Low Dose Naltrexone for Chronic Pain in Osteoarthritis and Inflammatory Arthritis

慢性疼痛影响超过1亿美国人，关节炎是最常见的原因。现有治疗 对于慢性关节炎疼痛只有轻微的效果，用于治疗疼痛的药物的风险是众多的， 继续被发现。慢性病的治疗是VA CSR&D的高度优先研究领域。 纳洛酮是一种阿片类拮抗剂，经FDA批准，每日口服剂量为50 mg，用于预防 酗酒者然而，在每天4 - 4.5 mg的低得多的剂量下，已经在小的、盲的、随机的、 改善纤维肌痛疼痛、克罗恩病胃肠道症状和 多发性硬化唯一的其他发表的数据是病例报告，复杂的区域疼痛综合征，下背部 疼痛和硬皮病然而，基于互联网的MD和患者对低剂量纳洛酮（LDN）的倡导 由于LDN可以在标签外使用，其使用大大超过了证据所证明的合理性。的 这种药物只能通过复方药房开具处方，因此患者每月的使用费用约为40美元。 在广泛使用的许多未经证实的治疗方法中，LDN特别令人感兴趣，因为LDN的结果 对病人的调查尤其令人印象深刻，因为它相当安全，而且它的好处似乎是合理的 - 是的有证据表明，中枢疼痛处理途径的调制和下行- 调节小胶质细胞中的炎症通路。考虑到提出的受益条件的多样性 从LDN和明确需要更好的方法来缓解疼痛的慢性疾病，高质量 在炎性和非炎性条件下都需要临床试验。小小的安慰剂- 对照研究，有能力检测与NSAID一样小的效应量或最有益的效应量 非药理学方法，建议作为通过VA考虑关键试验的先决条件 合作研究计划。 这项研究是一项随机、双盲、交叉、安慰剂对照的试验，在成人中进行， 骨关节炎或炎性关节炎和持续疼痛。将招募60名患者，为期12周， 他们将接受8周的LDN和4周的安慰剂。广泛接受的患者报告结局 将采取措施。共同主要终点是疼痛严重程度的降低或疼痛对疼痛的干扰。 在8周的LDN与4周的安慰剂相比，使用简明疼痛量表。其他病人- 报告的数据将用作次要结局和协变量，用于分析 对治疗的反应关键入选标准包括OA或IA的诊断和疼痛评分至少为4级的量表 0-10，这是一个被广泛接受的标准。出于安全性目的保守选择的关键排除标准， 包括阿片类药物使用或严重肝、肾或精神疾病。OA、IA和疼痛控制不足是 足够普遍，研究可以在两年内在一个中心完成。

Chronic pain affects over 100 million Americans, and arthritis is the most common cause. Existing treatments for chronic arthritic pain are only mildly effective, and risks of medications used to treat pain are numerous and continue to be discovered. Treatment of chronic is a high priority research area for VA CSR&D. Naltrexone is an opioid antagonist that is FDA approved in an oral daily dose of 50 mg to prevent recidivism in alcoholics. At much lower doses of 4 – 4.5 mg daily, however, it has been shown in small, blinded, randomized trials to improve pain in fibromyalgia, gastrointestinal symptoms in Crohn’s disease, and quality of life in multiple sclerosis. The only other published data are case reports in complex regional pain syndrome, low back pain, and scleroderma. However, advocacy of low-dose naltrexone (LDN) by internet-based MDs and patients is high, and since LDN can be prescribed off-label, its use greatly exceeds what is justified by evidence. The drug can be prescribed only via compounding pharmacies, so its use costs a patient ~$40/month. Among the many unproven treatments that are widely used, LDN is of particular interest because results of surveys of patients are particularly impressive, because it is quite safe, and because its benefit is plausible pharmacologically. There is evidence both for modulation of central pain-processing pathways and for down- regulation of inflammatory pathways in microglia. Considering the diversity of conditions proposed to benefit from LDN and the unequivocal need for better approaches to pain relief in chronic conditions, high-quality clinical trials are needed in both inflammatory and non-inflammatory conditions. This small but placebo- controlled study, powered to detect an effect size as small as that seen with NSAIDs or the most beneficial non-pharmacologic approaches, is proposed as a prerequisite for considering a pivotal trial through the VA Cooperative Studies Program. The proposed study is a randomized, double-blinded, cross-over, placebo-controlled trial in adults with osteoarthritis or inflammatory arthritis and persistent pain. Sixty patients will be enrolled for 12 weeks, during which they will receive LDN for 8 weeks and placebo for 4 weeks. Widely accepted patient-reported outcome measures will be used. The co-primary endpoints are reduction in pain severity or pain’s interference with function during 8 weeks of LDN compared to 4 weeks placebo, using the Brief Pain Inventory. Other patient- reported data will be used both as secondary outcomes and as covariates in analyzing determinants of response to treatment. Key inclusion criteria include diagnosis of OA or IA and pain rated at least 4 on a scale of 0-10, a widely accepted criterion. Key exclusion criteria, chosen conservatively for the purposes of safety, include opioid use or severe liver, kidney, or psychiatric disease. OA, IA, and inadequate control of pain are sufficiently common that the study can be completed in two years at a single center.