Gabapentin

加巴喷丁
  • 文章类型: Journal Article
    背景:加巴喷丁在孕妇中的使用越来越普遍,这凸显了评估其新生儿安全性的必要性。
    目的:本研究旨在通过一项队列研究和范围审查,对已发表的证据进行荟萃分析,调查加巴喷丁在妊娠期的胎儿安全性。
    方法:我们在1995年至2019年期间使用马尼托巴健康数据库进行了一项基于人群的队列研究。我们研究了怀孕期间加巴喷丁使用与主要先天性畸形患病率之间的关系,心脏和口面部畸形,和新生儿重症监护病房(NICU)入院使用多元回归模型。我们在MEDLINE和EMBASE数据库中搜索了从开始到2022年10月的文献,以确定相关的观察性研究,并使用随机效应模型进行了荟萃分析。包括我们的队列研究结果。
    结果:在289,227例怀孕中,870名孕妇接触加巴喷丁。妊娠早期加巴喷丁暴露与任何畸形风险增加无关(调整后的相对风险[aRR])1.16(95%置信区间[CI]0.92,1.46),心脏畸形(RR1.29,95%CI0.72,2.29),口面部畸形(RR1.37,95%CI0.50,3.75),和主要的先天性畸形(RR1.00,95%CI0.73,1.36)。而在任何三个月的暴露与NICU入院风险增加相关(aRR,1.99[95%CI1.70,2.32])。未调整结果的荟萃分析显示,重大先天性畸形的风险增加(RR1.44,95%CI1.28,1.61,I2=0%)。心脏畸形(RR1.66,95%CI1.11,2.47,I2=68%),和NICU入院(RR3.15,95%CI2.90,3.41,I2=10%),和口面畸形的增加趋势(RR1.98,95%CI0.79,5.00,I2=0%)。
    结论:在队列研究和汇总荟萃分析中,使用加巴喷丁与NICU入院风险增加相关。临床医生应在怀孕期间谨慎使用加巴喷丁,需要进一步研究。
    BACKGROUND: The increasing and prevalent use of gabapentin among pregnant people highlights the necessity to assess its neonatal safety.
    OBJECTIVE: This study aimed to investigate the foetal safety of gabapentin during pregnancy using a cohort study and scoping review with a meta-analysis of published evidence.
    METHODS: We conducted a population-based cohort study using the Manitoba health databases between 1995 and 2019. We examined the association between gabapentin use during pregnancy and the prevalence of major congenital malformations, cardiac and orofacial malformations, and neonatal intensive care unit (NICU) admissions using multivariate regression models. We searched the literature in MEDLINE and EMBASE databases from inception to October 2022 to identify relevant observational studies and conducted a meta-analysis using random-effects models, including our cohort study results.
    RESULTS: Of the 289,227 included pregnancies, 870 pregnant people were exposed to gabapentin. Gabapentin exposure during the First trimester was not associated with an increased risk of any malformations (adjusted relative risk [aRR]) 1.16 (95% confidence interval [CI] 0.92, 1.46), cardiac malformations (aRR 1.29, 95% CI 0.72, 2.29), orofacial malformations (aRR 1.37, 95% CI 0.50, 3.75), and major congenital malformations (aRR 1.00, 95% CI 0.73, 1.36). whereas exposure during any trimester was associated with an increased NICU admission risk (aRR, 1.99 [95% CI 1.70, 2.32]). The meta-analysis of unadjusted results revealed an increased risk of major congenital malformations (RR 1.44, 95% CI 1.28, 1.61, I2 = 0%), cardiac malformations (RR 1.66, 95% CI 1.11, 2.47, I2 = 68%), and NICU admissions (RR 3.15, 95% CI 2.90, 3.41, I2 = 10%), and increased trend of orofacial malformations (RR 1.98, 95% CI 0.79, 5.00, I2 = 0%).
    CONCLUSIONS: Gabapentin use was associated with an increased risk of NICU admissions in the cohort study and pooled meta-analysis. Clinicians should prescribe gabapentin with caution during pregnancy and further studies are warranted.
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  • 文章类型: Systematic Review
    目的:他的研究旨在系统评价加巴喷丁和普瑞巴林治疗急性带状疱疹神经痛的临床疗效。包括疼痛控制和不良反应的发生。
    方法:2023年10月在PubMed进行了系统的计算机化搜索,Embase,WebofScience,科克伦图书馆,VIP,CNKI,和万方数据库。检索了比较加巴喷丁类似物治疗急性带状疱疹神经痛的随机对照试验的数据。终点为视觉模拟评分(VAS)和第1、2和4周的不良反应。使用Revman5.4和Stata16提取符合纳入标准的研究数据进行荟萃分析和敏感性分析。
    结果:该研究包括来自6个随机对照试验的292名患者。其中,118人在加巴喷丁治疗组中,37人在普瑞巴林治疗组中,安慰剂对照组137例.加巴喷丁组疼痛减轻优于安慰剂组(P<0.05),但不良事件更常见.
    结论:加巴喷丁可有效减轻患者急性带状疱疹神经痛。普瑞巴林需要额外的随机对照试验来补充分析。
    CRD42023446643。
    OBJECTIVE: This study aimed to systematically evaluate the clinical efficacy of gabapentin and pregabalin in the treatment of acute herpes zoster (HZ) neuralgia, including pain control and the occurrence of adverse effects.
    METHODS: A systematic computerized search was conducted in October 2023 in PubMed, Embase, Web of Science, Cochrane Library, VIP, CNKI, and Wanfang databases. Data from randomized controlled trials (RCTs) comparing gabapentin analogs for the treatment of acute HZ neuralgia were searched. Endpoints were visual analog scores (Visual Analog Scale) and adverse effects at 1, 2, and 4 weeks. Data from studies that met the inclusion criteria were extracted for meta-analysis and sensitivity analysis using Revman 5.4 and Stata16.
    RESULTS: The study included 292 patients from 6 RCTs. Of these, 118 were in the gabapentin-treated group, 37 were in the pregabalin-treated group, and 137 were in the placebo-controlled group. The gabapentin group showed superior pain reduction compared with the placebo group ( P < 0.05), but adverse events were more frequent.
    CONCLUSIONS: Gabapentin can effectively reduce acute HZ neuralgia in patients. Pregabalin requires additional RCTs to supplement the analysis.
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  • 文章类型: Journal Article
    普瑞巴林是一种被批准用于治疗神经性疼痛和局灶性发作性癫痫发作的抗癫痫药物。在少数情况下,普瑞巴林与帕金森病有关.我们介绍了一例48岁女性,患有高血压,每天服用50mg氯沙坦。她的全科医生处方普瑞巴林150毫克/天用于纤维肌痛相关的疼痛。受试者在没有医疗建议的情况下将剂量加倍。增加剂量5天后,她开始经历与休息性震颤相关的运动困难和缓慢。神经影像学,电诊断研究,实验室考试并不引人注目。怀疑是继发性帕金森病,所以普瑞巴林被停用了.受试者在7天内完全康复。就作者所知,文献中仅报道了6例普瑞巴林诱发的帕金森病.普瑞巴林停药是最常见的治疗方法。所有个体在普瑞巴林停药后完全康复。普瑞巴林诱导的帕金森病的机制尚不完全清楚。
    Pregabalin is an anti-epileptic drug approved for the treatment of neuropathic pain and focal-onset seizures. In a few cases, pregabalin was associated with parkinsonism. We present a case of a 48-year-old female who had hypertension and was on losartan 50 mg/daily. Her general practitioner prescribed pregabalin 150 mg/daily for fibromyalgia-related pain. The subject doubled the dosage without medical advice. After 5 days of the increased dosage, she started to experience difficulty and slowness in movement associated with resting tremors. Neuroimaging, electrodiagnostic studies, and laboratory exams were unremarkable. Secondary parkinsonism was suspected, so pregabalin was discontinued. The subject fully recovered within 7 days. To the authors\' knowledge, only 6 cases of pregabalin-induced parkinsonism were reported in the literature. Pregabalin discontinuation was the most common management. All individuals fully recovered after pregabalin withdrawal. The mechanism of pregabalin-induced parkinsonism is not fully understood.
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    文章类型: Review
    持续改善疼痛管理的需求正在增长。这篇综述旨在确定有关疼痛管理化合物中常用成分的临床和治疗价值的文献:利多卡因,丁卡因,酮洛芬,氯胺酮,和加巴喷丁.Prospective,未来的研究应该进行,以确定确切的好处和副作用的复合疼痛管理疗法,使得这些化合物在认为适当时可以有效地利用。
    The need for continued improvement in pain management is growing. This review is aimed towards identifying the literature regarding clinical and therapeutic value of the commonly used ingredients in pain management compounds: lidocaine, tetracaine, ketoprofen, ketamine, and gabapentin. Prospectively, future studies should be conducted to identify the exact benefits and side effects of compounded pain management therapies, such that these compounds can be effectively utilized when deemed appropriate.
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  • 文章类型: Journal Article
    复杂区域疼痛综合征(CRPS)是一种使人衰弱的慢性疼痛病症,虽然极为罕见,对受影响的患者群体带来了巨大的负担。这种情况的复杂和模糊的病理生理学进一步使临床管理和治疗干预复杂化。此外,作为排除的诊断需要勤奋的检查,以确保准确的诊断和随后的针对性管理。布达佩斯诊断标准的制定有助于巩固CRPS的现有定义,但在确定潜在途径方面仍有大量工作。目前,通过神经元损伤的存在(CRPS1型)或不存在(CRPS2型)鉴定出两种不同的类型。目前针对这种疾病的管理范围广泛且不断增长,从物理和心理治疗等非侵入性方式到更侵入性的技术,如背根神经节刺激和潜在的截肢。理想的治疗干预措施本质上是多模式的,以解决CRPS可能的多因素病理发展。无论如何,对于继续研究以阐明CRPS发展过程中涉及的通路,以及对于各种治疗方式进行更有力的临床试验,仍存在着巨大的需求.
    复杂区域疼痛综合征(CRPS)是一种使人衰弱且复杂的疾病,患者的心理和情感负担需要多模式的治疗方法。布达佩斯标准的制定提供了一套可靠且经过良好测试的诊断标准,以帮助临床医生诊断CRPS。CRPS的病理生理学一直是具有挑战性的阐明与许多提出的机制,这表明这种情况的发展涉及一个多因素的过程。CRPS的非侵入性治疗对于解决这种疾病可能引起的身体限制以及解决涉及抑郁症和自杀意念发生率增加的重大心理负担至关重要。侵入性治疗提供了有希望的结果,尤其是在考虑背根神经节刺激时;然而,仍然需要更强有力的临床试验,尤其是考虑到一小部分患有难治性CRPS的患者采取截肢手术来控制疼痛症状时.
    Complex regional pain syndrome (CRPS) is a debilitating chronic pain condition that, although exceedingly rare, carries a significant burden for the affected patient population. The complex and ambiguous pathophysiology of this condition further complicates clinical management and therapeutic interventions. Furthermore, being a diagnosis of exclusion requires a diligent workup to ensure an accurate diagnosis and subsequent targeted management. The development of the Budapest diagnostic criteria helped to consolidate existing definitions of CRPS but extensive work remains in identifying the underlying pathways. Currently, two distinct types are identified by the presence (CRPS type 1) or absence (CRPS type 2) of neuronal injury. Current management directed at this disease is broad and growing, ranging from non-invasive modalities such as physical and psychological therapy to more invasive techniques such as dorsal root ganglion stimulation and potentially amputation. Ideal therapeutic interventions are multimodal in nature to address the likely multifactorial pathological development of CRPS. Regardless, a significant need remains for continued studies to elucidate the pathways involved in developing CRPS as well as more robust clinical trials for various treatment modalities.
    Complex regional pain syndrome (CRPS) is a debilitating and complex condition that places a significant physical, psychological and emotional burden upon afflicted patients necessitating multi-modal approaches to treatment.The development of the Budapest criteria provided a robust and well-tested set of diagnostic criteria to aid clinicians in the diagnosis of CRPS.The pathophysiology of CRPS has been challenging to elucidate with numerous proposed mechanisms, altogether suggesting a multi-factorial process is involved in the development of this condition.Non-invasive treatments for CRPS are essential in addressing the physical limitations this disease can cause as well as addressing the significant psychological burden that involves increased incidence of depression and suicidal ideation.Invasive treatments offer promising results, especially when considering dorsal root ganglion stimulation; however, the need for more robust clinical trials remains, especially when considering a small portion of patients who have refractory CRPS resort to amputation to control their pain symptoms.
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  • 文章类型: Journal Article
    阿片类药物危机已成为医学领域当前关注的问题。为了解决这些并发症,抗神经性疼痛药物已被认为是处方阿片类药物的替代品。
    这篇综述集中在神经调质的镇痛作用,比如加巴喷丁,度洛西汀,还有普瑞巴林,这为骨科手术后对麻醉性镇痛药的依赖提供了空间。
    在数据库搜索期间,初步结果确定了1,033条记录。删除重复项后,完成了每篇文章的初始筛选,确定了由于没有全文文章而要删除的记录。如果文章不是前瞻性或回顾性的,则被排除在外,展示了与本综述无关的药物(如三环抗抑郁药),或被认为与主题无关。
    最终,选择了19篇文章。三种不同的药物,加巴喷丁,普瑞巴林,还有度洛西汀,进行了分析,以汇编有关预防手部手术后阿片类药物过度使用和成瘾的有效性的数据。这篇综述确定了围手术期加巴喷丁的潜在证据,普瑞巴林,度洛西汀可减少术后疼痛并降低阿片类药物依赖。
    加巴喷丁,普瑞巴林,度洛西汀有可能进一步减轻术后疼痛和降低阿片类药物依赖。这篇综述为手外科的进一步研究创造了一个机会,以评估疼痛管理以减少阿片类药物依赖的更新方案。
    UNASSIGNED: The opioid crisis has become a present concern in the medical field. In an effort to address these complications, antineuropathic pain medications have been considered as alternatives to prescribed opioids.
    UNASSIGNED: This review focuses on the analgesic effects of neuromodulators, such as gabapentin, duloxetine, and pregabalin, that provide room for less dependence on narcotic analgesics following orthopedic surgery.
    UNASSIGNED: During the database searches, 1,033 records were identified as a preliminary result. After duplicates were removed, an initial screen of each article was completed which identified records to be removed due to absence of a full-text article. Articles were excluded if they were not either prospective or retrospective, showcased an irrelevant medication (such as tricyclic antidepressants) which are not pertinent to this review, or deemed to be unrelated to the topic.
    UNASSIGNED: Ultimately, 19 articles were selected. Three different drugs, gabapentin, pregabalin, and duloxetine, were analyzed to compile data on the effectiveness of preventing opioid overuse and addiction following hand surgery. This review identifies potential evidence that peri-operative gabapentin, pregabalin, and duloxetine administration decreases post-operative pain and lowers opioid dependency.
    UNASSIGNED: Gabapentin, pregabalin, and duloxetine have potential to further decrease post-operative pain and lower opioid dependency. This review creates an opening for further research in hand surgery to assess an updated protocol for pain management to reduce opioid dependency.
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  • 文章类型: Systematic Review
    背景:据文献报道,烧伤患者中神经性疼痛(NP)的患病率高达80%1。鉴于NP在烧伤患者中的复杂性和广泛的治疗方法,有必要对文献进行系统回顾,以总结我们目前对这一人群NP管理和治疗的理解.
    方法:本系统评价是根据系统评价和荟萃分析(PRISMA)指南的首选报告项目进行的。查询了以下数据库以识别相关文章:PubMed,科克伦,Embase,Scopus,奥维德,和WebofScience。主要结局指标是NP的发生率和管理。次要结果包括NP的危险因素。
    结果:包括来自11个不同国家的研究结果,获取4366例患者的结果。确定了烧伤患者神经性疼痛的危险因素,包括年龄较大,酒精和药物滥用,目前每天吸烟,总身体表面积烧伤(TBSA)住院时间更长。药物治疗包括加巴喷丁/普瑞巴林(n=7),抗坏血酸(n=1),和利多卡因(n=1)。总的来说,研究显示了关于药物治疗效果的不同结果。虽然某些研究表明加巴芬太尼可有效减轻神经性症状,其他人发现了相互矛盾的结果。关于非药物治疗,电惊厥治疗(n=1),电穿刺(n=1),神经释放/重建(n=2),和体感反馈康复(n=1)被使用,并证明在减轻疼痛强度和改善功能方面有希望。
    结论:尽管NP使大多数烧伤患者在受伤后很长时间受到影响,本系统综述显示病理生理学证据不足,结果,和NP中的风险因素,以及各种疗法的疗效。未来评估这些因素病因的前瞻性和随机研究可以大大改善我们的治疗策略。这可以在NP管理中开发出轮廓清晰且基于证据的协议,以期改善烧伤患者的生活质量以及心理和身体功能。
    BACKGROUND: The prevalence of neuropathic pain (NP) in burn patients is reported in the literature to be as high as 80%1. Given the complexity of NP in burn patients and the wide range of treatments available, a systematic review of the literature is warranted to summarize our current understanding of management and treatment of NP in this population.
    METHODS: This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. The following databases were queried to identify relevant articles: PubMed, Cochrane, Embase, Scopus, Ovid, and Web of Science. The main outcome measures were incidence and management of NP. Secondary outcomes included risk factors for NP.
    RESULTS: Included articles presented findings from 11 different countries, capturing outcomes for 4366 patients. Risk factors for neuropathic pain in burn patients were identified, including older age, alcohol and substance abuse, current daily smoking, greater % total body surface area burns (TBSA), and longer hospitalizations. Pharmacologic treatments included gabapentin/pregabalin (n = 7), ascorbic acid (n = 1), and lidocaine (n = 1). Overall, the studies showed varied results regarding the efficacy of pharmacological treatments. While certain studies demonstrated gabapentanoids to be effective in reducing neuropathic symptoms, others found conflicting results. With regards to non-pharmacologic treatments, electroconvulsive therapy (n = 1), electropuncture (n = 1), nerve release/reconstruction (n = 2), and somatosensory feedback rehabilitation (n = 1) were used and demonstrated promise in reducing pain intensity and improving functionality.
    CONCLUSIONS: Despite NP afflicting the majority of burn patients long after their injury, this systematic review demonstrates insufficient evidence on the pathophysiology, outcomes, and risk factors in NP, as well as the efficacy of various therapies. Future prospective and randomized studies evaluating the etiology of these factors can substantially improve our treatment strategies. This can allow for the development of well-delineated and evidence-based protocols in NP management in hopes of improving quality of life and both psychological and physical function in burn patients.
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  • 文章类型: Systematic Review
    目的:确定和评估当前的国家和国际临床更年期指导文件,并提取和比较最可靠示例的建议。
    方法:系统评价。
    方法:OvidMEDLINE,EMBASE,PsycINFO和WebofScience选择研究标准:从2015年到2023年7月20日发布的更年期实践指导文件。质量通过评估研究和评估指南II(AGREEII)工具进行评估。
    结果:确定了26篇指导文件。其中,5个临床实践指南(CPG)和1个非激素治疗立场声明符合AGREEII标准,即质量至少中等.五个CPG列出了与围绝经期和更年期相关的症状是血管舒缩症状(VMS),睡眠不安,肌肉骨骼疼痛,性功能或欲望下降,和情绪障碍(情绪低落,情绪变化或抑郁症状)。承认潜在的长期更年期后果是泌尿生殖器萎缩,心血管疾病和骨质疏松症的风险增加。VMS和更年期相关的情绪障碍是全身更年期激素治疗(MHT)的唯一一致适应症。一些CPG支持MHT预防或治疗骨质疏松症,但缺乏具体的指导。没有人建议将MHT用于认知症状或预防其他慢性疾病。针对围绝经期的建议很少。神经激肽3B拮抗剂,选择性5-羟色胺/去甲肾上腺素(去甲肾上腺素)再摄取抑制剂和加巴喷丁被推荐用于VMS的非激素药物,认知行为治疗和催眠一直被认为是潜在的益处.
    结论:最高质量的CPG始终推荐MHT用于VMS和更年期相关的情绪障碍,而临床抑郁症或认知症状,心脏代谢疾病和痴呆预防不是治疗指征.需要进一步的研究来为有症状的围绝经期妇女提供临床建议。
    OBJECTIVE: To identify and appraise current national and international clinical menopause guidance documents, and to extract and compare the recommendations of the most robust examples.
    METHODS: Systematic review.
    METHODS: Ovid MEDLINE, EMBASE, PsycINFO and Web of Science ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Practice guidance documents for menopause published from 2015 until 20 July 2023. Quality was assessed by the Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument.
    RESULTS: Twenty-six guidance papers were identified. Of these, five clinical practice guidelines (CPGs) and one non-hormonal therapy position statement met AGREE II criteria of being at least of moderate quality. The five CPGs listed symptoms associated with the perimenopause and menopause to be vasomotor symptoms (VMS), disturbed sleep, musculoskeletal pain, decreased sexual function or desire, and mood disturbance (low mood, mood changes or depressive symptoms). Acknowledged potential long-term menopause consequences were urogenital atrophy, and increased risks of cardiovascular disease and osteoporosis. VMS and menopause-associated mood disturbance were the only consistent indications for systemic menopausal hormone therapy (MHT). Some CPGs supported MHT to prevent or treat osteoporosis, but specific guidance was lacking. None recommended MHT for cognitive symptoms or prevention of other chronic disease. Perimenopause-specific recommendations were scant. A neurokinin 3B antagonist, selective serotonin/norepinephrine (noradrenaline) reuptake inhibitors and gabapentin were recommended non-hormonal medications for VMS, and cognitive behavioural therapy and hypnosis were consistently considered as being of potential benefit.
    CONCLUSIONS: The highest quality CPGs consistently recommended MHT for VMS and menopause-associated mood disturbance, whereas clinical depression or cognitive symptoms, and cardiometabolic disease and dementia prevention were not treatment indications. Further research is needed to inform clinical recommendations for symptomatic perimenopausal women.
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  • 文章类型: Review
    加巴喷丁和普瑞巴林,属于加巴喷丁类药物家族,被广泛使用,尤其是在神经性疼痛治疗中,由于它们在疼痛管理方面的有效性。尽管文献中清楚地描述了限制加巴喷丁类药物使用的许多合并症和症状,在哺乳期间使用它们的数据有限。一名33岁的女性患者在腰麻剖宫产后因神经性疼痛和左下肢肌肉无力而入院。我们旨在通过文献综述,介绍加巴喷丁对母乳喂养的持续性神经性疼痛患者的治疗。
    Gabapentin and pregabalin, which belong to the gabapentinoid drug family, are widely used, especially in neuropathic pain treatment, due to their effectiveness in pain management. Although many of the comorbidities and symptoms that limit the use of gabapentinoids are clearly described in the literature, there is limited data on their use during lactation. A 33-year-old female patient was admitted to our clinic with neuropathic pain and muscle weakness in her left lower extremity following spinal anesthesia for a cesarean section. We aimed to present the gabapentin treatment of a breastfeeding patient with persistent neuropathic pain in light of a literature review.
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  • 文章类型: Journal Article
    澳大利亚治疗用品管理局批准的加巴喷丁类药物处方适应症是难治性局灶性癫痫和神经性疼痛。在批准的适应症之外使用加巴喷丁类药物是常见的,但是这方面的证据是有限的,尤其是慢性非特异性背痛和非神经根性腿痛。加巴喷丁类药物的某些作用鼓励其非医疗用途(例如,欣快感,镇静,去抑制)。广泛的非医疗使用增加了意外和故意中毒的发生率。长期使用加巴喷丁类药物可能会产生依赖性,突然停止可能会引起戒断症状。如果继续使用的指征不清楚,建议逐渐减少剂量作为非处方的一种方法。临床医生应该考虑适应症,处方加巴喷丁类药物时的患者特征和获益概况。有些人,比如那些患有肾脏疾病的人,使用这些药物时,会增加伤害的风险。
    The Australian Therapeutic Goods Administration\'s approved indications for prescription of gabapentinoids are refractory focal epilepsy and neuropathic pain. Use of gabapentinoids outside of the approved indications is common, but evidence for this is limited, especially for chronic nonspecific back pain and nonradicular leg pain. Some effects of gabapentinoids encourage their nonmedical use (e.g. euphoria, sedation, disinhibition). Widespread nonmedical use has increased the incidence of accidental and deliberate poisonings. Dependence may develop with chronic use of gabapentinoids and abrupt cessation may induce withdrawal symptoms. If the indication for continued use is unclear, gradual dose tapering as a means of deprescribing is recommended. Clinicians should consider the indication, patient characteristics and harm-benefit profile when prescribing gabapentinoids. Some people, such as those with kidney disease, have an increased risk of harm when using these drugs.
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