This study will examine the safety and effectiveness of the experimental drug, neurotropin, for preventing or easing pain associated with fibromyalgia. A disorder that primarily affects women, fibromyalgia causes widespread aching and stiffness in muscles. Neurotropin has been used in Japan for many years to treat various chronic painful conditions, including fibromyalgia.

Women with fibromyalgia who have been treated unsuccessfully with standard therapy may be eligible for this study. Patients must have a history of widespread pain for more than half of the days in each of the three months before they enter the study. Candidates are screened with a medical history, physical examination, blood and urine tests, questionnaires and an electrocardiogram (EKG).

Participants take their usual medications for fibromyalgia in addition to either neurotropin or a placebo (look-alike medicine with no active ingredient). At 6 weeks and 12 weeks into the study, they return to the NIH Clinical Center for evaluation of their sensitivity to pain and level of physical capability. After 12 weeks, study subjects "cross-over" their medication; that is, patients who took neurotropin for the first 12 weeks of the study take placebo for the next 12 weeks, and vice-versa. Again, after 6 and 12 weeks, patients return for evaluation.

Participants have blood and urine tests six times during the study and complete questionnaires each week about their pain, symptoms, and activities.

Fibromyalgia (FM), a disabling disorder that primarily affects women, presents a therapeutic challenge and the development of a safe and effective treatement is being sought in several centers in Europe and the United States. Because or 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 design 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.

Thiryt 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 will be selected for this 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) 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 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. Nippon Zoki Pharmaceutical Co., Ltd. prepares both Neurotropin and placebo tablets and send directly to the NIH pharmacy. The NIH Pharmacy uses a table of random numbers to determine the order of medication. This is done by choosing a series of randomized numbers corresponding to the number of patients an dividing the series blocks of four (in each block of four, the two highest would receive the active medication first and the two lowest the placebo first). 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 each morning and evening), the dosage used in Japan and in another NIH protocol (00-NR-0200) for clinical trial of Neurotropin in patients with complex regional pain syndrome.

Before (first and fourth visits) each treatment phase and every 6 week (second, third, fifth and sixth visits) during each treatment, the FIQ, SF-36 and McGill Pain Questionnaire (MPQ), the manual tender point count, the dolorimetric estimate of overall tenderness and the six minute walk test will be measured . The FIQ provides 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. Differences in the FIQ scores during and at the end of the study period will be used as the primary outcome measure. The SF-36 questionnaire assesses health-related quality of life outcomes of therapeutic interventions. The MPQ will be used to confirm any changes in the frequency, intensity or characteristics of the pain. The 18 (9 bilateral) specified locations are examined for tender points to determine if there are changes. The dolorimetric measurement of mean pressure thresholds to elicit pain determined at three paired points (epicondyle, mid-trapezius, and thumbnail) assesses overall tenderness. The physical disability will be evaluated by a six-minute walk test. The results of all tests will be assessed for the two 12-week intervals to determine if there are any indications of differences using statistics for univariate one-way repeated measures analysis of variance. We anticipate that this study my require 2-3 years to complete.

• INCLUSION CRITERIA:

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. They must give informed consent to participate in this study. It is anticipated that almost all patients will be residents of Washington, D.C. area and that they will be able to travel to NIH for necessary preliminary studies and subsequent required evaluations. 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 fibromyalgia symptoms during the course of the study. The average score on the FIQ 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.

EXCLUSION CRITERIA:

Pregnant and lactating women are excluded because of the bodily changes that would occur during the study. As indicated above, a pregnancy test will be performed in women of childbearing age (up to age 55). The combination of widespread musculoskeletal pain, high tender point count, and nonrestorative sleep are usually sufficient criteria for the diagnosis of fibromyalgia and the patients referred for this study will have been well characterized in the Fibromyalgia Clinic at Georgetown University or by the referring physician. We will, however, by history, physical examination, screening laboratory studies and examination of the patient's medical records confirm the absence of any evidence for peripheral neuropathies, entrapment syndromes, neurologic disorders or metabolic/endocrine disorders, such as hypothyroidism, as well as the rheumatoid disorders that might be confused with fibromyalgia and confound the study. Patients who have abnormal screening test results or who have traumatic or non-traumatic disorders to which pain may be attributed. Also, 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.