Neurotropin to Treat Chronic Neuropathic Pain

Study Overview
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Brief Summary
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This study will examine the effectiveness of the drug neurotropin in treating chronic pain after injury to a limb or a large nerve. Two groups of patients will participate in this study: patients with complex regional pain syndrome type 1, or CRPS-I (also called reflex sympathetic dystrophy) and patients with complex regional pain syndrome type 2, or CRPS-II. CRPS-I is pain that develops after relatively minor injury to an arm or leg, but lasts much longer and is much more severe than would normally be expected. CRPS-II is pain resulting from injury to a large nerve. Candidates will have a history and physical examination, blood tests, and electrocardiogram. Participants will undergo the following tests and procedures: Patients with CRPS I and II will receive an individualized regimen of physical therapy and standard treatment to control their pain. In addition, they will receive neurotropin or placebo tablets for 5 weeks, then no trial medicine 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. Neither the patients nor the doctors will know who received which drug during the two intervals until the study is over. Patients will complete questionnaires about their pain, quality of life, and ability to perform daily living activities. They will have various tests to measure pain (such as sensitivity to heat and cold, to an electric current, to a mild pin prick, etc.); to provide information about changes in their condition (such as tests of range of motion of joints and limb size); to measure blood circulation and sweating in the arm or leg (such as measurements of blood flow to the limb, skin temperature, and sweat production), and other procedures.

Detailed Description
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Patients with Reflex Sympathetic Dystrophy (RSD), re-named Complex Regional Pain Syndrome, type I (CRPS-I), 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 has been used extensively in Japan to treat RSD and other painful conditions; however, the drug has not undergone clinical therapeutic testing in the United States. This protocol is to carry out double-blind, placebo-controlled, crossover studies about clinical efficacy of Neurotropin for acute pain in dental outpatients and for chronic pain in outpatients with CRPS-I or II.

Official Title
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Neurotropin for Acute Dental Pain and for Chronic Neuropathic Pain

Conditions
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Complex Regional Pain Syndrome Type I, Complex Regional Pain Syndrome Type II

Intervention / Treatment
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* Drug: Placebo
* Drug: Neurotropin


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: CRPS patients are referred with a diagnosis of CRPS-I or CRPS-II in one limb only, based on pain (1) that is post-traumatic and spread beyond the region of the injury; (2) has persisted for more than 2 weeks; and (3) is associated with swelling, altered skin color or skin temperature, altered sweating, allodynia or hyperesthesia or limitation of active movement. Atrophic changes in skin, hair loss or nail changes, or disuse atrophy of skeletal muscle may be present. Both sexes are to be studied. All ethnic and racial groups can participate. Patients must be willing to return to NIH for follow-up evaluation under this protocol. EXCLUSION CRITERIA: Pregnant and lactating women are excluded. Based on the oral surgeon's postoperative diagnosis, any extraction which is classified as producing unusual surgical trauma will result in exclusion from the remainder of the study. Dental subjects will also be excluded if they are not adequately sedated by midazolam alone and require intraoperative administration of an opioid drug such as fentanyl, administration of greater than 14.4 ml of local anesthetic (2% lidocaine with 1:100,000 epinephrine), or postoperative administration of a steroid for possible injury to the inferior alveolar nerve. Patients referred with CRPS-I or CRPS II who have abnormal screening test results or who have non-traumatic disorders to which pain may be attributed (gout, malignancy, arthritis, etc.) will be excluded. Any patients who have had ablative procedures for treatment of their neuropathic pain disorder will not be eligible for inclusion in this study. Patients who have a positive HIV result will be excluded. Subjects with obviously impaired mental capacity that precludes informed consent and ability to provide adequate self-ratings are to be excluded.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Placebo first, then Neurotropin (G-1)<br>Double blind cross-over study: receive placebo for 5 weeks and then Neurotropin for 5 weeks (after at least 1 week washout period). Assignment to each group was in random order, selected by the pharmacy with all others blind. | Drug: Placebo<br>* 4 tabs b.i.d.<br>* Other names: Drug A;Drug: Neurotropin<br>* 4 tabs b.i.d.<br>* Other names: Drug B;|
| Active Comparator: Neurotropin first, then Placebo (G-2)<br>Double blind cross-over study: receive Neurotropin for 5 weeks and then placebo for 5 weeks (after at least 1 week washout period). Assignment to each group was in random order, selected by the pharmacy with all others blind. | Drug: Placebo<br>* 4 tabs b.i.d.<br>* Other names: Drug A;Drug: Neurotropin<br>* 4 tabs b.i.d.<br>* Other names: Drug B;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Visual Analogue Scale (VAS) of Pain Scores After Administration of Test Drugs (Placebo or Neurotropin ) | Assessments of pain severity by the patient using a visual analogue scale ranging from 0 to 100 (mm), with 0 = no pain and 100 = maximal pain level. When it is difficult to recruit the patients, the interim analysis using these data is performed after completion of the study of first 16 patients (target number is 30). The data from 16 patients was analyzed while investigators were blinded to the treatment code (Drug A and B) provided by the NIH pharmacy. Only after the analysis was completed was the code unblinded. Placebo or Neurotropin in place of drug A or drug B. | VAS of each patient is measured after each 5-week treatment interval with placebo or Neurotropin. | 
| Numeric Rating Scale (NRS) of Pain Scores After Administration of Test Drugs (Neurotropin or Placebo) | Assessments of pain severity by the patient using a numeric rating scale ranging from 0 to 10 as a verbal response where 0 = no pain and 10 =maximal pain. When it is difficult to recruit the patients, the interim analysis using these data is performed after completion of the study of first 16 patients (target number is 30). The data from 16 patients was analyzed while the investigators are blinded to the treatment code (Drug A or B) provided by the NIH pharmacy. Only after the analysis was completed was the code unblinded. Placebo or Neurotropin in place of drug A or drug B. | NRS of each patient is measured after each five-week treatment interval with placebo or Neurotropin. | 
| McGill Pain Questionnaire (MPQ) of Scores After Administration of Test Drugs (Neurotropin or Placebo) | Assessments of pain severity by the patient using a McGill Pain Questionnaire which consists of 3 major classes of word descriptors-sensory, affective and evaluative - that are used by patients to specify subjective pain experience. Each word chosen from descriptor responses to 20 questions is given a value and the sum of the values of the responses provides a score which is an index of the pain severity with a minimum value of 20 and a maximal value of 78. When it is difficult to recruit the patients, the interim analysis using these data is performed after completion of the study of first 16 patients (target number is 30). The data from 16 patients was analyzed while investigators are blinded to the treatment code (drug A or B) provided by the NIH pharmacy. Only after the analysis was completed was the code unblinded. Placebo or Neurotropin in place of drug A or drug B. | MPQ of each patient is measured after each five-week treatment interval with drug A or drug B. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Analgesia, Causalgia, CRPS, Neuropathic Pain, Oral Surgery, Reflex Sympathetic Dystrophy, Sympathetic Nervous System, Chronic Regional Pain Syndrome