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Valadez-Lemus RE, Góngora-Alfaro JL, Jiménez-Vargas JM, Alamilla J, Mendoza-Muñoz N. Nanoencapsulation of amitriptyline enhances the potency of antidepressant-like effects and exhibits anxiolytic-like effects in Wistar rats. PLoS One 2025; 20:e0316389. [PMID: 40019891 PMCID: PMC11870345 DOI: 10.1371/journal.pone.0316389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Accepted: 12/10/2024] [Indexed: 03/03/2025] Open
Abstract
Depression poses a significant global health challenge, affecting an estimated 300 million people worldwide. While amitriptyline (Ami) remains one of the most effective antidepressants, its numerous side-effects contribute to a high dropout rate among patients. Addressing this issue requires exploring methods to enhance its bioavailability and reduce dosage. In this study, we describe a technique for producing amitriptyline nanoparticles (Ami-NPs) to improve the drug's efficiency. The effectiveness was assessed by comparing the dose-response curves of Ami-NPs and non-encapsulated Ami in male and female Wistar rats subjected to the forced swimming test (FST). Ami-NPs were fabricated using nanoprecipitation, with a copolymer of poly (methyl vinyl ether/maleic acid) as the encapsulant, and a 3% solution of poloxamer F-127 as surfactant stabilizer. A Box-Behnken design was used to optimize the production of Ami-NPs, resulting in nanoparticles with the following optimal characteristics: a size of 198.6 ± 38.1 nm, a polydispersity index of 0.005 ± 0.03 nm, a zeta potential of -32 ± 6 mV, and encapsulation efficiency of 79.1 ± 7.4%. Ami-NPs showed higher potency and efficacy in reducing immobility during the FST (ED50 = 7.06 mg/kg, Emax = 41.1%), compared to amitriptyline in solution (Ami-S) (ED50 = 11.89 mg/kg, Emax = 33.2%). The Emax of Ami-NPs occurred at 12 mg/kg, while Ami-S peaked at 15.8 mg/kg. In the open field test, only treatment with Ami-NPs (12 mg/kg) and the empty nanoparticles increased immobility. In the elevated plus-maze, treatment with Ami-NPs (12 mg/kg) significantly reduced closed-arm entries (2.1 ± 0.6), compared to control solution (9.5 ± 1.8), control nanoparticles (8 ± 1.0) and Ami-S (11.5 ± 2). In the marble burying test, Ami-NPs (12 mg/kg) significantly reduced buried marbles (2.4 ± 0.4) compared to control nanoparticles (8.7 ± 1.2). These findings suggest that Ami-NPs could be a promising approach to enhance Ami bioavailability, thereby increasing its potency and antidepressant efficacy, while improving anxiolytic-like effects.
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Affiliation(s)
| | - José L. Góngora-Alfaro
- Centro de Investigaciones Regionales “Dr. Hideyo Noguchi”, Universidad Autónoma de Yucatán, Yucatán, México
| | - Juana María Jiménez-Vargas
- Facultad de Ciencias Químicas, Universidad de Colima, Colima, México
- Consejo Nacional de Humanidades Ciencia y Tecnología (CONAHCYT), México City, México
| | - Javier Alamilla
- Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima, México
- Investigador por México-CONAHCYT-Universidad de Colima, Colima, México
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Rosner J, Attal N, Finnerup NB. Clinical pharmacology of neuropathic pain. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2024; 179:403-430. [PMID: 39580218 DOI: 10.1016/bs.irn.2024.10.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/25/2024]
Abstract
This chapter aims to review the current pharmacological options for neuropathic pain treatment, their mechanisms of action, and future directions for clinical practice. Achieving pain relief in neuropathic pain conditions remains a challenge in clinical practice. The field of pharmacotherapy for neuropathic pain has encountered significant difficulties in translating substantial advances in our understanding of the underlying pathophysiological mechanisms into clinically effective therapies. This chapter presents the drugs recommended for the pharmacotherapy of neuropathic pain, based on the widely accepted treatment guidelines formulated by the Neuropathic Pain Special Interest Group of the International Association for the Study of Pain. In addition to discussing how the evidence base is created as part of international consortia, the drugs are also examined in terms of their putative molecular mechanisms as well as pharmacological pleiotropy, i.e., their potential unspecific and multi-target effects resulting in modulation of neuronal hyperexcitability. The chapter closes with a discussion of potential future developments in the field.
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Affiliation(s)
- Jan Rosner
- Danish Pain Research Center, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Spinal Cord Injury Center, Balgrist University Hospital, University of Zurich, Zurich, Switzerland.
| | - Nadine Attal
- Inserm U987, APHP, CHU Ambroise Pare, UVSQ, Paris-Saclay University, Boulogne-Billancourt, France
| | - Nanna B Finnerup
- Danish Pain Research Center, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Neurology, Aarhus University Hospital, Aarhus, Denmark
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Sajedi F, Abdi A, Mehrpooya M, Faramarzi V, Mohammadi Y, Sheida F. Comparison of therapeutic effects of N-Acetylcysteine with pregabalin in improving the clinical symptoms of painful diabetic neuropathy: a randomized, double-blind clinical trial. Clin Diabetes Endocrinol 2024; 10:15. [PMID: 38641841 PMCID: PMC11031970 DOI: 10.1186/s40842-024-00172-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 01/31/2024] [Indexed: 04/21/2024] Open
Abstract
OBJECTIVES Painful diabetic neuropathy (PDN) is highly prevalent and annoyingly in patients with diabetes. The aim of this study was to investigate the effects of oral N-acetylcysteine (NAC) compared to pregabalin in PDN. METHODS One hundred two eligible patients with type 2 diabetes and PDN were randomly recievied pregabalin (150 mg/day) or N-Acetylcysteine (NAC) (600 mg/ twice a day) for 8 weeks. Mean pain score, Sleep interference score (SIS), Patient Global Impression of Change (PGIC), Clinical Global Impression of Change (CGIC), and also, serum levels of total antioxidant capacity (TAC), total thiol groups (TTG), catalase activity (CAT), nitric oxide (NO), and malondialdehyde (MDA) were assessed at baseline and at the end of the study. RESULTS NAC was well tolerated in all patients. The decrease in mean pain scores and increase in SIS was similar between two groups. More improvement in PGIC and CGIC from the baseline was reported in NAC group. NAC, significantly, decreased serum levels of MDA, and NO, but increased TAC, TTG, and CAT. Pregabalin, significantly, decreased serum levels of MDA, and NO and increased TAC. DISCUSSION NAC is efficacious in alleviate symptoms of PDN which is probably related to its antioxidant effects. TRIAL REGISTRATION The research protocol received approval from the Ethics Committee of Hamadan University of Medical Sciences (IR.UMSHA.REC.1397.137). The trial registry URL and number in Iranian Registry of Clinical Trials (IRCT): https://www.irct.ir/trial/33313 , IRCT20180814040795N2 (Registration date: 2019-01-21, Retrospectively registered).
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Affiliation(s)
- Firozeh Sajedi
- Department of Internal Medicine, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran.
| | - Arman Abdi
- Department of Internal Medicine, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Maryam Mehrpooya
- Department of Clinical Pharmacy, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Vida Faramarzi
- Department of Internal Medicine, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Younes Mohammadi
- Modeling of Noncommunicable Diseases Research Center, School of Public Health, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Fateme Sheida
- Cancer Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
- Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran
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Bonomo R, Bonomo G, Rubiu E, Iess G, Cammarata G, Innocenti N, Restelli F, Falco J, Porto E, Amato A, Zekaj E, Levi V. Integrative approaches in spinal cord stimulation: Neuropathic pain management and motor recovery in spinal cord injury. A narrative review. BRAIN & SPINE 2024; 4:102781. [PMID: 38601775 PMCID: PMC11004705 DOI: 10.1016/j.bas.2024.102781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 02/08/2024] [Accepted: 03/01/2024] [Indexed: 04/12/2024]
Abstract
Introduction Spinal cord stimulation is a widespread treatment of chronic neuropathic pain from different conditions. Several novel and improving technologies have been recently developed to increase the effect of neuromodulation in patients refractory to pharmacological therapy. Research question To explore spinal cord stimulation's mechanisms of action, indications, and management. Material and methods The paper initially explores the mechanism of action of this procedure based on the generation of an electric field between electrodes placed on the posterior dural surface of the spinal cord probably interfering with the transmission of pain stimuli to the brain. Subsequently, the most consolidated criteria for selecting patients for surgery, which constitute a major issue of debate, were defined. Thereafter, the fundamental patterns of stimulation were summarized by exploring the advantages and side effects. Lastly, the most common side effects and the related management were discussed. Results Proper selection of the patient is of paramount importance to achieve the best results from this specific neuromodulation treatment. Regarding the different types of stimulation patterns, no definite evidence-based guidelines exist on the most appropriate approach in relation to the specific type of neuropathic pain. Both burst stimulation and high-frequency stimulation are innovative techniques that reduce the risk of paresthesias compared with conventional stimulation. Discussion and conclusion Novel protocols of stimulation (burst stimulation and high frequency stimulation) may improve the trade-off between therapeutic benefits and potential side effects. Likewise, decreasing the rates of hardware-related complications will be also useful to increase the application of neuromodulation in clinical settings.
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Affiliation(s)
- Roberta Bonomo
- Department of Neurology, Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy
- School of Medicine and Surgery, Kore University of Enna, Enna, Italy
| | - Giulio Bonomo
- Functional Neurosurgery Unit, Department of Neurosurgery, Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy
- Department of Neurological Surgery, Policlinico “G. Rodolico-S. Marco” University Hospital, Catania, Italy
| | - Emanuele Rubiu
- Functional Neurosurgery Unit, Department of Neurosurgery, Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy
| | - Guglielmo Iess
- Functional Neurosurgery Unit, Department of Neurosurgery, Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy
| | - Giacomo Cammarata
- Department of Neurological Surgery, Policlinico “G. Rodolico-S. Marco” University Hospital, Catania, Italy
| | - Niccolò Innocenti
- Functional Neurosurgery Unit, Department of Neurosurgery, Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy
| | - Francesco Restelli
- Functional Neurosurgery Unit, Department of Neurosurgery, Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy
| | - Jacopo Falco
- Functional Neurosurgery Unit, Department of Neurosurgery, Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy
| | - Edoardo Porto
- Functional Neurosurgery Unit, Department of Neurosurgery, Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy
| | - Alessia Amato
- Department of Child Neuropsychiatry, Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy
| | - Edvin Zekaj
- Department of Neurosurgery, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
| | - Vincenzo Levi
- Functional Neurosurgery Unit, Department of Neurosurgery, Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy
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Mallick-Searle T, Adler JA. Update on Treating Painful Diabetic Peripheral Neuropathy: A Review of Current US Guidelines with a Focus on the Most Recently Approved Management Options. J Pain Res 2024; 17:1005-1028. [PMID: 38505500 PMCID: PMC10949339 DOI: 10.2147/jpr.s442595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Accepted: 02/26/2024] [Indexed: 03/21/2024] Open
Abstract
Painful diabetic peripheral neuropathy (DPN) is a highly prevalent and disabling complication of diabetes that is often misdiagnosed and undertreated. The management of painful DPN involves treating its underlying cause via lifestyle modifications and intensive glucose control, targeting its pathogenesis, and providing symptomatic pain relief, thereby improving patient function and health-related quality of life. Four pharmacologic options are currently approved by the US Food and Drug Administration (FDA) to treat painful DPN. These include three oral medications (duloxetine, pregabalin, and tapentadol extended release) and one topical agent (capsaicin 8% topical system). More recently, the FDA approved several spinal cord stimulation (SCS) devices to treat refractory painful DPN. Although not FDA-approved specifically to treat painful DPN, tricyclic antidepressants, serotonin/norepinephrine reuptake inhibitors, gabapentinoids, and sodium channel blockers are common first-line oral options in clinical practice. Other strategies may be used as part of individualized comprehensive pain management plans. This article provides an overview of the most recent US guidelines for managing painful DPN, with a focus on the two most recently approved treatment options (SCS and capsaicin 8% topical system), as well as evidence for using FDA-approved and guideline-supported drugs and devices. Also discussed are unmet needs for this patient population, and evidence for potential future treatments for painful DPN, including drugs with novel mechanisms of action, electrical stimulation devices, and nutraceuticals.
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Hashim M, Badruddeen, Akhtar J, Khan MI, Ahmad M, Islam A, Ahmad A. Diabetic Neuropathy: An Overview of Molecular Pathways and Protective Mechanisms of Phytobioactives. Endocr Metab Immune Disord Drug Targets 2024; 24:758-776. [PMID: 37867264 DOI: 10.2174/0118715303266444231008143430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 07/31/2023] [Accepted: 08/25/2023] [Indexed: 10/24/2023]
Abstract
Diabetic neuropathy (DN) is a common and debilitating complication of diabetes mellitus that affects the peripheral nerves and causes pain, numbness, and impaired function. The pathogenesis of DN involves multiple molecular mechanisms, such as oxidative stress, inflammation, and pathways of advanced glycation end products, polyol, hexosamine, and protein kinase C. Phytochemicals are natural compounds derived from plants that have various biological activities and therapeutic potential. Flavonoids, terpenes, alkaloids, stilbenes, and tannins are some of the phytochemicals that have been identified as having protective potential for diabetic neuropathy. These compounds can modulate various cellular pathways involved in the development and progression of neuropathy, including reducing oxidative stress and inflammation and promoting nerve growth and repair. In this review, the current evidence on the effects of phytochemicals on DN by focusing on five major classes, flavonoids, terpenes, alkaloids, stilbenes, and tannins, are summarized. This compilation also discusses the possible molecular targets of numerous pathways of DN that these phytochemicals modulate. These phytochemicals may offer a promising alternative or complementary approach to conventional drugs for DN management by modulating multiple pathological pathways and restoring nerve function.
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Affiliation(s)
- Mohd Hashim
- Faculty of Pharmacy, Integral University, Lucknow, Uttar Pradesh, India
| | - Badruddeen
- Faculty of Pharmacy, Integral University, Lucknow, Uttar Pradesh, India
| | - Juber Akhtar
- Faculty of Pharmacy, Integral University, Lucknow, Uttar Pradesh, India
| | | | - Mohammad Ahmad
- Faculty of Pharmacy, Integral University, Lucknow, Uttar Pradesh, India
| | - Anas Islam
- Faculty of Pharmacy, Integral University, Lucknow, Uttar Pradesh, India
| | - Asad Ahmad
- Faculty of Pharmacy, Integral University, Lucknow, Uttar Pradesh, India
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Tavakoli M, Klingelhöfer D, Fadavi H, Groneberg DA. The landscape of global research on diabetic neuropathy. Front Endocrinol (Lausanne) 2023; 14:1220896. [PMID: 38034004 PMCID: PMC10686065 DOI: 10.3389/fendo.2023.1220896] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 08/03/2023] [Indexed: 12/02/2023] Open
Abstract
Introduction Diabetic neuropathy (DN) is a prevalent and debilitating complication of diabetes, imposing a significant burden on individuals and healthcare systems worldwide. This study presents a comprehensive analysis of the global research landscape in DN, aiming to provide scientists, funders, and decision-makers with valuable insights into the current state of research and future directions. Methods Through a systematic review of published articles, key trends in DN research, including epidemiology, diagnosis, treatment strategies, and gaps in knowledge, are identified and discussed. Results The analysis reveals an increasing prevalence of DN alongside the rising incidence of diabetes, emphasizing the urgent need for effective prevention and management strategies. Furthermore, the study highlights the geographical imbalance in research activity, with a majority of studies originating from high-income countries. Discussion This study underscores the importance of fostering international collaboration to address the global impact of DN. Key challenges and limitations in DN research are also discussed, including the need for standardized diagnostic criteria, reliable biomarkers, and innovative treatment approaches. By addressing these gaps, promoting collaboration, and increasing research funding, we can pave the way for advancements in DN research and ultimately improve the lives of individuals affected by this debilitating condition.
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Affiliation(s)
- Mitra Tavakoli
- Exeter Centre of Excellence for Diabetes Research, National Institute for Health and Care Research (NIHR), University of Exeter Medical School, Exeter, United Kingdom
| | - Doris Klingelhöfer
- Institute of Occupational, Social and Environmental Medicine, Goethe University Frankfurt, Frankfurt, Germany
| | - Hassan Fadavi
- Exeter Centre of Excellence for Diabetes Research, National Institute for Health and Care Research (NIHR), University of Exeter Medical School, Exeter, United Kingdom
| | - David A. Groneberg
- Institute of Occupational, Social and Environmental Medicine, Goethe University Frankfurt, Frankfurt, Germany
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8
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Jang HN, Oh TJ. Pharmacological and Nonpharmacological Treatments for Painful Diabetic Peripheral Neuropathy. Diabetes Metab J 2023; 47:743-756. [PMID: 37670573 PMCID: PMC10695723 DOI: 10.4093/dmj.2023.0018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 06/28/2023] [Indexed: 09/07/2023] Open
Abstract
Diabetic peripheral neuropathy (DPN) is one of the most prevalent chronic complications of diabetes. The lifetime prevalence of DPN is thought to be >50%, and 15%-25% of patients with diabetes experience neuropathic pain, referred to as "painful DPN." Appropriate treatment of painful DPN is important because this pain contributes to a poor quality of life by causing sleep disturbance, anxiety, and depression. The basic principle for the management of painful DPN is to control hyperglycemia and other modifiable risk factors, but these may be insufficient for preventing or improving DPN. Because there is no promising diseasemodifying medication for DPN, the pain itself needs to be managed when treating painful DPN. Drugs for neuropathic pain, such as gabapentinoids, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, alpha-lipoic acid, sodium channel blockers, and topical capsaicin, are used for the management of painful DPN. The U.S. Food and Drug Administration (FDA) has approved pregabalin, duloxetine, tapentadol, and the 8% capsaicin patch as drugs for the treatment of painful DPN. Recently, spinal cord stimulation using electrical stimulation is approved by the FDA for the treatment for painful DPN. This review describes the currently available pharmacological and nonpharmacological treatments for painful DPN.
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Affiliation(s)
- Han Na Jang
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Tae Jung Oh
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
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Patel R. The circuit basis for chronic pain and its comorbidities. Curr Opin Support Palliat Care 2023; 17:156-160. [PMID: 37096597 PMCID: PMC10371057 DOI: 10.1097/spc.0000000000000650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/26/2023]
Abstract
PURPOSE OF REVIEW Chronic pain is poorly treated with many developing disabling comorbidities such as anxiety, depression and insomnia. Considerable evidence supports the idea that pain and anxiodepressive disorders share a common neurobiology and can mutually reinforce, which has significant long-term implications as the development of comorbidities leads to poorer treatment outcomes for both pain and mood disorders. This article will review recent advances in the understanding of the circuit basis for comorbidities in chronic pain. RECENT FINDINGS A growing number of studies have aimed to determine the mechanisms underlying chronic pain and comorbid mood disorders by using modern viral tracing tools for precise circuit manipulation with optogenetics and chemogenetics. These have revealed critical ascending and descending circuits, which advance the understanding of the interconnected pathways that modulate the sensory dimension of pain and the long-term emotional consequences of chronic pain. SUMMARY Comorbid pain and mood disorders can produce circuit-specific maladaptive plasticity; however, several translational issues require addressing to maximise future therapeutic potential. These include the validity of preclinical models, the translatability of endpoints and expanding analysis to the molecular and system levels.
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Wasan AD, Edwards RR, Kraemer KL, Jeong J, Kenney M, Luong K, Cornelius MC, Mickles C, Dharmaraj B, Sharif E, Stoltenberg A, Emerick T, Karp JF, Bair MJ, George SZ, Hooten WM. Back Pain Consortium (BACPAC): Protocol and Pilot Study Results for a Randomized Comparative-Effectiveness Trial of Antidepressants, Fear Avoidance Rehabilitation, or the Combination for Chronic Low Back Pain and Comorbid High Negative Affect. PAIN MEDICINE (MALDEN, MASS.) 2023; 24:S105-S114. [PMID: 36715655 PMCID: PMC10403304 DOI: 10.1093/pm/pnad006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 01/17/2023] [Accepted: 01/19/2023] [Indexed: 01/31/2023]
Abstract
OBJECTIVE Patients with chronic low back pain (CLBP) and comorbid depression or anxiety disorders are highly prevalent. Negative affect (NA) refers to a combination of negative thoughts, emotions, and behaviors. Patients with CLBP with high NA have greater pain, worse treatment outcomes, and greater prescription opioid misuse. We present the protocol for SYNNAPTIC (SYNergizing Negative Affect & Pain Treatment In Chronic pain). DESIGN A randomized comparative-effectiveness study of antidepressants, fear-avoidance rehabilitation, or their combination in 300 patients with CLBP with high NA. In the antidepressant- or rehabilitation-only arms, SYNNAPTIC includes an adaptive design of re-randomization after 4 months for nonresponders. SETTING A multisite trial conducted in routine pain clinical treatment settings: pain clinics and physical and occupational therapy treatment centers. METHODS Inclusion criteria include CLBP with elevated depression and anxiety symptoms. Antidepressant and rehabilitation treatments follow validated and effective protocols for musculoskeletal pain in patients with high NA. Power and sample size are based on superior outcomes of combination therapy with these same treatments in a 71-subject 4-arm pilot randomized controlled trial. CONCLUSIONS SYNNAPTIC addresses the lack of evidence-based protocols for the treatment of the vulnerable subgroup of patients with CLBP and high NA. We hypothesize that combination therapy of antidepressants plus fear-avoidance rehabilitation will be more effective than each treatment alone. TRIAL REGISTRATION ClinicalTrials.gov ID: NCT04747314.
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Affiliation(s)
- Ajay D Wasan
- Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15206, United States
| | - Robert R Edwards
- Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women’s Hospital, Boston, MA 02467, United States
| | - Kevin L Kraemer
- Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, United States
| | - Jong Jeong
- Department of Biostatistics, University of Pittsburgh School of Public Health, Pittsburgh, PA 15261, United States
| | - Megan Kenney
- Department of Occupational Therapy, School of Health and Rehabilitation Sciences, University of Pittsburgh, Pittsburgh, PA 15261, United States
| | - Kevin Luong
- Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15206, United States
| | - Marise C Cornelius
- Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women’s Hospital, Boston, MA 02467, United States
| | - Caitlin Mickles
- Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15206, United States
| | - Bhagya Dharmaraj
- Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15206, United States
| | - Essa Sharif
- Department of Anesthesiology, Mayo Medical School, Rochester, MA 55905, United States
| | - Anita Stoltenberg
- Department of Anesthesiology, Mayo Medical School, Rochester, MA 55905, United States
| | - Trent Emerick
- Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15206, United States
| | - Jordan F Karp
- Department of Psychiatry, University of Arizona College of Medicine, Tucson, AZ 85007, United States
| | - Matt J Bair
- Center for Health Information and Communication (CHIC), Health Services Research & Development (HSRD), Richard L Roudebush Veterans Affairs Medical Center, Indianapolis, IN 46202, United States
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Steven Z George
- Department of Orthopaedics, Duke University, Durham, NC 27710, United States
- Duke Clinical Research Institute, Duke University, Durham, NC 27701, United States
| | - William M Hooten
- Department of Anesthesiology, Mayo Medical School, Rochester, MA 55905, United States
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Pereira CDS, Cruz JN, Ferreira MKM, Baia-da-Silva DC, Fontes-Junior EA, Lima RR. Global Research Trends and Hotspots Analysis of the Scientific Production of Amitriptyline: A Bibliometric Approach. Pharmaceuticals (Basel) 2023; 16:1047. [PMID: 37513958 PMCID: PMC10386017 DOI: 10.3390/ph16071047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 07/18/2023] [Accepted: 07/20/2023] [Indexed: 07/30/2023] Open
Abstract
Amitriptyline was first introduced as a medication to treat depression. Over time, this substance has been used to treat other conditions, such as gastrointestinal disorders, fibromyalgia, neuropathic pain, and analgesia, among others. However, there are no published studies that provide a broad view of the possible motivations that have led to changes in the use of amitriptyline. In this study, we have identified the landscape of use for amitriptyline based on knowledge mapping of the 100 most-cited articles about this drug. We searched Web of Science Core Collection without time and language restrictions. We obtained 14,446 results, but we only used the 100 most-cited articles that had amitriptyline as the object of study. We collected the following information from each article: authors, country of the corresponding authors, year of publication, citation count, citation density (number of citations per year), and keywords. In addition, we seek to map in the chosen articles study design and research findings. We found that since 1980, the use of amitriptyline has expanded beyond depression, moving to off-label use to treat a variety of diseases and conditions, including post-herpetic neuralgia, neuropathic pain, primary fibrosis, fibromyalgia, and migraine, can be considered a drug with more clinical applicability than its original clinical indication.
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Affiliation(s)
- Cristian Dos Santos Pereira
- Laboratory of Functional and Structural Biology, Institute of Biological Sciences, Federal University do Pará, Belém 66075-110, Brazil
| | - Jorddy Neves Cruz
- Laboratory of Functional and Structural Biology, Institute of Biological Sciences, Federal University do Pará, Belém 66075-110, Brazil
| | - Maria Karolina Martins Ferreira
- Laboratory of Functional and Structural Biology, Institute of Biological Sciences, Federal University do Pará, Belém 66075-110, Brazil
| | - Daiane Claydes Baia-da-Silva
- Laboratory of Functional and Structural Biology, Institute of Biological Sciences, Federal University do Pará, Belém 66075-110, Brazil
| | - Eneas Andrade Fontes-Junior
- Laboratory of Pharmacology of Inflammation and Behavior, Federal University of Pará, Belém 66075-110, Brazil
| | - Rafael Rodrigues Lima
- Laboratory of Functional and Structural Biology, Institute of Biological Sciences, Federal University do Pará, Belém 66075-110, Brazil
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12
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Attal N, Bouhassira D, Colvin L. Advances and challenges in neuropathic pain: a narrative review and future directions. Br J Anaesth 2023; 131:79-92. [PMID: 37210279 DOI: 10.1016/j.bja.2023.04.021] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 03/20/2023] [Accepted: 04/05/2023] [Indexed: 05/22/2023] Open
Abstract
Over the past few decades, substantial advances have been made in neuropathic pain clinical research. An updated definition and classification have been agreed. Validated questionnaires have improved the detection and assessment of acute and chronic neuropathic pain; and newer neuropathic pain syndromes associated with COVID-19 have been described. The management of neuropathic pain has moved from empirical to evidence-based medicine. However, appropriately targeting current medications and the successful clinical development of drugs acting on new targets remain challenging. Innovative approaches to improving therapeutic strategies are required. These mainly encompass rational combination therapy, drug repurposing, non-pharmacological approaches (such as neurostimulation techniques), and personalised therapeutic management. This narrative review reports historical and current perspectives regarding the definitions, classification, assessment, and management of neuropathic pain and explores potential avenues for future research.
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Affiliation(s)
- Nadine Attal
- Inserm U987, UVSQ-Paris-Saclay University, Ambroise Pare Hospital, Boulogne-Billancourt, France.
| | - Didier Bouhassira
- Inserm U987, UVSQ-Paris-Saclay University, Ambroise Pare Hospital, Boulogne-Billancourt, France
| | - Lesley Colvin
- University of Dundee, Ninewells Medical School, Ninewells Hospital, Dundee, UK
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13
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Ismail CAN. Issues and challenges in diabetic neuropathy management: A narrative review. World J Diabetes 2023; 14:741-757. [PMID: 37383599 PMCID: PMC10294062 DOI: 10.4239/wjd.v14.i6.741] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 02/24/2023] [Accepted: 04/11/2023] [Indexed: 06/14/2023] Open
Abstract
Diabetic neuropathy (DN) is a devastating disorder with an increasing prevalence globally. This epidemic can pose a critical burden on individuals and com-munities, subsequently affecting the productivity and economic output of a country. With more people living a sedentary lifestyle, the incidence of DN is escalating worldwide. Many researchers have relentlessly worked on ways to combat this devastating disease. Their efforts have given rise to a number of commercially available therapies that can alleviate the symptoms of DN. Unfortunately, most of these therapies are only partially effective. Worse still, some are associated with unfavorable side effects. This narrative review aims to highlight current issues and challenges in the management of DN, especially from the perspective of molecular mechanisms that lead to its progression, with the hope of providing future direction in the management of DN. To improve the approaches to diabetic management, the suggested resolutions in the literature are also discussed in this review. This review will provide an in-depth understanding of the causative mechanisms of DN, apart from the insights to improve the quality and strategic approaches to DN management.
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Affiliation(s)
- Che Aishah Nazariah Ismail
- Department of Physiology, School of Medical Sciences, University Sains Malaysia Health Campus, Kubang Kerian 16150, Kelantan, Malaysia
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14
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Birkinshaw H, Friedrich CM, Cole P, Eccleston C, Serfaty M, Stewart G, White S, Moore RA, Phillippo D, Pincus T. Antidepressants for pain management in adults with chronic pain: a network meta-analysis. Cochrane Database Syst Rev 2023; 5:CD014682. [PMID: 37160297 PMCID: PMC10169288 DOI: 10.1002/14651858.cd014682.pub2] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/11/2023]
Abstract
BACKGROUND Chronic pain is common in adults, and often has a detrimental impact upon physical ability, well-being, and quality of life. Previous reviews have shown that certain antidepressants may be effective in reducing pain with some benefit in improving patients' global impression of change for certain chronic pain conditions. However, there has not been a network meta-analysis (NMA) examining all antidepressants across all chronic pain conditions. OBJECTIVES To assess the comparative efficacy and safety of antidepressants for adults with chronic pain (except headache). SEARCH METHODS We searched CENTRAL, MEDLINE, Embase, CINAHL, LILACS, AMED and PsycINFO databases, and clinical trials registries, for randomised controlled trials (RCTs) of antidepressants for chronic pain conditions in January 2022. SELECTION CRITERIA We included RCTs that examined antidepressants for chronic pain against any comparator. If the comparator was placebo, another medication, another antidepressant, or the same antidepressant at different doses, then we required the study to be double-blind. We included RCTs with active comparators that were unable to be double-blinded (e.g. psychotherapy) but rated them as high risk of bias. We excluded RCTs where the follow-up was less than two weeks and those with fewer than 10 participants in each arm. DATA COLLECTION AND ANALYSIS: Two review authors separately screened, data extracted, and judged risk of bias. We synthesised the data using Bayesian NMA and pairwise meta-analyses for each outcome and ranked the antidepressants in terms of their effectiveness using the surface under the cumulative ranking curve (SUCRA). We primarily used Confidence in Meta-Analysis (CINeMA) and Risk of Bias due to Missing Evidence in Network meta-analysis (ROB-MEN) to assess the certainty of the evidence. Where it was not possible to use CINeMA and ROB-MEN due to the complexity of the networks, we used GRADE to assess the certainty of the evidence. Our primary outcomes were substantial (50%) pain relief, pain intensity, mood, and adverse events. Our secondary outcomes were moderate pain relief (30%), physical function, sleep, quality of life, Patient Global Impression of Change (PGIC), serious adverse events, and withdrawal. MAIN RESULTS This review and NMA included 176 studies with a total of 28,664 participants. The majority of studies were placebo-controlled (83), and parallel-armed (141). The most common pain conditions examined were fibromyalgia (59 studies); neuropathic pain (49 studies) and musculoskeletal pain (40 studies). The average length of RCTs was 10 weeks. Seven studies provided no useable data and were omitted from the NMA. The majority of studies measured short-term outcomes only and excluded people with low mood and other mental health conditions. Across efficacy outcomes, duloxetine was consistently the highest-ranked antidepressant with moderate- to high-certainty evidence. In duloxetine studies, standard dose was equally efficacious as high dose for the majority of outcomes. Milnacipran was often ranked as the next most efficacious antidepressant, although the certainty of evidence was lower than that of duloxetine. There was insufficient evidence to draw robust conclusions for the efficacy and safety of any other antidepressant for chronic pain. Primary efficacy outcomes Duloxetine standard dose (60 mg) showed a small to moderate effect for substantial pain relief (odds ratio (OR) 1.91, 95% confidence interval (CI) 1.69 to 2.17; 16 studies, 4490 participants; moderate-certainty evidence) and continuous pain intensity (standardised mean difference (SMD) -0.31, 95% CI -0.39 to -0.24; 18 studies, 4959 participants; moderate-certainty evidence). For pain intensity, milnacipran standard dose (100 mg) also showed a small effect (SMD -0.22, 95% CI -0.39 to 0.06; 4 studies, 1866 participants; moderate-certainty evidence). Mirtazapine (30 mg) had a moderate effect on mood (SMD -0.5, 95% CI -0.78 to -0.22; 1 study, 406 participants; low-certainty evidence), while duloxetine showed a small effect (SMD -0.16, 95% CI -0.22 to -0.1; 26 studies, 7952 participants; moderate-certainty evidence); however it is important to note that most studies excluded participants with mental health conditions, and so average anxiety and depression scores tended to be in the 'normal' or 'subclinical' ranges at baseline already. Secondary efficacy outcomes Across all secondary efficacy outcomes (moderate pain relief, physical function, sleep, quality of life, and PGIC), duloxetine and milnacipran were the highest-ranked antidepressants with moderate-certainty evidence, although effects were small. For both duloxetine and milnacipran, standard doses were as efficacious as high doses. Safety There was very low-certainty evidence for all safety outcomes (adverse events, serious adverse events, and withdrawal) across all antidepressants. We cannot draw any reliable conclusions from the NMAs for these outcomes. AUTHORS' CONCLUSIONS Our review and NMAs show that despite studies investigating 25 different antidepressants, the only antidepressant we are certain about for the treatment of chronic pain is duloxetine. Duloxetine was moderately efficacious across all outcomes at standard dose. There is also promising evidence for milnacipran, although further high-quality research is needed to be confident in these conclusions. Evidence for all other antidepressants was low certainty. As RCTs excluded people with low mood, we were unable to establish the effects of antidepressants for people with chronic pain and depression. There is currently no reliable evidence for the long-term efficacy of any antidepressant, and no reliable evidence for the safety of antidepressants for chronic pain at any time point.
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Affiliation(s)
- Hollie Birkinshaw
- Department of Psychology, University of Southampton, Southampton, UK
| | | | - Peter Cole
- Oxford Pain Relief Unit, Churchill Hospital, Oxford University Hospitals NHS Trust, Oxford, UK
| | | | | | | | - Simon White
- School of Pharmacy and Bioengineering, Keele University, Keele, UK
| | | | | | - Tamar Pincus
- Department of Psychology, University of Southampton, Southampton, UK
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15
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Smith S, Normahani P, Lane T, Hohenschurz-Schmidt D, Oliver N, Davies AH. Prevention and Management Strategies for Diabetic Neuropathy. LIFE (BASEL, SWITZERLAND) 2022; 12:life12081185. [PMID: 36013364 PMCID: PMC9410148 DOI: 10.3390/life12081185] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 07/17/2022] [Accepted: 07/28/2022] [Indexed: 11/16/2022]
Abstract
Diabetic neuropathy (DN) is a common complication of diabetes that is becoming an increasing concern as the prevalence of diabetes rapidly rises. There are several types of DN, but the most prevalent and studied type is distal symmetrical polyneuropathy, which is the focus of this review and is simply referred to as DN. It can lead to a wide range of sensorimotor and psychosocial symptoms and is a major risk factor for diabetic foot ulceration and Charcot neuropathic osteoarthropathy, which are associated with high rates of lower limb amputation and mortality. The prevention and management of DN are thus critical, and clinical guidelines recommend several strategies for these based on the best available evidence. This article aims to provide a narrative review of DN prevention and management strategies by discussing these guidelines and the evidence that supports them. First, the epidemiology and diverse clinical manifestations of DN are summarized. Then, prevention strategies such as glycemic control, lifestyle modifications and footcare are discussed, as well as the importance of early diagnosis. Finally, neuropathic pain management strategies and promising novel therapies under investigation such as neuromodulation devices and nutraceuticals are reviewed.
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Affiliation(s)
- Sasha Smith
- Section of Vascular Surgery, Department of Surgery and Cancer, Imperial College London, London W6 8RF, UK; (S.S.); (P.N.); (T.L.)
- Imperial Vascular Unit, Imperial College Healthcare NHS Trust, London W6 8RF, UK
| | - Pasha Normahani
- Section of Vascular Surgery, Department of Surgery and Cancer, Imperial College London, London W6 8RF, UK; (S.S.); (P.N.); (T.L.)
- Imperial Vascular Unit, Imperial College Healthcare NHS Trust, London W6 8RF, UK
| | - Tristan Lane
- Section of Vascular Surgery, Department of Surgery and Cancer, Imperial College London, London W6 8RF, UK; (S.S.); (P.N.); (T.L.)
- Department of Vascular Surgery, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK
| | - David Hohenschurz-Schmidt
- Pain Research Group, Department of Surgery and Cancer, Imperial College London, London SW10 9NH, UK;
| | - Nick Oliver
- Section of Metabolic Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London W2 1PG, UK;
- Division of Medicine and Integrated Care, Imperial College Healthcare NHS Trust, London W2 1NY, UK
| | - Alun Huw Davies
- Section of Vascular Surgery, Department of Surgery and Cancer, Imperial College London, London W6 8RF, UK; (S.S.); (P.N.); (T.L.)
- Imperial Vascular Unit, Imperial College Healthcare NHS Trust, London W6 8RF, UK
- Correspondence:
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16
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Fang XX, Wang H, Song HL, Wang J, Zhang ZJ. Neuroinflammation Involved in Diabetes-Related Pain and Itch. Front Pharmacol 2022; 13:921612. [PMID: 35795572 PMCID: PMC9251344 DOI: 10.3389/fphar.2022.921612] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Accepted: 05/12/2022] [Indexed: 12/25/2022] Open
Abstract
Diabetes mellitus (DM) is a global epidemic with increasing incidence, which results in diverse complications, seriously affects the patient quality of life, and brings huge economic burdens to society. Diabetic neuropathy is the most common chronic complication of DM, resulting in neuropathic pain and chronic itch. The precise mechanisms of diabetic neuropathy have not been fully clarified, hindering the exploration of novel therapies for diabetic neuropathy and its terrible symptoms such as diabetic pain and itch. Accumulating evidence suggests that neuroinflammation plays a critical role in the pathophysiologic process of neuropathic pain and chronic itch. Indeed, researchers have currently made significant progress in knowing the role of glial cells and the pro-inflammatory mediators produced from glial cells in the modulation of chronic pain and itch signal processing. Here, we provide an overview of the current understanding of neuroinflammation in contributing to the sensitization of the peripheral nervous system (PNS) and central nervous system (CNS). In addition, we also summarize the inflammation mechanisms that contribute to the pathogenesis of diabetic itch, including activation of glial cells, oxidative stress, and pro-inflammatory factors. Targeting excessive neuroinflammation may provide potential and effective therapies for the treatment of chronic neuropathic pain and itch in DM.
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Affiliation(s)
- Xiao-Xia Fang
- Department of Human Anatomy, School of Medicine, Nantong University, Nantong, China
- Department of Medical Functional Laboratory, School of Medicine, Nantong University, Nantong, China
| | - Heng Wang
- Department of Human Anatomy, School of Medicine, Nantong University, Nantong, China
| | - Hao-Lin Song
- Department of Human Anatomy, School of Medicine, Nantong University, Nantong, China
| | - Juan Wang
- Department of Human Anatomy, School of Medicine, Nantong University, Nantong, China
| | - Zhi-Jun Zhang
- Department of Human Anatomy, School of Medicine, Nantong University, Nantong, China
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17
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Pharmacogenetics and Pain Treatment with a Focus on Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and Antidepressants: A Systematic Review. Pharmaceutics 2022; 14:pharmaceutics14061190. [PMID: 35745763 PMCID: PMC9228102 DOI: 10.3390/pharmaceutics14061190] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 05/29/2022] [Accepted: 05/30/2022] [Indexed: 11/17/2022] Open
Abstract
Background: This systematic review summarizes the impact of pharmacogenetics on the effect and safety of non-steroidal anti-inflammatory drugs (NSAIDs) and antidepressants when used for pain treatment. Methods: A systematic literature search was performed according to the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines regarding the human in vivo efficacy and safety of NSAIDs and antidepressants in pain treatment that take pharmacogenetic parameters into consideration. Studies were collected from PubMed, Scopus, and Web of Science up to the cutoff date 18 October 2021. Results: Twenty-five articles out of the 6547 initially detected publications were identified. Relevant medication–gene interactions were noted for drug safety. Interactions important for pain management were detected for (1) ibuprofen/CYP2C9; (2) celecoxib/CYP2C9; (3) piroxicam/CYP2C8, CYP2C9; (4) diclofenac/CYP2C9, UGT2B7, CYP2C8, ABCC2; (5) meloxicam/CYP2C9; (6) aspirin/CYP2C9, SLCO1B1, and CHST2; (7) amitriptyline/CYP2D6 and CYP2C19; (8) imipramine/CYP2C19; (9) nortriptyline/CYP2C19, CYP2D6, ABCB1; and (10) escitalopram/HTR2C, CYP2C19, and CYP1A2. Conclusions: Overall, a lack of well powered human in vivo studies assessing the pharmacogenetics in pain patients treated with NSAIDs or antidepressants is noted. Studies indicate a higher risk for partly severe side effects for the CYP2C9 poor metabolizers and NSAIDs. Further in vivo studies are needed to consolidate the relevant polymorphisms in NSAID safety as well as in the efficacy of NSAIDs and antidepressants in pain management.
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18
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Sloan G, Alam U, Selvarajah D, Tesfaye S. The Treatment of Painful Diabetic Neuropathy. Curr Diabetes Rev 2022; 18:e070721194556. [PMID: 34238163 DOI: 10.2174/1573399817666210707112413] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 02/18/2021] [Accepted: 03/08/2021] [Indexed: 11/22/2022]
Abstract
Painful diabetic peripheral neuropathy (painful-DPN) is a highly prevalent and disabling condition, affecting up to one-third of patients with diabetes. This condition can have a profound impact resulting in a poor quality of life, disruption of employment, impaired sleep, and poor mental health with an excess of depression and anxiety. The management of painful-DPN poses a great challenge. Unfortunately, currently there are no Food and Drug Administration (USA) approved disease-modifying treatments for diabetic peripheral neuropathy (DPN) as trials of putative pathogenetic treatments have failed at phase 3 clinical trial stage. Therefore, the focus of managing painful- DPN other than improving glycaemic control and cardiovascular risk factor modification is treating symptoms. The recommended treatments based on expert international consensus for painful- DPN have remained essentially unchanged for the last decade. Both the serotonin re-uptake inhibitor (SNRI) duloxetine and α2δ ligand pregabalin have the most robust evidence for treating painful-DPN. The weak opioids (e.g. tapentadol and tramadol, both of which have an SNRI effect), tricyclic antidepressants such as amitriptyline and α2δ ligand gabapentin are also widely recommended and prescribed agents. Opioids (except tramadol and tapentadol), should be prescribed with caution in view of the lack of definitive data surrounding efficacy, concerns surrounding addiction and adverse events. Recently, emerging therapies have gained local licenses, including the α2δ ligand mirogabalin (Japan) and the high dose 8% capsaicin patch (FDA and Europe). The management of refractory painful-DPN is difficult; specialist pain services may offer off-label therapies (e.g. botulinum toxin, intravenous lidocaine and spinal cord stimulation), although there is limited clinical trial evidence supporting their use. Additionally, despite combination therapy being commonly used clinically, there is little evidence supporting this practise. There is a need for further clinical trials to assess novel therapeutic agents, optimal combination therapy and existing agents to determine which are the most effective for the treatment of painful-DPN. This article reviews the evidence for the treatment of painful-DPN, including emerging treatment strategies such as novel compounds and stratification of patients according to individual characteristics (e.g. pain phenotype, neuroimaging and genotype) to improve treatment responses.
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Affiliation(s)
- Gordon Sloan
- Diabetes Research Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospitals, NHS Foundation Trust, Sheffield, UK
| | - Uazman Alam
- Department of Cardiovascular and Metabolic Medicine and the Pain Research Institute, Institute of Life Course and Medical Sciences, University of Liverpool, and Liverpool University Hospital, NHS Foundation Trust, Liverpool, UK
- Division of Diabetes, Endocrinology and Gastroenterology, Institute of Human Development, University of Manchester, Manchester, UK
| | - Dinesh Selvarajah
- Diabetes Research Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospitals, NHS Foundation Trust, Sheffield, UK
- Department of Oncology and Human Metabolism, University of Sheffield, Sheffield, UK
| | - Solomon Tesfaye
- Diabetes Research Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospitals, NHS Foundation Trust, Sheffield, UK
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19
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Abstract
Managing chronic pain remains a major unmet clinical challenge. Patients can be treated with a range of interventions, but pharmacotherapy is the most common. These include opioids, antidepressants, calcium channel modulators, sodium channel blockers, and nonsteroidal anti-inflammatory drugs. Many of these drugs target a particular mechanism; however, chronic pain in many diseases is multifactorial and induces plasticity throughout the sensory neuroaxis. Furthermore, comorbidities such as depression, anxiety, and sleep disturbances worsen quality of life. Given the complexity of mechanisms and symptoms in patients, it is unsurprising that many fail to achieve adequate pain relief from a single agent. The efforts to develop novel drug classes with better efficacy have not always proved successful; a multimodal or combination approach to analgesia is an important strategy in pain control. Many patients frequently take more than one medication, but high-quality evidence to support various combinations is often sparse. Ideally, combining drugs would produce synergistic action to maximize analgesia and reduce side effects, although sub-additive and additive analgesia is still advantageous if additive side-effects can be avoided. In this review, we discuss pain mechanisms, drug actions, and the rationale for mechanism-led treatment selection.Abbreviations: COX - cyclooxygenase, CGRP - calcitonin gene-related peptide, CPM - conditioned pain modulation, NGF - nerve growth factor, NNT - number needed to treat, NMDA - N-methyl-d-aspartate, NSAID - nonsteroidal anti-inflammatory drugs, TCA - tricyclic antidepressant, SNRI - serotonin-noradrenaline reuptake inhibitor, QST - quantitative sensory testing.
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Affiliation(s)
- Ryan Patel
- Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, UK
| | - Anthony H Dickenson
- Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, UK
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20
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Hopster K, Driessen B. Pharmacology of the Equine Foot: Medical Pain Management for Laminitis. Vet Clin North Am Equine Pract 2021; 37:549-561. [PMID: 34674911 DOI: 10.1016/j.cveq.2021.08.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
One of the biggest challenges in managing laminitis in horses remains the control of pain. The best analgesic approach is a multimodal approach, including nonsteroidal anti-inflammatory drugs, opioids, and/or constant rate infusions of α-2 agonists, ketamine, and lidocaine. Recent literature indicates that amitriptyline and soluble epoxide hydrolase inhibitor might be beneficial. Clinically oriented studies will be needed if they have a place in laminitis pain management. The systemic pain control can be combined with local techniques such as long-acting local anesthetics or epidural catheterization that allows for administration of potent analgesic therapy with a lower risk of negative side effects.
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Affiliation(s)
- Klaus Hopster
- Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, 382 West Street Road, Kennett Square, PA 19348, USA.
| | - Bernd Driessen
- Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, 382 West Street Road, Kennett Square, PA 19348, USA
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21
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Sloan G, Selvarajah D, Tesfaye S. Pathogenesis, diagnosis and clinical management of diabetic sensorimotor peripheral neuropathy. Nat Rev Endocrinol 2021; 17:400-420. [PMID: 34050323 DOI: 10.1038/s41574-021-00496-z] [Citation(s) in RCA: 210] [Impact Index Per Article: 52.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/15/2021] [Indexed: 02/08/2023]
Abstract
Diabetic sensorimotor peripheral neuropathy (DSPN) is a serious complication of diabetes mellitus and is associated with increased mortality, lower-limb amputations and distressing painful neuropathic symptoms (painful DSPN). Our understanding of the pathophysiology of the disease has largely been derived from animal models, which have identified key potential mechanisms. However, effective therapies in preclinical models have not translated into clinical trials and we have no universally accepted disease-modifying treatments. Moreover, the condition is generally diagnosed late when irreversible nerve damage has already taken place. Innovative point-of-care devices have great potential to enable the early diagnosis of DSPN when the condition might be more amenable to treatment. The management of painful DSPN remains less than optimal; however, studies suggest that a mechanism-based approach might offer an enhanced benefit in certain pain phenotypes. The management of patients with DSPN involves the control of individualized cardiometabolic targets, a multidisciplinary approach aimed at the prevention and management of foot complications, and the timely diagnosis and management of neuropathic pain. Here, we discuss the latest advances in the mechanisms of DSPN and painful DSPN, originating both from the periphery and the central nervous system, as well as the emerging diagnostics and treatments.
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Affiliation(s)
- Gordon Sloan
- Diabetes Research Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | - Dinesh Selvarajah
- Diabetes Research Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
- Department of Oncology and Human Metabolism, University of Sheffield, Sheffield, UK
| | - Solomon Tesfaye
- Diabetes Research Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.
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22
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Kale MB, Bajaj K, Umare M, Wankhede NL, Taksande BG, Umekar MJ, Upaganlawar A. Exercise and Nutraceuticals: Eminent approach for Diabetic Neuropathy. Curr Mol Pharmacol 2021; 15:108-128. [PMID: 34191703 DOI: 10.2174/1874467214666210629123010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 02/28/2021] [Accepted: 03/05/2021] [Indexed: 11/22/2022]
Abstract
Diabetic neuropathy is an incapacitating chronic pathological condition that encompasses a large group of diseases and manifestations of nerve damage. It affects approximately 50% of patients with diabetes mellitus. Autonomic, sensory, and motor neurons are affected. Disabilities are severe, along with poor recovery and diverse pathophysiology. Physical exercise and herbal-based therapies have the potential to decrease the disabilities associated with diabetic neuropathy. Aerobic exercises like walking, weight lifting, the use of nutraceuticals and herbal extracts are found to be effective. Literature from the public domain was studied emphasizing various beneficial effects of different exercises, use of herbal and nutraceuticals for their therapeutic action in diabetic neuropathy. Routine exercises and administration of herbal and nutraceuticals, either the extract of plant material containing the active phytoconstituent or isolated phytoconstituent at safe concentration, have been shown to have promising positive action in the treatment of diabetic neuropathy. Exercise has shown promising effects on vascular and neuronal health and has proven to be well effective in the treatment as well as prevention of diabetic neuropathy by various novel mechanisms, including herbal and nutraceuticals therapy is also beneficial for the condition. They primarily show the anti-oxidant effect, secretagogue, anti-inflammatory, analgesic, and neuroprotective action. Severe adverse events are rare with these therapies. The current review investigates the benefits of exercise and nutraceutical therapies in the treatment of diabetic neuropathy.
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Affiliation(s)
- Mayur Bhimrao Kale
- Shrimati Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur 441002, Maharashtra, India
| | - Komal Bajaj
- Shrimati Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur 441002, Maharashtra, India
| | - Mohit Umare
- Shrimati Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur 441002, Maharashtra, India
| | - Nitu L Wankhede
- Shrimati Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur 441002, Maharashtra, India
| | | | - Milind Janrao Umekar
- Shrimati Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur 441002, Maharashtra, India
| | - Aman Upaganlawar
- SNJB's Shriman Sureshdada Jain College of Pharmacy, Neminagar, Chandwad-42310, Nasik, Maharashtra, India
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23
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Luna C, Mizerska K, Quirce S, Belmonte C, Gallar J, Acosta MDC, Meseguer V. Sodium Channel Blockers Modulate Abnormal Activity of Regenerating Nociceptive Corneal Nerves After Surgical Lesion. Invest Ophthalmol Vis Sci 2021; 62:2. [PMID: 33393968 PMCID: PMC7797933 DOI: 10.1167/iovs.62.1.2] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Purpose To test the effect of different sodium channel blockers on the electrical activity of corneal nociceptors in intact and surgically injured corneas. Methods In anesthetized guinea pigs, a 4-mm diameter corneal flap was performed in one eye at a midstromal depth using a custom-made microkeratome. At different times after surgery (3 hours to 15 days), the electrical activity of corneal nociceptor fibers was recorded from ciliary nerve filaments in the superfused eye in vitro. Mechanical threshold was measured using calibrated von Frey hairs; chemical stimulation was performed applying 30-second CO2 gas pulses. The characteristics of the spontaneous and stimulus-evoked activity of corneal nociceptors recorded from intact and lesioned corneas, before and after treatment with the sodium channel blockers lidocaine, carbamazepine, and amitriptyline, were compared. Results No spontaneous or stimulus-evoked impulse activity was detected inside the flap at any of the studied time points. However, both were recorded from mechanonociceptor and polymodal nociceptors fibers in the surrounding corneal tissue, being significantly higher (sensitization) 24 to 48 hours after surgery. In these fibers, none of the tested drugs affected mechanical threshold, but they significantly reduced the CO2 response of polymodal nociceptors of intact and injured corneas. Likewise, they diminished significantly the transient increase in spontaneous and stimulus-evoked activity of sensitized polymodal nociceptors. Conclusions Na+ channel blockers decrease the excitability of intact and sensitized corneal nociceptor fibers, thus acting as potential tools to attenuate their abnormal activity, which underlies the spontaneous pain, hyperalgesia, and allodynia often accompanying surgical corneal lesions, as occurs after photorefractive surgery.
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Affiliation(s)
- Carolina Luna
- Instituto de Neurociencias, Universidad Miguel Hernández - CSIC, San Juan de Alicante, Spain
| | - Kamila Mizerska
- Instituto de Neurociencias, Universidad Miguel Hernández - CSIC, San Juan de Alicante, Spain
| | - Susana Quirce
- Instituto de Neurociencias, Universidad Miguel Hernández - CSIC, San Juan de Alicante, Spain
| | - Carlos Belmonte
- Instituto de Neurociencias, Universidad Miguel Hernández - CSIC, San Juan de Alicante, Spain
| | - Juana Gallar
- Instituto de Neurociencias, Universidad Miguel Hernández - CSIC, San Juan de Alicante, Spain.,Instituto de Investigación Sanitaria y Biomédica de Alicante, San Juan de Alicante, Spain
| | - María Del Carmen Acosta
- Instituto de Neurociencias, Universidad Miguel Hernández - CSIC, San Juan de Alicante, Spain
| | - Víctor Meseguer
- Instituto de Neurociencias, Universidad Miguel Hernández - CSIC, San Juan de Alicante, Spain
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Sánchez-Salcedo JA, Cabrera MME, Molina-Jiménez T, Cortes-Altamirano JL, Alfaro-Rodríguez A, Bonilla-Jaime H. Depression and Pain: use of antidepressant. Curr Neuropharmacol 2021; 20:384-402. [PMID: 34151765 PMCID: PMC9413796 DOI: 10.2174/1570159x19666210609161447] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 04/03/2021] [Accepted: 04/03/2021] [Indexed: 11/24/2022] Open
Abstract
Background: Emotional disorders are common comorbid affectations that exacerbate the severity and persistence of chronic pain. Specifically, depressive symptoms can lead to an excessive duration and intensity of pain. Clinical and preclinical studies have been focused on the underlying mechanisms of chronic pain and depression comorbidity and the use of antidepressants to reduce pain. Aim: This review provides an overview of the comorbid relationship of chronic pain and depression, the clinical and pre-clinical studies performed on the neurobiological aspects of pain and depression, and the use of antidepressants as analgesics. Methods: A systematic search of literature databases was conducted according to pre-defined criteria. The authors independently conducted a focused analysis of the full-text articles. Results: Studies suggest that pain and depression are highly intertwined and may co-exacerbate physical and psychological symptoms. One important biochemical basis for pain and depression focuses on the serotonergic and norepinephrine system, which have been shown to play an important role in this comorbidity. Brain structures that codify pain are also involved in mood. It is evident that using serotonergic and norepinephrine antidepressants are strategies commonly employed to mitigate pain Conclusion: Literature indicates that pain and depression impact each other and play a prominent role in the development and maintenance of other chronic symptoms. Antidepressants continue to be a major therapeutic tool for managing chronic pain. Tricyclic antidepressants (TCAs) are more effective in reducing pain than Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin-Noradrenaline Reuptake Inhibitors (SNRIs).
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Affiliation(s)
- José Armando Sánchez-Salcedo
- Doctorado en Ciencias Biológicas y de la Salud. Universidad Autónoma Metropolitana-Iztapalapa, UAM-I, Apartado Postal 55 535, C.P. 09340, Ciudad de México, Mexico
| | - Maribel Maetizi Estevez Cabrera
- Doctorado en Ciencias Biológicas y de la Salud. Universidad Autónoma Metropolitana-Iztapalapa, UAM-I, Apartado Postal 55 535, C.P. 09340, Ciudad de México, Mexico
| | - Tania Molina-Jiménez
- Facultad de Química Farmacéutica Biológica, Universidad Veracruzana. Circuito Gonzálo Aguirre Beltrán Sn, Zona Universitaria. C.P. 91090 Xalapa-Enríquez
| | - José Luis Cortes-Altamirano
- División de Neurociencias, Instituto Nacional de Rehabilitación "Luis Guillermo Ibarra Ibarra", Secretaría de Salud, Ciudad de México, Mexico
| | - Alfonso Alfaro-Rodríguez
- División de Neurociencias, Instituto Nacional de Rehabilitación "Luis Guillermo Ibarra Ibarra", Secretaría de Salud, Ciudad de México, Mexico
| | - Herlinda Bonilla-Jaime
- Departamento de Biología de la Reproducción, Universidad Autónoma Metropolitana-Iztapalapa. Apartado Postal 55 535, C.P. 09340, Ciudad de México, Mexico
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Gajda JM, Asiedu M, Morrison G, Dunning JA, Ghoreishi-Haack N, Barth AL. NYX-2925, A NOVEL, NON-OPIOID, SMALL-MOLECULE MODULATOR OF THE N-METHYL-d-ASPARTATE RECEPTOR (NMDAR), DEMONSTRATES POTENTIAL TO TREAT CHRONIC, SUPRASPINAL CENTRALIZED PAIN CONDITIONS. MEDICINE IN DRUG DISCOVERY 2021. [DOI: 10.1016/j.medidd.2020.100067] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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Sasaki H, Takatsuna H, Inoue T, Matsui D, Sakoda H, Yokoyama M, Shiosakai K, Seki H, Uetake Y, Okuizumi K. A Cross-sectional Survey of Patients with Suspected Diabetic Peripheral Neuropathic Pain in Japan. Intern Med 2021; 60:357-365. [PMID: 32921690 PMCID: PMC7925283 DOI: 10.2169/internalmedicine.5512-20] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Objective The burden of diabetic peripheral neuropathic pain (DPNP) is poorly understood. The present study reported on the current status of DPNP in Japan, to improve our understanding of this condition among healthcare providers and inform future clinical research on its prevalence, diagnosis, and management. Methods A cross-sectional, observational study (UMIN000037023) was conducted via a web-based survey. The primary endpoints were the frequency of patients with bilateral foot symptoms, consulting a doctor, understanding DPNP, and reporting problems in daily life, as well as the treatment awareness of patients. Patients Adults ≥20 years old who were registered in the Rakuten Insight Disease Panel and receiving anti-diabetic therapy in Japan were included. Results Bilateral foot pain symptoms were reported by 1,768/7,754 (22.8%) respondents, most commonly intense numbness (13.0%). Of those with symptoms, 55.3% consulted a doctor; the most common reason for not seeking consultation was feeling that symptoms were insufficiently severe to bother their doctor (89.4%). Nearly 60% reported understanding the causes of their symptoms, with diabetes-associated neurologic deficits (58.8%) most commonly identified. About one-quarter reported daily life problems, including an inability to walk for long periods (58.3%) and feeling anxious (58.1%). Treatment awareness was reported by 18.2%; oral medications were commonly recognized (64.6%). Conclusion In Japan, 22.8% of patients with diabetes have bilateral foot pain symptoms; some experience problems in their daily life without understanding the causes of their symptoms. This supports the importance of actions to increase awareness and minimize DPNP-associated impairment of daily life in patients with diabetes.
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Affiliation(s)
- Hideyuki Sasaki
- Division of Diabetes and Metabolism, Satellite Clinic for Integrative and Anti-Aging Medicine, Wakayama Medical University, Japan
| | | | | | - Daiju Matsui
- Medical Affairs Division, Daiichi Sankyo Co., Ltd., Japan
| | - Hiroshi Sakoda
- Medical Affairs Division, Daiichi Sankyo Co., Ltd., Japan
| | | | - Kazuhito Shiosakai
- Digital Transformation Management Division, Daiichi Sankyo Co., Ltd., Japan
| | | | | | - Kaoru Okuizumi
- Medical Affairs Division, Daiichi Sankyo Co., Ltd., Japan
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Beyond pain: can antidepressants improve depressive symptoms and quality of life in patients with neuropathic pain? A systematic review and meta-analysis. Pain 2020; 160:2186-2198. [PMID: 31145210 DOI: 10.1097/j.pain.0000000000001622] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Neuropathic pain can be a predictor of severe emotional distress, up to full-blown depressive states. In these patients, it is important to move beyond the sole treatment of pain, to recognize depressive symptoms, and to ultimately improve the quality of life. We systematically searched for published and unpublished clinical trials assessing the efficacy and tolerability of antidepressants vs placebo on depression, anxiety and quality of life in patients with neuropathic pain, and pooled data in a meta-analysis. A total of 37 studies fulfilled eligibility criteria and 32 provided data for meta-analysis. Antidepressants were more effective than placebo in improving depressive symptoms (standardized mean difference -0.11; 95% confidence interval -0.20 to -0.02), although the magnitude of effect was small, with a number needed to treat of 24. No significant difference emerged between antidepressants and placebo in reducing anxiety. Quality of life seemed improved in patients on antidepressants, as did pain. Acceptability and tolerability were higher in patients on placebo. To the best of our knowledge, this is the first meta-analysis specifically focusing on the effect of antidepressants on psychiatric symptoms and quality of life in patients with neuropathic pain. Our findings suggest that despite their potential benefit in patients with neuropathic pain, antidepressants should be prescribed with particular care because they might be less tolerable in such a fragile population. However, our findings warrant further research to explore how a correct use of antidepressants can help patients to cope with the consequences of neuropathic pain on their psychosocial health and quality of life.
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Phạm TL, Kim DW. Poly(lactic-co-glycolic acid) nanomaterial-based treatment options for pain management: a review. Nanomedicine (Lond) 2020; 15:1897-1913. [PMID: 32757701 DOI: 10.2217/nnm-2020-0114] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Neuropathic pain is one of the most intense types of chronic pain; it constitutes a pervasive complaint throughout the public health system. With few effective treatments, it remains a significant challenge. Commercially available drugs for neuropathic pain are still limited and have disappointing efficacy. Therefore, chronic neuropathic pain imposes a tremendous burden on patients' quality of life. Recently, the introduction and application of nanotechnology in multiple fields has accelerated the development of new drugs. This review highlights the application of poly(lactic-co-glycolic acid) nanomaterial-based vehicles for drug delivery and how they improve the therapeutic outcomes for neuropathic pain treatment. Finally, future developments for pain research and effective management are presented.
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Affiliation(s)
- Thuỳ Linh Phạm
- Department of Medical Science, Chungnam National University College of Medicine, Daejeon, 35015, Republic of Korea
- Department of Anatomy, Brain Research Institute, Chungnam National University College of Medicine, Daejeon, 35015, Republic of Korea
- Department of Histology & Embryology, Hai Phong University of Medicine & Pharmacy Hospital, Hai Phong, 042-12, Vietnam
| | - Dong Woon Kim
- Department of Medical Science, Chungnam National University College of Medicine, Daejeon, 35015, Republic of Korea
- Department of Anatomy, Brain Research Institute, Chungnam National University College of Medicine, Daejeon, 35015, Republic of Korea
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Araki E, Goto A, Kondo T, Noda M, Noto H, Origasa H, Osawa H, Taguchi A, Tanizawa Y, Tobe K, Yoshioka N. Japanese Clinical Practice Guideline for Diabetes 2019. Diabetol Int 2020; 11:165-223. [PMID: 32802702 PMCID: PMC7387396 DOI: 10.1007/s13340-020-00439-5] [Citation(s) in RCA: 267] [Impact Index Per Article: 53.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Indexed: 01/09/2023]
Affiliation(s)
- Eiichi Araki
- Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Atsushi Goto
- Department of Health Data Science, Graduate School of Data Science, Yokohama City University, Yokohama, Japan
| | - Tatsuya Kondo
- Department of Diabetes, Metabolism and Endocrinology, Kumamoto University Hospital, Kumamoto, Japan
| | - Mitsuhiko Noda
- Department of Diabetes, Metabolism and Endocrinology, Ichikawa Hospital, International University of Health and Welfare, Ichikawa, Japan
| | - Hiroshi Noto
- Division of Endocrinology and Metabolism, St. Luke’s International Hospital, Tokyo, Japan
| | - Hideki Origasa
- Department of Biostatistics and Clinical Epidemiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Haruhiko Osawa
- Department of Diabetes and Molecular Genetics, Ehime University Graduate School of Medicine, Toon, Japan
| | - Akihiko Taguchi
- Department of Endocrinology, Metabolism, Hematological Science and Therapeutics, Graduate School of Medicine, Yamaguchi University, Ube, Japan
| | - Yukio Tanizawa
- Department of Endocrinology, Metabolism, Hematological Science and Therapeutics, Graduate School of Medicine, Yamaguchi University, Ube, Japan
| | - Kazuyuki Tobe
- First Department of Internal Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
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Araki E, Goto A, Kondo T, Noda M, Noto H, Origasa H, Osawa H, Taguchi A, Tanizawa Y, Tobe K, Yoshioka N. Japanese Clinical Practice Guideline for Diabetes 2019. J Diabetes Investig 2020; 11:1020-1076. [PMID: 33021749 PMCID: PMC7378414 DOI: 10.1111/jdi.13306] [Citation(s) in RCA: 176] [Impact Index Per Article: 35.2] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Accepted: 05/24/2020] [Indexed: 01/09/2023] Open
Affiliation(s)
- Eiichi Araki
- Department of Metabolic MedicineFaculty of Life SciencesKumamoto UniversityKumamotoJapan
| | - Atsushi Goto
- Department of Health Data ScienceGraduate School of Data ScienceYokohama City UniversityYokohamaJapan
| | - Tatsuya Kondo
- Department of Diabetes, Metabolism and EndocrinologyKumamoto University HospitalKumamotoJapan
| | - Mitsuhiko Noda
- Department of Diabetes, Metabolism and EndocrinologyIchikawa HospitalInternational University of Health and WelfareIchikawaJapan
| | - Hiroshi Noto
- Division of Endocrinology and MetabolismSt. Luke's International HospitalTokyoJapan
| | - Hideki Origasa
- Department of Biostatistics and Clinical EpidemiologyGraduate School of Medicine and Pharmaceutical SciencesUniversity of ToyamaToyamaJapan
| | - Haruhiko Osawa
- Department of Diabetes and Molecular GeneticsEhime University Graduate School of MedicineToonJapan
| | - Akihiko Taguchi
- Department of Endocrinology, Metabolism, Hematological Science and TherapeuticsGraduate School of MedicineYamaguchi UniversityUbeJapan
| | - Yukio Tanizawa
- Department of Endocrinology, Metabolism, Hematological Science and TherapeuticsGraduate School of MedicineYamaguchi UniversityUbeJapan
| | - Kazuyuki Tobe
- First Department of Internal MedicineGraduate School of Medicine and Pharmaceutical SciencesUniversity of ToyamaToyamaJapan
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32
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Alam U, Sloan G, Tesfaye S. Treating Pain in Diabetic Neuropathy: Current and Developmental Drugs. Drugs 2020; 80:363-384. [DOI: 10.1007/s40265-020-01259-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
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Bibliometric Study of the Comorbidity of Pain and Depression Research. Neural Plast 2019; 2019:1657498. [PMID: 31772566 PMCID: PMC6854239 DOI: 10.1155/2019/1657498] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 08/27/2019] [Indexed: 12/28/2022] Open
Abstract
Background Comorbid pain and depression occur with high prevalence in clinical observations, and published academic journals about them have been increasing in number over time. However, few studies used the bibliometric method to analyze the general aspects of scientific researches on the comorbidity of pain and depression. The aim of this study is to systematically provide global scientific research in the comorbidity of pain and depression from 1980 to 2018. Methods The published papers were searched between 1980 and 2018 in Web of Science. Publications related to comorbid pain and depression research were included. The language was restricted to English, and no species limitations were specified. Results A total of 2,519 papers met the inclusion criteria in our study. The results revealed that the publications had a significant growth over time in the comorbidity of pain and depression research (P < 0.001) by linear regression analyses. The United States had the largest number of publications and citations and the highest value of H-index. According to subject categories of Web of Science, research areas of the 2,519 papers mainly focused on clinical neurology (28.78%), neurosciences (22.9%), and psychiatry (22.23%). In accordance with types of pain, headache (19.09%) was the most popular topic in the included papers on comorbid pain and depression research. Conclusions The findings provide useful information for pain and depression researchers to detect new areas related to collaborators, cooperative institutions, popular topics, and research frontiers.
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Skånland SS, Cieślar-Pobuda A. Off-label uses of drugs for depression. Eur J Pharmacol 2019; 865:172732. [PMID: 31622593 DOI: 10.1016/j.ejphar.2019.172732] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 10/09/2019] [Accepted: 10/11/2019] [Indexed: 02/08/2023]
Abstract
The prescription of drugs for depression is rising rapidly. One of the reasons for this trend is their many off-label uses. Up to one third of all prescriptions are for non-indicated use, which in addition to drug repurposing includes different dosing or duration than those recommended. In this review, we elaborate on what antidepressants can treat besides depression. The five classes of drugs for depression are introduced, and their mechanisms of action and serious side effects are described. The most common off-label uses of antidepressants are discussed, with a special focus on treating eating disorders, sleep problems, smoking cessation and managing chronic pain. Depression is often a comorbidity when antidepressants are chosen as therapy, but good therapeutic effects have been observed for other conditions also when depression is not involved. Finally, a new type of antidepressant developed from the hallucinogenic "party drug" ketamine is briefly introduced. This recent development suggests that antidepressants will keep playing a central role in medicine for years to come.
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Affiliation(s)
- Sigrid S Skånland
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; The K. G. Jebsen Centre for B Cell Malignancies, Institute for Clinical Medicine, University of Oslo, Oslo, Norway; K. G. Jebsen Centre for Cancer Immunotherapy, Institute for Clinical Medicine, University of Oslo, Oslo, Norway
| | - Artur Cieślar-Pobuda
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; K. G. Jebsen Centre for Cancer Immunotherapy, Institute for Clinical Medicine, University of Oslo, Oslo, Norway; Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo, Oslo, Norway.
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Jang JH, Kim YK, Jung WM, Kim HK, Song EM, Kim HY, Oh JY, Park JY, Ryu Y, Song MY, Park HJ. Acupuncture Improves Comorbid Cognitive Impairments Induced by Neuropathic Pain in Mice. Front Neurosci 2019; 13:995. [PMID: 31616240 PMCID: PMC6763606 DOI: 10.3389/fnins.2019.00995] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Accepted: 09/03/2019] [Indexed: 12/17/2022] Open
Abstract
Growing evidence indicates that neuropathic pain is frequently accompanied by cognitive impairments, which aggravate the quality of life of chronic pain patients. Here, we investigated whether acupuncture treatments can improve cognitive dysfunction as well as allodynia induced by neuropathic pain in mice. One week after the left partial sciatic nerve ligation (PSNL), acupuncture treatments on the acupoints GB30-GB34 (AP1), HT7-GV20 (AP2), or control points (CP) were performed for 4 weeks. Notably, the significant attenuations of mechanical allodynia and cognitive impairment were observed in the AP1 group, but not in PSNL, AP2, or CP groups. A random decision forest classifier based on the pain and cognitive functions displayed that the acupuncture group was clearly segregated from the other groups. We also demonstrated that acupuncture restored the reduced field excitatory post-synaptic potentials and was able to elevate the expression levels of glutamate receptors (NR2B and GluR1) in the hippocampus. Moreover, the expressions of Ca2+/calmodulin-dependent protein kinase II and synaptic proteins (pPSD-95 and pSyn-1) were enhanced by acupuncture treatment. These results suggest that acupuncture can enhance hippocampal long-term action through the regulation of the synaptic efficacy and that acupuncture may provide a viable option for managing both pain and cognitive functions associated with chronic neuropathic pain.
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Affiliation(s)
- Jae-Hwan Jang
- Acupuncture and Meridian Science Research Center, Kyung Hee University, Seoul, South Korea.,Department of Korean Medical Science, Graduate School of Korean Medicine, Kyung Hee University, Seoul, South Korea.,BK21 PLUS Korean Medicine Science Center, College of Korean Medicine, Kyung Hee University, Seoul, South Korea
| | - Yu-Kang Kim
- Acupuncture and Meridian Science Research Center, Kyung Hee University, Seoul, South Korea.,Department of Korean Medical Science, Graduate School of Korean Medicine, Kyung Hee University, Seoul, South Korea
| | | | - Hyung-Kyu Kim
- Department of Oral Physiology, School of Dentistry, Kyungpook National University, Daegu, South Korea
| | - Eun-Mo Song
- Department of Physical Medicine and Rehabilitation, Graduate School of Korean Medicine, Kyung Hee University, Seoul, South Korea
| | - Hee-Young Kim
- College of Korean Medicine, Daegu Haany University, Daegu, South Korea
| | - Ju-Young Oh
- Acupuncture and Meridian Science Research Center, Kyung Hee University, Seoul, South Korea.,Department of Korean Medical Science, Graduate School of Korean Medicine, Kyung Hee University, Seoul, South Korea.,BK21 PLUS Korean Medicine Science Center, College of Korean Medicine, Kyung Hee University, Seoul, South Korea
| | - Ji-Yeun Park
- College of Korean Medicine, Daejeon University, Daejeon, South Korea
| | - Yeonhee Ryu
- Korea Institute of Oriental Medicine, Daejeon, South Korea
| | - Mi-Yeon Song
- Department of Physical Medicine and Rehabilitation, Graduate School of Korean Medicine, Kyung Hee University, Seoul, South Korea
| | - Hi-Joon Park
- Acupuncture and Meridian Science Research Center, Kyung Hee University, Seoul, South Korea.,Department of Korean Medical Science, Graduate School of Korean Medicine, Kyung Hee University, Seoul, South Korea.,BK21 PLUS Korean Medicine Science Center, College of Korean Medicine, Kyung Hee University, Seoul, South Korea
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Abstract
PURPOSE OF REVIEW Diabetic peripheral neuropathy eventually affects nearly 50% of adults with diabetes during their lifetime and is associated with substantial morbidity including pain, foot ulcers, and lower limb amputation. This review summarizes the epidemiology, risk factors, and management of diabetic peripheral neuropathy and related lower extremity complications. RECENT FINDINGS The prevalence of peripheral neuropathy is estimated to be between 6 and 51% among adults with diabetes depending on age, duration of diabetes, glucose control, and type 1 versus type 2 diabetes. The clinical manifestations are variable, ranging from asymptomatic to painful neuropathic symptoms. Because of the risk of foot ulcer (25%) and amputation associated with diabetic peripheral neuropathy, aggressive screening and treatment in the form of glycemic control, regular foot exams, and pain management are important. There is an emerging focus on lifestyle interventions including weight loss and physical activity as well. The American Diabetes Association has issued multiple recommendation statements pertaining to diabetic neuropathies and the care of the diabetic foot. Given that approximately 50% of adults with diabetes will be affected by peripheral neuropathy in their lifetime, more diligent screening and management are important to reduce the complications and health care burden associated with the disease.
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Affiliation(s)
- Caitlin W Hicks
- Division of Vascular Surgery and Endovascular Therapy, Johns Hopkins University School of Medicine, 600 N Wolfe Street, Halsted 668, Baltimore, MD, 21287, USA
| | - Elizabeth Selvin
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 2024 E. Monument St., Suite 2-600, Baltimore, MD, 21287, USA.
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Siemian JN, Shang L, Seaman RW, Zhu Q, Zhang Y, Li JX. Effects of imidazoline I2 receptor agonists on reserpine-induced hyperalgesia and depressive-like behavior in rats. Behav Pharmacol 2019; 30:429-434. [PMID: 30383551 PMCID: PMC6494737 DOI: 10.1097/fbp.0000000000000454] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Pharmacotherapies for fibromyalgia treatment are lacking. This study examined the antinociceptive and antidepressant-like effects of imidazoline I2 receptor (I2R) agonists in a reserpine-induced model of fibromyalgia in rats. Rats were treated for 3 days with vehicle or reserpine. The von Frey filament test was used to assess the antinociceptive effects of I2 receptor agonists, and the forced swim test was used to assess the antidepressant-like effects of these drugs. 2-BFI (3.2-10 mg/kg, intraperitoneally), phenyzoline (17.8-56 mg/kg, intraperitoneally), and CR4056 (3.2-10 mg/kg, intraperitoneally) all dose-dependently produced significant antinociceptive effects, which were attenuated by the I2R antagonist idazoxan. Only CR4056 significantly reduced the immobility time in the forced swim test in both vehicle-treated and reserpine-treated rats. These data suggest that I2R agonists may be useful to treat fibromyalgia-related pain and comorbid depression.
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Affiliation(s)
- Justin N. Siemian
- Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, New York, USA
| | - Li Shang
- Department of Nursing, Affiliated Yantai Hospital of Binzhou Medical University, Yantai, Shandong, China
| | - Robert W. Seaman
- Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, New York, USA
| | - Qing Zhu
- Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, New York, USA
- School of Pharmacy, Nantong University, Nantong, Jiangsu, China
| | - Yanan Zhang
- Research Triangle Institute, Research Triangle Park, North Carolina, USA
| | - Jun-Xu Li
- Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, New York, USA
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Abstract
The global epidemic of prediabetes and diabetes has led to a corresponding epidemic of complications of these disorders. The most prevalent complication is neuropathy, of which distal symmetric polyneuropathy (for the purpose of this Primer, referred to as diabetic neuropathy) is very common. Diabetic neuropathy is a loss of sensory function beginning distally in the lower extremities that is also characterized by pain and substantial morbidity. Over time, at least 50% of individuals with diabetes develop diabetic neuropathy. Glucose control effectively halts the progression of diabetic neuropathy in patients with type 1 diabetes mellitus, but the effects are more modest in those with type 2 diabetes mellitus. These findings have led to new efforts to understand the aetiology of diabetic neuropathy, along with new 2017 recommendations on approaches to prevent and treat this disorder that are specific for each type of diabetes. In parallel, new guidelines for the treatment of painful diabetic neuropathy using distinct classes of drugs, with an emphasis on avoiding opioid use, have been issued. Although our understanding of the complexities of diabetic neuropathy has substantially evolved over the past decade, the distinct mechanisms underlying neuropathy in type 1 and type 2 diabetes remains unknown. Future discoveries on disease pathogenesis will be crucial to successfully address all aspects of diabetic neuropathy, from prevention to treatment.
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Feldman EL, Callaghan BC, Pop-Busui R, Zochodne DW, Wright DE, Bennett DL, Bril V, Russell JW, Viswanathan V. Diabetic neuropathy. Nat Rev Dis Primers 2019; 5:42. [PMID: 31197183 PMCID: PMC7096070 DOI: 10.1038/s41572-019-0097-9] [Citation(s) in RCA: 115] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The global epidemic of prediabetes and diabetes has led to a corresponding epidemic of complications of these disorders. The most prevalent complication is neuropathy, of which distal symmetric polyneuropathy (for the purpose of this Primer, referred to as diabetic neuropathy) is very common. Diabetic neuropathy is a loss of sensory function beginning distally in the lower extremities that is also characterized by pain and substantial morbidity. Over time, at least 50% of individuals with diabetes develop diabetic neuropathy. Glucose control effectively halts the progression of diabetic neuropathy in patients with type 1 diabetes mellitus, but the effects are more modest in those with type 2 diabetes mellitus. These findings have led to new efforts to understand the aetiology of diabetic neuropathy, along with new 2017 recommendations on approaches to prevent and treat this disorder that are specific for each type of diabetes. In parallel, new guidelines for the treatment of painful diabetic neuropathy using distinct classes of drugs, with an emphasis on avoiding opioid use, have been issued. Although our understanding of the complexities of diabetic neuropathy has substantially evolved over the past decade, the distinct mechanisms underlying neuropathy in type 1 and type 2 diabetes remains unknown. Future discoveries on disease pathogenesis will be crucial to successfully address all aspects of diabetic neuropathy, from prevention to treatment.
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Affiliation(s)
- Eva L. Feldman
- Department of Neurology, University of Michigan, Ann Arbor, MI, USA.,
| | | | - Rodica Pop-Busui
- Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes (MEND), University of Michigan, Ann Arbor, MI, USA
| | - Douglas W. Zochodne
- Division of Neurology, Department of Medicine and the Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Douglas E. Wright
- Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, USA
| | - David L. Bennett
- Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, UK
| | - Vera Bril
- Division of Neurology, Department of Medicine, University of Toronto and University Health Network, Toronto, Ontario, Canada.,Institute for Research and Medical Consultations, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - James W. Russell
- Department of Neurology, University of Maryland and VA Maryland Health Care System, Baltimore, MD, USA
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Dar MS, Bég SA. TNM cancer staging: can it help develop a novel staging system for type 2 diabetes? Diabetes Metab Syndr Obes 2018; 11:845-853. [PMID: 30568472 PMCID: PMC6276824 DOI: 10.2147/dmso.s179963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Type 2 diabetes (DM2) constitutes 90%-95% of the diabetes cases and is increasing at an alarming rate in the world. The Centers for Disease Control and Prevention (CDC) estimates that more than 29 million people in the United States have diabetes, which often causes mortality from macrovascular complications and morbidity from microvascular complications. Despite these troubling facts, there is currently no widely accepted staging system for DM2 like there is for cancer. TNM oncologic staging has taken a complex condition like cancer and conveyed likelihood of survival in simple alpha-numeric terms that both patients and providers can understand. Oncology is now entering the era of precision medicine where cancer treatment is increasingly being tailored to each patient's cancer. In contrast, DM2 lacks a staging system and remains a largely invisible disease even though it kills more Americans and costs more to treat than cancer. Is a comparable staging system for DM2 possible? We propose the Diabetes Staging System for DM2 that utilizes macrovascular events, microvascular complications, estimated glomerular filtration rate (GFR), and hemoglobin A1C to stage DM2.
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Affiliation(s)
- Moahad S Dar
- Department of Veteran Affairs, Greenville Health Care Center, Greenville, NC, USA,
- Division of Endocrinology & Metabolism, Department of Internal Medicine, Brody School of Medicine at East Carolina University, Greenville, NC, USA,
| | - Sami A Bég
- Proactive Living Inc., Columbia, SC, USA
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Sibiya N, Mabandla M. The pectin-insulin patch application prevents the onset of peripheral neuropathy-like symptoms in streptozotocin-induced diabetic rats. Can J Physiol Pharmacol 2018; 96:1286-1292. [PMID: 30326192 DOI: 10.1139/cjpp-2018-0415] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Peripheral neuropathic condition is amongst the classical symptoms of progressed diabetes. An intensive glycemic control with insulin injections has been shown to delay the onset and the progression of this condition in diabetes. In this study, we investigated the effect of pectin-insulin patch application on peripheral neuropathic symptoms in streptozotocin-induced diabetic rats. Pectin-insulin patches (20.0, 40.8, and 82.9 μg/kg) were daily applied thrice in streptozotocin-induced diabetic rats for 45 days. The diabetic animals sham treated with insulin-free patch served as negative control, while diabetic animals receiving subcutaneous insulin served as positive controls. The locomotor activity, gripping strength, and thermal perception were assessed at day 36, day 40, and day 44, respectively. On the 45th day, the animals were sacrificed, after which the plasma insulin, nitric oxide, C-reactive protein, tumor necrosis factor alpha, and malondialdehyde were measured. The patch application attenuated hyperglycemia with an improvement in the locomotor activity, thermal perception, and gripping strength in diabetic animals. Furthermore, the application of the patch augmented plasma nitric oxide while attenuating plasma malondialdehyde and tumor necrosis factor alpha. The application of pectin-insulin patch delays the onset of peripheral neuropathic-like symptoms in diabetic animals.
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Affiliation(s)
| | - Musa Mabandla
- b School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa
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Zafeiri M, Tsioutis C, Kleinaki Z, Manolopoulos P, Ioannidis I, Dimitriadis G. Clinical Characteristics of Patients with co-Existent Diabetic Peripheral Neuropathy and Depression: A Systematic Review. Exp Clin Endocrinol Diabetes 2018; 129:77-85. [PMID: 30257266 DOI: 10.1055/a-0741-6937] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Abstract
Objectives Both diabetic peripheral neuropathy and depression have significant implications on patients’ quality of life, management and outcomes. We aimed to evaluate all available evidence concerning patients with co-existent diabetic peripheral neuropathy and depression, and describe their clinical characteristics, in order to promote early recognition and management.
Methods Systematic search of PubMed for studies providing data on patients with diabetic peripheral neuropathy and depression. The primary outcome was to evaluate all available evidence related to characteristics of diabetes, diabetic peripheral neuropathy and depression. Secondary study outcomes included comorbid conditions and complications in these patients.
Results Final analysis included 24 studies with data on 205 patients. Most patients were adults between 18–65 years of age. Mean HbA1c value was above 8% and most patients were treated with insulin. Neuropathy was predominantly painful and most patients with available data were considered to have major depressive disorder. In addition to diabetic peripheral neuropathy and depression, diabetes-related complications were recorded in 43 patients, the most common being autonomic neuropathy, retinopathy and nephropathy. The most frequently reported comorbidities were weight loss (72 patients), impotence (60 patients), hypertension (23 patients) and coronary artery disease (22 patients).
Conclusions The present study describes the characteristics of patients with co-existent diabetic peripheral neuropathy and depression, aiming for prompt detection, prevention of further deterioration and improvement of patient outcomes. Available evidence shows that the majority of these patients are adults, with painful peripheral neuropathy and with insulin-treated and inadequately controlled diabetes.
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Affiliation(s)
- Maria Zafeiri
- Diabetes and Obesity Center, Konstantopouleio Hospital, Nea Ionia, Athens, Greece
- Society of Junior Doctors, Athens, Greece
| | - Constantinos Tsioutis
- Society of Junior Doctors, Athens, Greece
- School of Medicine, European University Cyprus, Nicosia, Cyprus
| | - Zoe Kleinaki
- Society of Junior Doctors, Athens, Greece
- School of Medicine, European University Cyprus, Nicosia, Cyprus
| | - Philip Manolopoulos
- Society of Junior Doctors, Athens, Greece
- School of Medicine, European University Cyprus, Nicosia, Cyprus
| | - Ioannis Ioannidis
- Diabetes and Obesity Center, Konstantopouleio Hospital, Nea Ionia, Athens, Greece
- 1st Department of Internal Medicine, Konstantopouleio Hospital, Nea Ionia, Athens, Greece
| | - George Dimitriadis
- 2nd Department of Internal Medicine, Research Institute and Diabetes Centre, National and Kapodistrian University of Athens, Attikon University Hospital, Haidari, Athens, Greece
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A Dual Noradrenergic Mechanism for the Relief of Neuropathic Allodynia by the Antidepressant Drugs Duloxetine and Amitriptyline. J Neurosci 2018; 38:9934-9954. [PMID: 30249798 DOI: 10.1523/jneurosci.1004-18.2018] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Revised: 06/27/2018] [Accepted: 07/22/2018] [Indexed: 12/21/2022] Open
Abstract
In addition to treating depression, antidepressant drugs are also a first-line treatment for neuropathic pain, which is pain secondary to lesion or pathology of the nervous system. Despite the widespread use of these drugs, the mechanism underlying their therapeutic action in this pain context remains partly elusive. The present study combined data collected in male and female mice from a model of neuropathic pain and data from the clinical setting to understand how antidepressant drugs act. We show two distinct mechanisms by which the selective inhibitor of serotonin and noradrenaline reuptake duloxetine and the tricyclic antidepressant amitriptyline relieve neuropathic allodynia. One of these mechanisms is acute, central, and requires descending noradrenergic inhibitory controls and α2A adrenoceptors, as well as the mu and delta opioid receptors. The second mechanism is delayed, peripheral, and requires noradrenaline from peripheral sympathetic endings and β2 adrenoceptors, as well as the delta opioid receptors. We then conducted a transcriptomic analysis in dorsal root ganglia, which suggested that the peripheral component of duloxetine action involves the inhibition of neuroimmune mechanisms accompanying nerve injury, including the downregulation of the TNF-α-NF-κB signaling pathway. Accordingly, immunotherapies against either TNF-α or Toll-like receptor 2 (TLR2) provided allodynia relief. We also compared duloxetine plasma levels in the animal model and in patients and we observed that patients' drug concentrations were compatible with those measured in animals under chronic treatment involving the peripheral mechanism. Our study highlights a peripheral neuroimmune component of antidepressant drugs that is relevant to their delayed therapeutic action against neuropathic pain.SIGNIFICANCE STATEMENT In addition to treating depression, antidepressant drugs are also a first-line treatment for neuropathic pain, which is pain secondary to lesion or pathology of the nervous system. However, the mechanism by which antidepressant drugs can relieve neuropathic pain remained in part elusive. Indeed, preclinical studies led to contradictions concerning the anatomical and molecular substrates of this action. In the present work, we overcame these apparent contradictions by highlighting the existence of two independent mechanisms. One is rapid and centrally mediated by descending controls from the brain to the spinal cord and the other is delayed, peripheral, and relies on the anti-neuroimmune action of chronic antidepressant treatment.
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Dewanjee S, Das S, Das AK, Bhattacharjee N, Dihingia A, Dua TK, Kalita J, Manna P. Molecular mechanism of diabetic neuropathy and its pharmacotherapeutic targets. Eur J Pharmacol 2018; 833:472-523. [DOI: 10.1016/j.ejphar.2018.06.034] [Citation(s) in RCA: 117] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Revised: 06/15/2018] [Accepted: 06/26/2018] [Indexed: 02/07/2023]
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Haneda M, Noda M, Origasa H, Noto H, Yabe D, Fujita Y, Goto A, Kondo T, Araki E. Japanese Clinical Practice Guideline for Diabetes 2016. J Diabetes Investig 2018; 9:657-697. [PMID: 29582574 PMCID: PMC5934251 DOI: 10.1111/jdi.12810] [Citation(s) in RCA: 144] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Accepted: 01/25/2018] [Indexed: 01/09/2023] Open
Affiliation(s)
| | | | | | | | - Daisuke Yabe
- Department of Diabetes, Endocrinology and NutritionKyoto University Graduate School of MedicineKyotoJapan
| | | | - Atsushi Goto
- Center for Public Health SciencesNational Cancer CenterTokyoJapan
| | - Tatsuya Kondo
- Department of Metabolic MedicineKumamoto UniversityKumamotoJapan
| | - Eiichi Araki
- Department of Metabolic MedicineKumamoto UniversityKumamotoJapan
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Affiliation(s)
- K. Hopster
- Department of Clinical Studies New Bolton Center School of Veterinary Medicine University of Pennsylvania Kennett Square Pennsylvania USA
| | - A. W. Eps
- Department of Clinical Studies New Bolton Center School of Veterinary Medicine University of Pennsylvania Kennett Square Pennsylvania USA
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Haneda M, Noda M, Origasa H, Noto H, Yabe D, Fujita Y, Goto A, Kondo T, Araki E. Japanese Clinical Practice Guideline for Diabetes 2016. Diabetol Int 2018; 9:1-45. [PMID: 30603347 PMCID: PMC6224875 DOI: 10.1007/s13340-018-0345-3] [Citation(s) in RCA: 136] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Indexed: 01/09/2023]
Affiliation(s)
| | | | | | | | - Daisuke Yabe
- Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | | | - Atsushi Goto
- Center for Public Health Sciences, National Cancer Center, Tokyo, Japan
| | - Tatsuya Kondo
- Department of Metabolic Medicine, Kumamoto University, Kumamoto, Japan
| | - Eiichi Araki
- Department of Metabolic Medicine, Kumamoto University, Kumamoto, Japan
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