagnóstico , Neuralgia/etiologia , Neuralgia/cirurgia , Descompressão Cirúrgica
2.
Sci Adv ; 9(4): eade7002, 2023 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-36706180

RESUMO

Microglia are important mediators of neuroinflammation, which underlies neuropathic pain. However, the molecular checkpoints controlling microglial reactivity are not well-understood. Here, we investigated the role of Orai1 channels for microglia-mediated neuroinflammation following nerve injury and find that deletion of Orai1 in microglia attenuates Ca2+ signaling and the production of inflammatory cytokines by proalgesic agonists. Conditional deletion of Orai1 attenuated microglial proliferation in the dorsal horn, spinal cytokine levels, and potentiation of excitatory neurotransmission following peripheral nerve injury. These cellular effects were accompanied by mitigation of pain hyperalgesia in microglial Orai1 knockout mice. A small-molecule Orai1 inhibitor, CM4620, similarly mitigated allodynia in male mice. Unexpectedly, these protective effects were not seen in female mice, revealing sexual dimorphism in Orai1 regulation of microglial reactivity and hyperalgesia. Together, these findings indicate that Orai1 channels are key regulators of the sexually dimorphic role of microglia for the neuroinflammation that underlies neuropathic pain.


Assuntos
Microglia , Neuralgia , Camundongos , Masculino , Feminino , Animais , Microglia/metabolismo , Hiperalgesia/genética , Doenças Neuroinflamatórias , Neuralgia/genética , Camundongos Knockout , Citocinas/metabolismo , Medula Espinal , Proteína ORAI1/genética
3.
Sci Rep ; 13(1): 489, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36627362

RESUMO

Posterior hypothalamus (PH), an important part of the descending pain processing pathway, has been found to be activated in trigeminal autonomic cephalalgias. However, there are very few studies conducted and information regarding its implications in trigeminal neuropathic pain (TNP). Therefore, we aimed to ascertain whether optogenetic inhibition of PH could affect the outcomes of a chronic constriction injury in the infraorbital nerve (CCI-ION) rat model. Animals were divided into the TNP animal, sham, and naive-control groups. CCI-ION surgery was performed to mimic TNP symptoms, and the optogenetic or null virus was injected into the ipsilateral PH. In vivo single-unit extracellular recordings were obtained from both the ipsilateral ventrolateral periaqueductal gray (vlPAG) and contralateral ventral posteromedial (VPM) thalamus in stimulation "OFF" and "ON" conditions. Alterations in behavioral responses during the stimulation-OFF and stimulation-ON states were examined. We observed that optogenetic inhibition of the PH considerably improved behavioral responses in TNP animals. We found increased and decreased firing activity in the vlPAG and VPM thalamus, respectively, during optogenetic inhibition of the PH. Inhibiting PH attenuates trigeminal pain signal transmission by modulating the vlPAG and trigeminal nucleus caudalis, thereby providing evidence of the therapeutic potential of PH in TNP management.


Assuntos
Neuralgia , Neuralgia do Trigêmeo , Ratos , Animais , Ratos Sprague-Dawley , Optogenética , Neuralgia/terapia , Neuralgia/metabolismo , Hipotálamo Posterior/metabolismo , Hiperalgesia/metabolismo
4.
Pain Manag ; 13(1): 25-34, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36606500

RESUMO

Aim: The study was designed to evaluate the modulation of mTOR complex 1 (mTORC1) and IL-6 genes following the use of mirror therapy (MT) and pregabalin in complex regional pain syndrome type-1 patients. Materials & methods: Two groups of 20 patients: MT group received MT and pregabalin, control therapy group received pregabalin. Neuropathic pain symptom inventory (NPSI), numeric rating scale - pain, modified motor activity log, SF-12 questionnaire for quality of life and IL-6 and mTORC1 expression were evaluated. Results: Group MT demonstrated a statistically significant improvement in NPSI burning, NPSI allodynia and numeric rating scale pain scores, modified motor activity log and SF-12 scores. Significant downregulation of mTORC1 and IL-6 observed in both. Conclusion: MT is a significant adjunct to pregabalin in improving motor function, quality of life and alleviating pain in complex regional pain syndrome type 1. Clinical Trial Registration: CTRI/2019/01/017272 (ClinicalTrials.gov).


Complex regional pain syndrome is a form of long-term pain that involves an arm or a leg. It can develop after an injury, a surgery or a stroke. Although many drugs have been used for its treatment, the limited relief that these drugs produce along with their side effects have shifted focus to other physical and psychological modes of therapy. Mirror therapy is one such modality where the image of normal functioning limb seen in a mirror placed over the affected limb leads to pain relief in the affected limb. We have provided evidence that mirror therapy can reduce the pain of this syndrome and also decrease the levels of pain related genes in the body. This will help us to devise better treatment strategies for complex regional pain syndrome.


Assuntos
Síndromes da Dor Regional Complexa , Neuralgia , Humanos , Pregabalina/uso terapêutico , Interleucina-6/uso terapêutico , Terapia de Espelho de Movimento , Qualidade de Vida , Neuralgia/tratamento farmacológico , Síndromes da Dor Regional Complexa/tratamento farmacológico , Resultado do Tratamento
5.
BMC Palliat Care ; 22(1): 4, 2023 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-36609269

RESUMO

BACKGROUND: Limited efficacy has been observed when using opioids to treat neuropathic pain. Lidocaine patches reduce neuropathic pain in postherpetic neuralgia, but their benefits for cancer-related neuropathic pain remain unclear. This study aimed to investigate a treatment for cancer-related neuropathic pain. METHODS: We conducted a prospective, open-label, single-arm study to assess the efficacy and safety of lidocaine transdermal patches in patients experiencing localized, superficial, neuropathic cancer pain. Terminal cancer patients already receiving opioid treatment participated in the 3-day study. The primary endpoint was pain intensity evaluated by the numerical rating scale (NRS). The secondary endpoints were the pain relief score and the quality of analgesic treatment. RESULTS: The results showed a significant difference in the median NRS over 3 days (Kruskal-Wallis test, p < 0.0001). The median NRS pain intensity from Day 1 to Day 3 was 4.0 with 95% C.I. (3.3, 5.0), 3.0 (2.5, 3.5), and 2.6 (2.0, 3.0), respectively. The difference between the median NRS pain intensities of any 2 days was significant (Wilcoxon signed-rank test, p < 0.0001). The generalized estimating equation (GEE) estimation model showed significant differences between the NRS pain intensities on any 2 days. There was no significant difference in the pain relief score or the quality of analgesic treatment. CONCLUSIONS: In this study, the 5% lidocaine transdermal patch reduced the NRS pain intensity in neuropathic cancer patients already receiving opioid treatment. Treatment of localized and superficial neuropathic pain caused by cancer was well tolerated and effective.


Assuntos
Neoplasias , Neuralgia , Humanos , Lidocaína/uso terapêutico , Lidocaína/efeitos adversos , Analgésicos Opioides/uso terapêutico , Medição da Dor , Estudos Prospectivos , Adesivo Transdérmico , Neuralgia/etiologia , Neuralgia/induzido quimicamente , Analgésicos/uso terapêutico , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Resultado do Tratamento
6.
In Vivo ; 37(1): 47-56, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36593011

RESUMO

BACKGROUND/AIM: Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of cancer treatment, resulting in pain, numbness, instability, and thus affecting quality of life (QoL), occasionally leading to discontinuation of chemotherapy. Pharmacological treatments are not sufficient. Non-pharmacological interventions (NPIs) have also been tried. This study aimed to systematically review the efficacy of NPIs on pain and QoL in patients suffering from CIPN. MATERIALS AND METHODS: The databases searched were Pubmed, Cohrane, and Scopus for randomized controlled trials (RCTs) published in the last 5 years (2017-2022). Studies were considered eligible, if they assessed adult patients suffering from CIPN because of any chemotherapeutic drug for any type and any stage of cancer and if study protocols included non-pharmacological intervention with a structured protocol. RESULTS: A total of 1,496 records were identified. Finally, 10 RCTs including 495 patients (253 in the intervention group and 242 in the control group) were included for meta-analysis. Intervention protocols included acupuncture (n=6), exercise (n=3), and yoga (n=1). NPIs significantly reduced neuropathic pain. However, the effect on QoL was not significant. CONCLUSION: NPIs are beneficial in the treatment of pain in patients with CIPN but their impact on QoL is not statistically supported. Larger sample sizes, more homogenous in outcome measures and interventions are needed to further explore NPIs' efficacy on CIPN symptoms.


Assuntos
Antineoplásicos , Neoplasias , Neuralgia , Polineuropatias , Adulto , Humanos , Antineoplásicos/uso terapêutico , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Polineuropatias/terapia , Polineuropatias/tratamento farmacológico , Neuralgia/induzido quimicamente , Neuralgia/terapia , Qualidade de Vida
7.
BMC Anesthesiol ; 23(1): 22, 2023 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-36639747

RESUMO

PURPOSE: The simultaneous use of drugs with different mechanisms of analgesic action is a strategy for achieving effective pain control while minimizing dose-related side effects. Choline was described to potentiate the analgesic action of parecoxib sodium at small doses in several inflammatory pain models. However, these findings are still very limited, and more associated data are required to confirm the effectiveness of the combined choline and parecoxib sodium therapy against inflammatory pain. METHODS: Adult rats were randomly divided into 9 groups (N = 6/group). The sham surgery group received an intraperitoneal (i.p.) injection of saline. Rats with chronic constriction injury (CCI) of the sciatic nerve received saline, choline (cho, 6, 12 and 24 mg/kg), parecoxib sodium (pare, 3, 6, and 12 mg/kg), or a combination of choline 6 mg/kg and parecoxib sodium 3 mg/kg. Mechanical and heat pain thresholds were measured at 30 min after drug treatment at Days 3, 5, 7, 10, and 14 after CCI. Another 30 rats were divided into 5 groups (N = 6/group): the sham, CCI + saline, CCI + cho-6 mg/kg, CCI + pare-3 mg/kg, and CCI + cho-6 mg/kg + pare-3 mg/kg groups. After repeated drug treatment for 7 days, five rats were randomly selected from each group, and the lumbar dorsal root ganglia (DRGs) (L4-6) were harvested for western blot analysis. RESULTS: Choline significantly attenuated mechanical and heat hypersensitivity in CCI rats at 12 and 24 mg/kg doses (P < 0.05) but was not effective at the 6 mg/kg dose. Parecoxib sodium exerted significant pain inhibitory effects at the 6 and 12 mg/kg doses (P < 0.05) but not at the 3 mg/kg dose. Combining a low dose of choline (6 mg/kg) and parecoxib sodium (3 mg/kg) produced significant pain inhibition in CCI rats and reduced the expression of high mobility group protein 1 (HMGB1) and nuclear factor-kappa Bp65 (NF-κBp65) in L4-6 DRGs. CONCLUSION: 1. In a rat model of chronic neuropathic pain (CCI), at a certain dose, choline or parecoxib sodium can alleviate mechanical pain and thermal hyperalgesia caused by CCI. 2. The combination of choline and parecoxib sodium in nonanalgesic doses can effectively relieve neuropathic pain, and its mechanism may be related to the inhibition of the high mobility group protein 1 (HMGB1)/Toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) pathway.


Assuntos
Colina , Isoxazóis , Neuralgia , Animais , Ratos , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Constrição , Proteína HMGB1 , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Neuralgia/tratamento farmacológico , Neuralgia/etiologia , Ratos Sprague-Dawley , Nervo Isquiático , Colina/farmacologia , Isoxazóis/farmacologia
8.
Langenbecks Arch Surg ; 408(1): 39, 2023 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-36652009

RESUMO

PURPOSE: Neuropathic pain is a complication after groin hernia surgery. Triple neurectomy of the iliohypogastric nerve, ilioinguinal nerve and genitofemoral nerve is an efficient treatment modality, with several surgical approaches. The minimally invasive endoscopic method to neurectomy was specifically investigated in this meta-analysis. Our aim is to determine the efficacy of this method in the treatment of chronic neuropathic pain posthernia repair surgery. METHODS: A systematic review was conducted using four databases to search for the keywords ("endoscopic retroperitoneal neurectomy" and "laparoscopic retroperitoneal neurectomy"). The NCBI National Library of Medicine, Cochrane Library, MEDLINE Complete and BioMed Central were last searched on 26 May 2022. Randomised control trials and retrospective or prospective papers involving endoscopic retroperitoneal neurectomy operations after inguinal hernia repair were included. All other surgeries, procedures and study designs were excluded. The internal quality of included studies was assessed using the Newcastle-Ottawa Scale. The percentage of patients who had reduction in pain ("positive treatment outcome") was used to assess the procedure's effectiveness in each analysis. RESULTS: Five comparable endoscopic retroperitoneal neurectomy studies with a total of 142 patients were analysed. Both the Wald test (Q (6) = 1.79, = .775) and the probability ratio test (Q (6) = 4.24, = .374) provide similar findings (0.000, 0.0% [0.0%; 78%]). The meta-analysis' key finding is that the intervention was up to 78% effective (95% confidence interval, 71%; 84%). CONCLUSION: Endoscopic retroperitoneal neurectomy can be an effective treatment option for postoperative neuropathic pain relief following surgical hernia repair. Although there is limited reported experience with this technique, it may provide a clinical benefit to the patient. We recommend further prospective data and long-term follow-up studies be conducted to confirm and expand on these outcomes.


Assuntos
Dor Crônica , Hérnia Inguinal , Laparoscopia , Neuralgia , Humanos , Dor Crônica/etiologia , Dor Crônica/cirurgia , Denervação/efeitos adversos , Hérnia Inguinal/cirurgia , Hérnia Inguinal/complicações , Herniorrafia/efeitos adversos , Herniorrafia/métodos , Laparoscopia/métodos , Neuralgia/etiologia , Neuralgia/cirurgia , Dor Pós-Operatória/etiologia , Estudos Retrospectivos
9.
Forensic Toxicol ; 41(1): 142-150, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36652069

RESUMO

PURPOSE: MDA-19 or BZO-HEXOXIZID (N'-[(3Z)-1-(1-hexyl)-2-oxo-1,2-dihydro-3H-indol-3-ylidene]-benzohydrazide), in a more recent nomenclature, was first synthesized in 2008 as a selective type-2 cannabinoid receptor (CB2) agonist due to its potential to treat neuropathic pain. In Brazil, this substance was identified in a series of 53 apprehensions between September 2021 and February 2022. Nevertheless, what intrigues toxicologists is that BZO-HEXOXIZID does not exert significant type-1 cannabinoid receptor (CB1) agonism-which is responsible for the well-known psychoactivity of Δ-9-tetrahydrocannabinol. Thus, the objective of this work is to report the first apprehension and identification of BZO-HEXOXIZID in Brazil and to discuss pharmacologically the possible reasons why a CB2 agonist has been incorporated to the illicit market. METHODS: Suspected seized samples were sent to the Laboratory of the Scientific Police of the State of Sao Paulo. After the screening, samples were confirmed for the presence of BZO-HEXOXIZID using chromatography gas-mass spectrometry, Fourier-transform infrared spectroscopy and nuclear magnetic resonance techniques. RESULTS: Of the 53 samples analyzed, 25 contained only BZO-HEXOXIZID and 28 with mixtures, of which 11 with the CB1 agonist ADB-BUTINACA. Other substances were found in association such as cocaine and caffeine. CONCLUSIONS: BZO-HEXOXIZID was detected in a series of seized materials for the first time in Brazil. Nevertheless, there are still unanswered questions regarding the use of this selective CB2 agonist as a drug of abuse.


Assuntos
Agonistas de Receptores de Canabinoides , Neuralgia , Humanos , Agonistas de Receptores de Canabinoides/farmacologia , Cromatografia Gasosa-Espectrometria de Massas , Brasil , Receptores de Canabinoides
10.
Inn Med (Heidelb) ; 64(1): 25-33, 2023 Jan.
Artigo em Alemão | MEDLINE | ID: mdl-36645434

RESUMO

Patients with incurable cancer can suffer from a variety of symptoms that adversely impact the quality of life. Pain, nausea and vomiting are common symptoms in this context. These symptoms can be tumor-related, tumor-associated or treatment-related but can also have independent causes. The aim of this article is to present the complexity of these symptoms, symptom assessment and the current treatment guidelines. Apart from physical causes, there may also be psychological, social or spiritual causes for these distressing symptoms. In addition to pharmacological treatment, a comprehensive needs-oriented approach involving treatment by a multiprofessional team (doctors, nurses, physiotherapists, psychologists, art and music therapists, social workers, pastoral workers) consisting of healthcare professionals and volunteers can help to alleviate symptoms. The differentiation of nociceptive and neuropathic pain is indicative for the selection of medication in pain management, and medication should be individually titrated. For the treatment of nausea and vomiting, an etiology-based approach should be used and the receptor specificity of antiemetics should be considered. If symptoms can be anticipated, at least an adequate medication should generally be prescribed for the possible needs, and if symptoms persist a basic medication should be the rule. Guidelines, such as the S3 guidelines on supportive therapy in oncology patients and the S3 guidelines on palliative care for patients with incurable cancer, are principles for routine clinical practice.


Assuntos
Neoplasias , Neuralgia , Humanos , Cuidados Paliativos , Qualidade de Vida , Vômito/terapia , Náusea/etiologia , Neoplasias/complicações , Neuralgia/complicações
11.
Br J Dermatol ; 188(1): 41-51, 2023 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-36689519

RESUMO

BACKGROUND: Pain is rated by patients with hidradenitis suppurativa (HS) as the disease's most impactful symptom. HS therapies are often insufficient to control inflammatory disease activity and pain. A better understanding of patient experiences with pain may improve patient-provider relationships and help identify strategies for addressing HS pain. OBJECTIVES: This qualitative study sought to characterize lived pain experiences of those with HS. METHODS: English-speaking patients ≥ 18 years old with a dermatologist-confirmed diagnosis of HS and an average numerical rating scale pain score of ≥ 1 over the preceding week were recruited from a single academic medical centre in Atlanta, Georgia, USA. Semistructured interviews were conducted from November 2019 to March 2020 to explore participants' HS pain experiences and the subsequent impact on their lives. Thematic saturation was reached after interviewing 21 participants. Interviews were audio recorded, transcribed, and analysed using thematic analysis. RESULTS: Among 21 study participants, the median 7-day average pain score was 6 (interquartile range 3-7; scale ranges from 0 to 10, with 10 being most pain). Participants' descriptions of pain were consistent with nociceptive pain, neuropathic pain and itch. Pain impacted multiple life domains, including physical limitations (decreased mobility and impaired sleep), decreased psychological wellbeing (irritability, depression, loss of control, and difficulty communicating pain experiences) and impaired social relationships (social isolation, intimacy problems and difficulty fulfilling social responsibilities). Although participants reported chronic discomfort, acutely painful and unpredictable HS disease flares caused more distress and quality-of-life (QoL) burden. Participants frequently treated their pain without input from the medical team, sometimes with unsafe medication doses or combinations. Factors contributing to self-management of pain included difficulty accessing timely outpatient care during disease flares and fear of stigma from healthcare providers. CONCLUSIONS: When present, HS-related pain may impact not only physical wellbeing but also mental health and relationships. In addition to therapies that target the inflammatory disease burden, treating the symptom of pain may improve patients' QoL and wellbeing. Because patients with HS have difficulty explaining their pain, proactively asking them about pain may identify unmet needs, facilitate better pain control and improve QoL. Further, the influence of HS-related pain on numerous aspects of QoL suggests the need for multidisciplinary, patient-centred approaches to HS pain management.


Assuntos
Hidradenite Supurativa , Neuralgia , Humanos , Adolescente , Hidradenite Supurativa/diagnóstico , Qualidade de Vida , Manejo da Dor , Efeitos Psicossociais da Doença
12.
J Vis Exp ; (191)2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36688541

RESUMO

The tibial neuroma transposition (TNT) is a rat model in which allodynia at the neuroma site (tibial nerve) can be independently evaluated from allodynia at the plantar surface of the hind paw innervated by the intact sural nerve. This TNT model is suitable to test therapies for neuroma pain, such as the potential superiority of certain surgical therapies that are already used in the clinic, or to evaluate new drugs and their effect on both pain modalities in the same animal. In this model, a distal lesion (neurotmesis) is made in the tibial nerve, and the proximal nerve end is transposed and fixed subcutaneously and pretibially to enable assessments of the neuroma site with a 15 g Von Frey monofilament. To assess allodynia over the sural nerve, Von Frey monofilaments can be used via the up-down method on the plantar lateral region of the hind paw. After cutting the tibial nerve, mechanical hypersensitivity develops at the neuroma site within 1 week after surgery and persists at least until 12 weeks after surgery. Allodynia at the sural innervated plantar surface develops within 3 weeks after surgery compared to the contralateral limb. At 12 weeks, a neuroma forms on the proximal end of the severed tibial nerve, indicated by dispersion and swirling of axons. For the TNT model surgery, multiple critical (micro)surgical steps need to be followed, and some surgery practice under terminal anesthesia is advised. Compared to other neuropathic pain models, such as the spared nerve injury model, allodynia over the neuroma site can be independently tested from sural nerve hypersensitivity in the TNT model. However, the neuroma site can be tested only in rats, not in mice. The tips and directions provided in this protocol can help research groups working on pain successfully implement the TNT model in their facility.


Assuntos
Neuralgia , Neuroma , Ratos , Camundongos , Animais , Hiperalgesia/tratamento farmacológico , Modelos Animais de Doenças , Nervo Tibial/cirurgia , Neuroma/etiologia , Neuroma/cirurgia
13.
PLoS One ; 18(1): e0280593, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36662848

RESUMO

BACKGROUND: Pregabalin is a drug used to treat neuropathic pain, and its use has increased substantially since 2007. Early trials found a strong treatment effect on pain for post-herpetic neuralgia and diabetic neuropathy. However more recent studies have failed to replicate these results. METHODS: This meta-epidemiological study aimed to assess change in the reported effectiveness of pregabalin in neuropathic pain trials over time, and if a change is present, determine any associated factors. DATA SOURCES: We performed electronic searches for published trials in Medline, Embase and Cochrane Central Register of Controlled Trials databases; and unpublished trials on ClinicalTrials.gov, the EU Clinical Trials Register, and the Australia New Zealand Clinical Trials Registry with no restrictions. STUDY SELECTION: We included randomized, placebo-controlled trials of pregabalin for treatment of neuropathic pain in adults. DATA EXTRACTION AND SYNTHESIS: Two authors independently extracted study data: sample size and mean baseline, end-point and change in pain scores with measures of variance, trial end year, publication year, clinical indication, funding source, country of study, treatment duration, treatment dose, mean age and percentage male. PRIMARY OUTCOME MEASURE: We defined treatment effect as the mean difference in pain scores between pregabalin and placebo groups at trial end-point and assessed for change over time using a random-effects meta-regression, adjusted for sample size, indication, treatment duration (weeks) and treatment dose. RESULTS: We included 38 randomized published trials (9038 participants) and found that between 2003 and 2020, the reported treatment effect of pregabalin decreased by 0.4 points (95% CI: 0.3 to 0.6; p<0.001) on an 11-point pain scale per 5-year interval, from 1.3 points (95% CI: 1.0 to 1.5) in trials conducted in 2001-2005, to 0.3 (95% CI: -0.1 to 0.7) in trials conducted in 2016-2020. The reported treatment effect was lower than the minimal clinically important difference (MCID) of 1.7 points across all time periods, doses and most indications and was not found to be associated with study characteristics. CONCLUSIONS: The reported treatment effect or analgesic efficacy of pregabalin from clinical trials has diminished over time. Clinical recommendations may need to be re-evaluated to account for recent evidence and to consider whether pregabalin therapy is indicated.


Assuntos
Neuropatias Diabéticas , Neuralgia Pós-Herpética , Neuralgia , Adulto , Humanos , Masculino , Analgésicos/uso terapêutico , Neuropatias Diabéticas/tratamento farmacológico , Neuropatias Diabéticas/epidemiologia , Neuralgia/tratamento farmacológico , Neuralgia/epidemiologia , Neuralgia Pós-Herpética/tratamento farmacológico , Neuralgia Pós-Herpética/epidemiologia , Pregabalina/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto
14.
Neurosci Lett ; 796: 137064, 2023 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-36638955

RESUMO

Neuropathic pain has become a global public problem and health burden. Pharmacological interventions are the primary treatment, but the drug cure rate is low with side effects. There is an urgent need to develop novel treatment approaches. High frequency electrical stimulation (KHES) has been widely applied in clinical analgesia. However, its mechanism is poorly understood. In this study, datasets related to neuropathic pain were obtained from the GEO database. The differentially expressed genes (DEGs) and key genes were analyzed through functional enrichment analysis, showing that most of the pathways involve the inflammation. The MyD88 and NFκB pathways were further studied. KHES significantly alleviated mechanical and thermal allodynia in chronic constriction injury of the sciatic nerve mice. KHES also inhibited the increase in Myd88 and p-NFκB expression. The administration of NFκB pathway activator partly reversed the antinociceptive effects of KHES, and NFκB pathway inhibitor achieved analgesic effects similar to those of KHES. Therefore, KHES might be a novel intervention for the treatment of neuropathic pain.


Assuntos
Hiperalgesia , Neuralgia , Ratos , Camundongos , Animais , Hiperalgesia/tratamento farmacológico , Fator 88 de Diferenciação Mieloide/metabolismo , Ratos Sprague-Dawley , Constrição , Nervo Isquiático/lesões , Neuralgia/metabolismo , NF-kappa B/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo
15.
Annu Rev Pharmacol Toxicol ; 63: 565-583, 2023 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-36662582

RESUMO

The study of chronic pain continues to generate ever-increasing numbers of publications, but safe and efficacious treatments for chronic pain remain elusive. Recognition of sex-specific mechanisms underlying chronic pain has resulted in a surge of studies that include both sexes. A predominant focus has been on identifying sex differences, yet many newly identified cellular mechanisms and alterations in gene expression are conserved between the sexes. Here we review sex differences and similarities in cellular and molecular signals that drive the generation and resolution of neuropathic pain. The mix of differences and similarities reflects degeneracy in peripheral and central signaling processes by which neurons, immune cells, and glia codependently drive pain hypersensitivity. Recent findings identifying critical signaling nodes foreshadow the development of rationally designed, broadly applicable analgesic strategies. However, the paucity of effective, safe pain treatments compels targeted therapies as well to increase therapeutic options that help reduce the global burden of suffering.


Assuntos
Dor Crônica , Neuralgia , Feminino , Humanos , Masculino , Dor Crônica/tratamento farmacológico , Caracteres Sexuais , Neuralgia/tratamento farmacológico , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Neurônios
16.
PLoS One ; 18(1): e0280425, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36662897

RESUMO

microRNAs (miRNAs) are extracellularly released by cells for intercellular communication, while intracellularly, they inhibit the expression of specific genes. An increasing number of studies suggest that extracellular miRNAs have great potential as both therapeutic targets and disease-specific biomarkers in a variety of diseases, including pain disorders. However, little is known about miRNA release from dorsal root ganglion (DRG) neurons in neuropathic pain caused by peripheral nerve injury. In this study, we investigated the changes in the extracellular release of miRNAs from DRG neurons in a rat model of neuropathic pain induced by chronic constriction injury of the sciatic nerve. We found increased release of six miRNAs (let-7d, miR-21, miR-142-3p, miR-146b, miR-203-3p and miR-221) from primary cultured DRG neurons prepared from rats 7 days after nerve injury. Among these, miR-221 was also increased in serum from days 7 to 28 after nerve injury. In contrast, serum miR-221 levels and its release from DRG neurons were unchanged in an inflammatory pain model produced by intraplantar injection of complete Freund's adjuvant. These results suggest that the increased release of specific miRNAs by DRG neurons may be involved in the pathophysiology of neuropathic pain through extracellular as well as intracellular mechanisms. Furthermore, serum miR-221 may be useful as a biomarker of neuropathic pain caused by peripheral nerve injury.


Assuntos
MicroRNAs , Neuralgia , Traumatismos dos Nervos Periféricos , Ratos , Animais , Gânglios Espinais/metabolismo , Traumatismos dos Nervos Periféricos/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Neuralgia/etiologia , Nervo Isquiático/lesões
17.
Cells ; 12(2)2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36672219

RESUMO

Drugs enhancing the availability of noradrenaline are gaining prominence in the therapy of chronic neuropathic pain. However, underlying mechanisms are not well understood, and research has thus far focused on α2-adrenergic receptors and neuronal excitability. Adrenergic receptors are also expressed on glial cells, but their roles toward antinociception are not well deciphered. This study addresses the contribution of ß2-adrenergic receptors (ß2-ARs) to the therapeutic modulation of neuropathic pain in mice. We report that selective activation of ß2-ARs with Formoterol inhibits pro-inflammatory signaling in microglia ex vivo and nerve injury-induced structural remodeling and functional activation of microglia in vivo. Systemic delivery of Formoterol inhibits behaviors related to neuropathic pain, such as mechanical hypersensitivity, cold allodynia as well as the aversive component of pain, and reverses chronically established neuropathic pain. Using conditional gene targeting for microglia-specific deletion of ß2-ARs, we demonstrate that the anti-allodynic effects of Formoterol are primarily mediated by microglia. Although Formoterol also reduces astrogliosis at late stages of neuropathic pain, these functions are unrelated to ß2-AR signaling in microglia. Our results underline the value of developing microglial ß2-AR agonists for relief from neuropathic pain and clarify mechanistic underpinnings.


Assuntos
Microglia , Neuralgia , Camundongos , Animais , Neuralgia/tratamento farmacológico , Hiperalgesia/tratamento farmacológico , Receptores Adrenérgicos , Fumarato de Formoterol/farmacologia , Fumarato de Formoterol/uso terapêutico
18.
Int J Mol Sci ; 24(2)2023 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-36674724

RESUMO

The GTP cyclohydrolase 1 enzyme (GTPCH1) is the rate-limiting enzyme of the tetrahydrobiopterin (BH4) biosynthetic pathway. Physiologically, BH4 plays a crucial role as an essential cofactor for the production of catecholamine neurotransmitters, including epinephrine, norepinephrine and dopamine, as well as the gaseous signaling molecule, nitric oxide. Pathological levels of the cofactor have been reported in a number of disease states, such as inflammatory conditions, neuropathic pain and cancer. Targeting the GTPCH1 enzyme has great potential in the management of a number of disease pathologies associated with dysregulated BH4 physiology. This study is an in silico investigation of the human GTPCH1 enzyme using virtual screening and molecular dynamic simulation to identify molecules that can be repurposed to therapeutically target the enzyme. A three-tier molecular docking protocol was employed in the virtual screening of a comprehensive library of over 7000 approved medications and nutraceuticals in order to identify hit compounds capable of binding to the GTPCH1 binding pocket with the highest affinity. Hit compounds were further verified by molecular dynamic simulation studies to provide a detailed insight regarding the stability and nature of the binding interaction. In this study, we identify a number of drugs and natural compounds with recognized anti-inflammatory, analgesic and cytotoxic effects, including the aminosalicylate olsalazine, the antiepileptic phenytoin catechol, and the phlorotannins phlorofucofuroeckol and eckol. Our results suggest that the therapeutic and clinical effects of hit compounds may be partially attributed to the inhibition of the GTPCH1 enzyme. Notably, this study offers an understanding of the off-target effects of a number of compounds and advocates the potential role of aminosalicylates in the regulation of BH4 production in inflammatory disease states. It highlights an in silico drug repurposing approach to identify a potential means of safely targeting the BH4 biosynthetic pathway using established therapeutic agents.


Assuntos
GTP Cicloidrolase , Neuralgia , Humanos , GTP Cicloidrolase/genética , GTP Cicloidrolase/química , Biopterina/farmacologia , Reposicionamento de Medicamentos , Simulação de Acoplamento Molecular , Neuralgia/metabolismo , Óxido Nítrico/metabolismo
19.
Int J Mol Sci ; 24(2)2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36675275

RESUMO

Central neuropathic pain is not only characterized by reflexive pain responses, but also emotional or affective nonreflexive pain responses, especially in women. Some pieces of evidence suggest that the activation of the neuroimmune system may be contributing to the manifestation of mood disorders in patients with chronic pain conditions, but the mechanisms that contribute to the development and chronicity of CNP and its associated disorders remain poorly understood. This study aimed to determine whether neuroinflammatory factor over-expression in the spinal cord and supraspinal structures may be associated with reflexive and nonreflexive pain response development from acute SCI phase to 12 weeks post-injury in female mice. The results show that transient reflexive responses were observed during the SCI acute phase associated with transient cytokine overexpression in the spinal cord. In contrast, increased nonreflexive pain responses were observed in the chronic phase associated with cytokine overexpression in supraspinal structures, especially in mPFC. In addition, results revealed that besides cytokines, the mPFC showed an increased glial activation as well as CX3CL1/CX3CR1 upregulation in the neurons, suggesting the contribution of neuron-glia crosstalk in the development of nonreflexive pain responses in the chronic spinal cord injury phase.


Assuntos
Neuralgia , Traumatismos da Medula Espinal , Feminino , Camundongos , Animais , Doenças Neuroinflamatórias , Medula Espinal , Neuralgia/complicações , Neuroglia , Traumatismos da Medula Espinal/complicações
20.
J Ethnopharmacol ; 305: 116065, 2023 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-36587876

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Neuropathic pain can be debilitating and drastically affects the quality of life of those patients suffering from this condition. The Chinese herb Notopterygium incisum Ting ex H.T. Chang has long been used to disperse "cold". One under examined clinical feature of neuropathic pain is sensitivity to cold. Patients with neuropathic pain or arthritis usually describe a worsening of symptoms during the winter. AIMS OF THIS STUDY: We proposed to test the hypothesis that Notopterygium incisum has a positive effect on the cold sensitivity found in neuropathic pain. MATERIALS AND METHODS: In this study, we established chronic constriction injury (CCI) and cisplatin induced neuropathic pain mice models. Behavioral experiments and physiological examination methods were employed to investigate the effect of water extract of Notopterygium incisum (WN) on cold pain. RESULTS: We found WN reduced cold pain and allyl isothiocyanate (AITC, Transient Receptor Potential A1 (TRPA1 agonist)) induced pain. WN inhibited AITC induced calcium response in HEK 293 cells transfected with TRPA1 and dorsal root ganglion (DRG) neurons. Moreover, we found that oral administration of WN reduced cold allodynia and mechanical allodynia caused by (CCI) and cisplatin induced neuropathic pain. We also observed that oral administration of WN decreased responses to AITC in DRG neurons as well as expression of TRPA1 in the WN treated neuropathic pain model. CONCLUSIONS: The present study provide evidence that Notopterygium incisum alleviates cold allodynia in CCI and cisplatin induced neuropathic pain mouse models. WN alleviated neuropathic pain induced cold allodynia via directly modulating TRPA1. Our findings identify WN as a promising candidate for treating neuropathic pain that highlights a new mechanism of Notopterygium incisum on 'disperse cold'.


Assuntos
Hiperalgesia , Neuralgia , Camundongos , Humanos , Animais , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Cisplatino , Células HEK293 , Qualidade de Vida , Canal de Cátion TRPA1/metabolismo , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Gânglios Espinais/metabolismo
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