Experimental Therapeutics for Chronic Pain and Symptoms Management

复杂区域疼痛综合征I型(CRPS-I)患者，以前被称为反射性交感神经营养不良症，具有慢性创伤后疼痛，扩散到任何单一周围神经的分布范围之外，没有重大周围神经损害的证据。一种类似的疾病，焦虑症，重新命名为CRPS-II，表现出明显的神经损伤证据。目前还没有针对这些疾病的成功药物治疗。神经妥乐平是一种从接种牛痘病毒的兔皮肤组织中提取的非蛋白质提取物。由组织提取物制成的神经妥乐平片在日本已被广泛用于治疗CRPS和其他疼痛疾病；然而，该药物尚未在美国进行临床治疗测试。方案(00-NR-0200)旨在进行关于神经妥拉平(FDA IND#60,994)对CRPS-I或II级门诊患者慢性神经性疼痛的临床疗效的双盲、安慰剂对照、交叉研究。 这项双盲交叉研究的受试者接受5周的神经妥乐平或安慰剂片剂治疗，然后至少1周内没有试验药物，然后在接下来的5周内服用另一种试验药物。也就是说，前5周服用安慰剂的患者将在后5周服用神经妥拉平，反之亦然。符合国际疼痛研究协会建立的诊断标准的30名男性和女性患者(年龄范围：18岁及以上)将被选为研究对象，这些患者用目前的标准治疗方案治疗失败。CRPS患者口服试验药物(4片，每日2次)，疗程5周。在洗脱期(至少1周)后，对同一患者给予另一种试验药物。分别于治疗前及治疗后5周测定痛感(面积、自发疼痛强度、痛觉异常、痛觉过敏)、生活质量(SF-36问卷)、自主神经功能(皮肤颜色、皮肤血流量、温度)、患肢肿胀、关节活动范围。该方案已经完成了16名患者的登记。进行了中期分析，研究小组决定根据中期分析的结果终止研究。该议定书的终止获得了IRB的批准。 一项平行的方案正在评估神经妥乐平治疗纤维肌痛(FM)的使用，这是一种主要影响女性的致残性障碍，是一种治疗挑战。由于日本报道的神经妥拉平治疗FM的疗效，我们计划进行一项双盲、安慰剂对照、交叉研究来证实这些报道。这项研究旨在测试神经妥乐平治疗是否会影响自发性疼痛、对特定部位压力引起的疼痛的敏感性，和/或患者在正常活动中发挥作用的能力，以及影响纤维肌痛患者经常出现的疲劳、睡眠障碍、焦虑和情绪障碍。 符合美国风湿病学会建立的FM诊断标准的女性患者(年龄范围：18岁及以上)被选为研究对象，她们曾用目前的标准治疗方案治疗失败。标准是(A)在前三个月的每个月中，有超过半天的广泛性疼痛(在所有象限和背部)的历史，以及(B)18个考点的所需投标点数量(11)，这将在首次体检时确定。对于三级护理环境中的患者，纤维肌痛影响问卷(FIQ：一种简短的10项自我管理的身体功能、工作能力和执行日常生活活动、抑郁、焦虑、睡眠、疼痛、僵硬和疲劳的能力)的平均得分约为50分(100分为最高，得分越高，表明健康损害越严重)，我们将仅包括在初始评估中FIQ得分大于30的患者。要进入这项研究，患者必须愿意继续只使用他们目前的药物(包括抗抑郁药)或在研究过程中与控制FM症状有关的其他形式的护理。 由于神经妥拉平可能需要几周的时间才能起作用，而且FM具有如此自发的波动过程，在这项研究中，测试片将在12周的间隔内服用。神经妥乐平或匹配的安慰剂将被随机分配为第一治疗。在最初12周的治疗中，患者将服用神经妥拉平或安慰剂片剂。在超过一周的洗脱期后，患者将接受第二次为期12周的安慰剂(对于那些接受神经妥乐平片的患者)或神经妥乐平片(对于那些接受安慰剂片剂的患者)。在这两个治疗阶段，患者被指示每天服用8片(每天两次4片)，这是日本使用的剂量，以及用于CRPS患者临床试验的另一种NIH方案(00-NR-0200)中使用的剂量。 在每个治疗阶段前和每个治疗阶段中每隔6周，测量FIQ、SF-36、手动压痛点计数、总压痛的测压和6分钟步行试验。研究期间和研究结束时FIQ分数的差异将被用作主要结果衡量标准。审查18(9个双边)指定地点的投标点。在三个成对的点(上髁、斜方肌和拇指甲)确定的诱发疼痛的平均压力阈值的测压法评估总体压痛。目前，该方案共筛选出56名患者，28名患者已完成研究，12名患者退出，3名患者正在积极入选。

Patients with Complex Regional Pain Syndrome, type I (CRPS-I), formerly termed Reflex Sympathetic Dystrophy, have chronic, post-traumatic pain that spreads beyond the distribution of any single peripheral nerve without evidence of major peripheral nerve damage. A similar disorder, Causalgia, re-named CRPS-II, presents with clear evidence of nerve injury. No successful drug treatment exists for these disorders. Neurotropin is a non-protein extract of cutaneous tissue from rabbits inoculated with vaccinia virus. Neurotropin tablets, prepared from the tissue extract, have been used extensively in Japan to treat CRPS and other painful conditions; however, the drug has not undergone clinical therapeutic testing in the United States. Protocol (00-NR-0200) was designed to carry out double-blind, placebo-controlled, crossover studies about clinical efficacy of Neurotropin (FDA IND # 60,994) for chronic neuropathic pain in outpatients with CRPS-I or II. Subjects of this double blind cross-over study receive Neurotropin or placebo tablets for 5 weeks, then no trial medication for at least 1 week, and then the other trial drug for the next 5 weeks. That is, patients who took placebo the first 5 weeks will take Neurotropin the second 5 weeks and vice versa. Thirty male and female patients (age range: 18 and older) meeting the diagnostic criteria established by the International Association for the Study of Pain for diagnosis of CRPS who have been treated unsuccessfully with a current standard therapeutic regimen will be selected for the study. The CRPS patients are given the test drug (4 tablets, twice daily) orally for 5 weeks. After the washout period (at least 1 week), the other test drug was administered to the same patient. Before first treatment phase and after 5 weeks of each treatment phase, the pain sensation (area, spontaneous pain intensity, allodynia, hyperalgesia), quality of life (SF-36 questionnaire), autonomic function (skin color, skin blood flow and temperature), edema/swelling of affected limb, and active range of motion of involved joints are measured. The protocol has completed enrolment of 16 patients. An interim analyses was conducted and the research team decided to terminate the study based on the findings of the interim analysis. IRB approval was obtained for the termination of the protocol. A parallel protocol is evaluating the use of neurotropin for fibromyalgia (FM), a disabling disorder that primarily affects women and presents a therapeutic challenge. Because of the reported efficacy of Neurotropin for treatment of FM in Japan, we have planned a double-blind, placebo-controlled, crossover studies to confirm these reports. The study is designed to test whether Neurotropin treatment will affect spontaneous pain, sensitivity to pressure-induced pain at specific locations, and/or the ability of the patient to function in normal activities as well as affect the fatigue, sleep disturbance, anxiety and mood disorder frequently seen in fibromyalgia patients. Female patients (age range: 18 and older) meeting the criteria established by the American College of Rheumatology for diagnosis of FM who have been treated unsuccessfully with a current standard therapeutic regimen are selected for the study. The criteria are (A) a history of widespread pain (in all quadrants and back) for more than half of the days in each of the prior three months and (B) the required number (11) of tender points of 18 test sites, which will be determined during the initial physical examination. The average score on the Fibromyalgia Impact Questionnaire (FIQ: a brief 10-item self-administered measure of physical functioning, ability to work and perform activities of daily living, depression, anxiety, sleep, pain, stiffness and fatigue) for patients seen in tertiary care settings is about 50 (with 100 being the maximum, a higher score indicating a greater impairment of health) and we will include only those patients in whom the FIQ score is greater than 30 at the initial evaluation. To be admitted to this study, patients must be willing to continue using only their present medications (including antidepressants) or other forms of care related to the control of FM symptoms during the course of the study. Because Neurotropin may take several weeks to have an effect and because FM has such a spontaneously fluctuating course, in this study test tablets will be administered over a 12-week interval. Neurotropin or matching placebo will be randomly assigned as the first treatment. During the first 12-week treatment patients will be given Neurotropin or placebo tablets. After more than 1 week wash-out period, the patient will receive a second 12-week supply of placebo (for those patients who received Neurotropin tablets) or Neurotropin tablets (for those patients who received placebo tablets). In both treatment phases, the patient is instructed to take 8 tablets daily (4 tablets twice daily), the dosage used in Japan and in another NIH protocol (00-NR-0200) for clinical trial of Neurotropin in patients with CRPS. Before each treatment phase and every 6 week during each treatment phase, the FIQ, SF-36, the manual tender point count, the dolorimetric estimate of overall tenderness and the six minute walk test are measured. Differences in the FIQ scores during and at the end of the study period will be used as the primary outcome measure. The 18 (9 bilateral) specified locations are examined for tender points. The dolorimetric measurement of mean pressure thresholds to elicit pain determined at three paired points (epicondyle, mid-trapezius, and thumbnail) assesses overall tenderness. Currently, the protocol has screened a total of 56 patients, 28 patients have completed the study, 12 dropped out, and 3 are actively enrolled.