In-Silico Validation and Fabrication of Matrix Diffusion-Based Polymeric Transdermal Patches for Repurposing Gabapentin Hydrochloride in Neuropathic Pain
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Background: Gabapentin (GBP) is an FDA-approved drug for the treatment of partial and secondary generalized seizures, apart from being used for diabetic neuropathic pain. GBP displays a highly intricate mechanism of action and its inhibitory response in elevated antagonism of NMDA (N-methyl-D-aspartate receptor) receptor and thus, can be repurposed for controlling neuropathic pain. Objective: Therefore, in the present study, we have selected hBCATc (humanPyridoxal 5’-phosphate- dependent branched-chain aminotransferase cytosolic) gene that is highly expressed in silico validation through neuropathic stressed conditions. Thereafter, have analysed the GBP as its competitive inhibitor by in silico validation through homology modelling, molecular docking, also predicting its structural alerts and pharmacokinetic suitability through ADMET. However, and GBP was found to be a potential drug in controlling neuropathic pain, still, it has certain critical and pharmacokinetic limitations; therefore, the need for its targeted delivery was required, and the same was attained by designing a GBP loaded transdermal patch (GBP-TDP). Methods: A suitable and equally efficacious GBP - TDP was developed by a solvent evaporation method using PVP and HPMC in the ratio of 2:1 as a polymer base for reservoir type of TDP. Also, PEG 400 was used as a plasticizer, and PVA (4%) was taken for backing membrane preparation, and then the optimized GBP-TDP was subjected for physical characterization, optimization and ex vivo release kinetics. Results: The results showed desired specifications with uneven and flaky surface appearance giving an avenue for controlled release of the drugs with 92.34 ± 1.43% of drug release in 10 hours, further suggesting that GBP-TDP can be used as an effective tool against diabetic neuropathy pain. Conclusion: In this study, we have repurposed Gabapentin to treat diabetic neuropathy and validated the same by conducting a detailed in silico evaluation starting from homology Modelling of the target protein hBCATc, cross verified by the Ramachandran plot analysis with the most favoured region of 92.1% (encompassing 303 residues out of 386).Abstract Gabapentin is an anticonvulsant that successfully treats many neuropathic pain syndromes, although the mechanism of its antihyperalgesic action remains elusive. This study aims to help delineate gabapentin's antihyperalgesic mechanisms. We assessed the effectiveness of gabapentin at decreasing mechanical and cold hypersensitivity induced in a rat model of neuropathic pain. Thus, we compared the effectiveness of pre‐ or post‐treatment with systemic or intrathecal (i.t.) gabapentin at reducing the development and maintenance of the neuropathic pain symptoms. Gabapentin successfully decreased mechanical and cold hypersensitivity, both as a pretreatment and post‐treatment. Furthermore, both i.t. and systemic administration of gabapentin were effective in reducing the behavioral hypersensitivity; however, the i.t. administration was superior to the systemic. We also examined gabapentin's effects at inhibiting hindpaw formalin‐induced release of excitatory amino acids (EAAs) in the spinal cord dorsal horn (SCDH) both in naïve rats and in rats with neuropathic pain. We present the first evidence that gabapentin reduces the formalin‐induced release of both glutamate and aspartate in SCDH. Furthermore, i.t. gabapentin reduces the enhanced noxious stimulus‐induced spinal release of glutamate seen in neuropathic rats. These data suggest that gabapentin reduces neuropathic pain symptoms by inhibiting the release of glutamate in the SCDH.
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Aim: In the present study, we aimed to systematically evaluate the effects of gabapentin and pregabalin, which are believed to be safe and well-tolerated and have analgesic, anticonvulsant, and anxiolytic effects, in the treatment of neuropathic pain after spinal cord injury despite their high side effect profiles.Material and Methods: A literature search of numerous electronic databases was performed. A combination of key words was used to retrieve studies published until November 1, 2018 correlated with the point of interest. The key words used were as follows: “spinal cord injury,” “neuropathic pain,” “gabapentin,” and “pregabalin.” Studies that met the inclusion criteria and were Level of I clinical trials were included in the study. The included studies were statistically evaluated. Results: In total, 125,515 publications were retrieved using the aforementioned key words. 19 studies on the use of gabapentin and pregabalin for the treatment of neuropathic pain associated with spinal cord injury were retrieved through. Conclusion: Studies suggested that available treatment modalities did not provide satisfactory outcomes for patients with neuropathic pain related to spinal cord injury. However, gabapentin and pregabalin were preferred as the first-line drugs in the treatment of neuropathic pain. The efficacy of gabapentin in the treatment of neuropathic pain after spinal cord injury has only been investigated in a few recent studies; data in these studies are not sufficiently clear and will need further clarification.
Pregabalin
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Common causes of neuropathic pain are diabetes and herpes zoster, with 15% of patients with long-standing diabetes and 11% of herpes patients suffering from this pain. Gabapentin and pregabalin modulate the α2δ calcium-channel subunits, possibly decreasing the neurotransmitter release associated with the central sensitisation that occurs in neuropathic pain. Gabapentin has been shown to be effective in neuropathic pain and, recently, so has pregabalin. These agents seem to have similar efficacy when used alone, but this needs to be tested in a head-to-head trial. A clinical trial comparing morphine, gabapentin or their combination at lower doses showed that the combination of morphine and gabapentin reduced the pain score to a greater extent than either agent alone. This combination treatment represents a novel approach to neuropathic pain.
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We report and discuss a case of severe neuropathic orbital pain refractory to standard analgesics that responded well to treatment with the anticonvulsant gabapentin. Gabapentin may be a useful adjuvant analgesic in the treatment of neuropathic pain.
Refractory (planetary science)
Pregabalin
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Gabapentin is an antiepileptic drug prescribed for several neuropathic pain conditions. This study aimed to evaluate gabapentin (GAB) trough plasma concentration range and the applicability of therapeutic drug monitoring in patients with neuropathic pain. Fifty-three patients with neuropathic pain, aged 20 to 75, received gabapentin as treatment for at least 7 days. Gabapentin plasma concentration was sampled before GAB administration and quantified by liquid chromatography with a UV detector. GAB trough plasma concentration ranged between 0.40 and 11.94 µg/mL in patients with chronic neuropathic pain. No differences were observed in terms of GAB plasma concentrations between responsive and non-responsive patients. Our data suggest that the reference ranges suggested in the literature for patients with epilepsy should not be used for patients with neuropathic pain. Therapeutic drug monitoring of GAB was shown to be an important tool to assess treatment adherence.
Therapeutic Drug Monitoring
Therapeutic effect
Pregabalin
Therapeutic index
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This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the analgesic efficacy of gabapentin for chronic neuropathic pain. To assess the adverse effects associated with the clinical use of gabapentin for chronic neuropathic pain.
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OBJECTIVE: To evaluate the role of gabapentin for the treatment of neuropathic pain. DATA SOURCES: Clinical literature was identified through MEDLINE (from 1990 to October 1999). Key search terms were gabapentin and pain. DATA SYNTHESIS: Neuropathic pain can be a problematic, chronic syndrome that is frequently refractory to current drug treatments. Gabapentin is a newer generation antiepileptic drug that is commonly used in treatment of neuropathic pain. An evaluation of clinical trials using gabapentin to treat neuropathic pain was performed. CONCLUSIONS: Gabapentin appears to be effective in treating various neuropathic pain disorders. Gabapentin may have advantages over current therapies, such as a favorable safety profile and lack of drug interactions; however, cost issues and limited experience may limit the use of gabapentin as a first-line option.
Pregabalin
Refractory (planetary science)
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AbstractWe report and discuss a case of severe neuropathic orbital pain refractory to standard analgesics that responded well to treatment with the anticonvulsant gabapentin. Gabapentin may be a useful adjuvant analgesic in the treatment of neuropathic pain.Key Words: Gabapentinneuropathicorbitalpain Additional informationNotes on contributorsPaul A. SloanCherokee Layson-Wolf, PharmD, is Assistant Professor at the University of Maryland School of Pharmacy. At the time that this review was conducted, she was a Community Care Pharmacy Practice Resident at Virginia Commonwealth University.Perry G. Fine, MD, is Professor of Anesthesiology, School of Medicine and Associate Medical Director, Pain Management Center at the University of Utah Health Sciences Center, Salt Lake City; and National Medical Director, VistaCare, based in Scottsdale, AZ. This commentary is based on an article in Dr. Fine's VistaCare Palliative Medicine Monitor.Jonathan R. Gavrin, MD, is the Internet editor for the Journal. He is Associate Professor of Anesthesiology and Adjunct Associate Professor of Medicine at the University of Washington School of Medicine; Associate Member, Fred Hutchinson Cancer Research Center; and Associate Director for Clinical Anesthesia Services, Harborview Medical Center.Philip J. Wiffen, is the Regional Pharmaceutical and Prescribing Adviser, Anglia & Oxford Region of the National Health Service Executive, a member of the Oxford Regional Pain Relief Unit and Coordinating Editor of the Cochrane Collaboration Pain Palliative and Supportive Care Collaborative Review Group.Philip J. Wiffen, BPharm, MRPharmS, MFPHM (Hon) is Regional Pharmaceutical and Prescribing Adviser, Anglia & Oxford Region of the National Health Service Executive, a member of the Pain Relief Unit, Churchill Hospital, and Coordinating Editor, Cochrane Collaboration Pain Palliative and Supportive Care Collaborative Review Group.Howard A. Heit, practices pain medicine and addiction medicine in Fairfax, Virginia, and is Assistant Clinical Professor of Medicine at Georgetown University, Washington, DC. Dr. Heit was a member of the Liaison Committee on Pain and Addiction.Philip J. Wiffen, is Regional Pharmaceutical and Prescribing Adviser, Anglia & Oxford Region of the National Health Service, a member of the Pain Relief Unit at Churchill Hospital and Coordinating Editor of the Cochrane Collaboration Pain Palliative and Supportive Care Collaborative Review Group.
Pain medicine
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Since conventional analgesics have showed limited therapertic value in the treatment of painful neuropathy, the new anticonvulsant gabapentin, has been tried and turned out to be effective and safe in the treatment for various forms of neuropathic pain. The basic pathophysiology of neuropathic pains is abnormal neuronal hyperactivity similar to epileptic seizures. Therefore, we could expect that neuropathic pain would be suppressed by anticonvulsants which inhibit abnormal excessive neuronal output and nerve conduction. This report include effective pain relief in four cases of neuropathic pain with gabapentin without any significant complications.
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