Complex Regional Pain Syndrome Type I, Complex Regional Pain Syndrome Type II
Conditions
Keywords
Analgesia, Causalgia, CRPS, Neuropathic Pain, Oral Surgery, Reflex Sympathetic Dystrophy, Sympathetic Nervous System, Chronic Regional Pain Syndrome
Brief summary
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
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.
Interventions
DRUGPlacebo
4 tabs b.i.d.
DRUGNeurotropin
4 tabs b.i.d.
Sponsors
National Institutes of Health Clinical Center (CC)
National Institute of Neurological Disorders and Stroke (NINDS)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
National Institute of Nursing Research (NINR)
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Visual Analogue Scale (VAS) of Pain Scores After Administration of Test Drugs (Placebo or Neurotropin ) | VAS of each patient is measured after each 5-week treatment interval with 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. |
| Numeric Rating Scale (NRS) of Pain Scores After Administration of Test Drugs (Neurotropin or Placebo) | NRS of each patient is measured after each five-week treatment interval with placebo or Neurotropin. | 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. |
| McGill Pain Questionnaire (MPQ) of Scores After Administration of Test Drugs (Neurotropin or Placebo) | MPQ of each patient is measured after each five-week treatment interval with drug A or drug B. | 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. |
Countries
United States
Participant flow
Recruitment details
Most patients are recruited by direct physician referral or through the Patient Recruitment and Public Liaison (PRPL) office. Potential subjects are determined to be qualified by screening at Clinical Center, NIH in the US.
Pre-assignment details
Patients who have abnormal results from routine laboratory test or are positive for HIV are excluded. Women who are pregnant or positive for pregnancy test are excluded. Also patients who have non-traumatic pain disorders or are obviously have impaired mental capacity are excluded.
Participants by arm
| Arm | Count |
|---|---|
| Placebo First, Then Neurotropin Receive Placebo 4 tabs b.i.d. for 5 weeks and then Neurotropin 4 tabs b.i.d. for 5 weeks (after at least 1 week washout period) | 11 |
| Neurotropin First, Then Placebo Receive Neurotropin 4 tabs b.i.d. for 5 weeks and then Placebo 4 tabs b.i.d. for 5 weeks (after at least 1 week washout period) | 10 |
| Total | 21 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention (5 Weeks) | Adverse Event | 1 | 0 |
| Second Intervention (5 Weeks) | Protocol Violation | 1 | 1 |
Baseline characteristics
| Characteristic | Neurotropin First, Then Placebo | Placebo First, Then Neurotropin | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 2 Participants | 2 Participants |
| Age, Categorical >=65 years | 1 Participants | 0 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants | 9 Participants | 18 Participants |
| Age, Continuous | 46.5 years STANDARD_DEVIATION 13.2 | 37.3 years STANDARD_DEVIATION 13.2 | 41.7 years STANDARD_DEVIATION 13.7 |
| Region of Enrollment United States | 10 participants | 11 participants | 21 participants |
| Sex: Female, Male Female | 5 Participants | 10 Participants | 15 Participants |
| Sex: Female, Male Male | 5 Participants | 1 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1 / 11 | 0 / 10 |
| serious Total, serious adverse events | 0 / 11 | 0 / 10 |
Outcome results
Primary
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.
Time frame: MPQ of each patient is measured after each five-week treatment interval with drug A or drug B.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| VAS After Placebo Treatment First in G-1 | McGill Pain Questionnaire (MPQ) of Scores After Administration of Test Drugs (Neurotropin or Placebo) | 22.4 units on a scale | Standard Error 5.9 |
| VAS After Neurotropin Treatment Second in G-1 | McGill Pain Questionnaire (MPQ) of Scores After Administration of Test Drugs (Neurotropin or Placebo) | 33.1 units on a scale | Standard Error 4 |
| VAS After Neurotropin Treatment First in G-2 | McGill Pain Questionnaire (MPQ) of Scores After Administration of Test Drugs (Neurotropin or Placebo) | 25.4 units on a scale | Standard Error 4.9 |
| VAS After Placebo Treatment Second in G-2 | McGill Pain Questionnaire (MPQ) of Scores After Administration of Test Drugs (Neurotropin or Placebo) | 27.1 units on a scale | Standard Error 5.7 |
Comparison: Data from 16 patients is analyzed using one-sided paired t-test without breaking treatment code (Drug A or B) to determine if (1) the study should be terminated (if 0.0058 ≤ p), (2) the study should be terminated with rejection of the null hypothesis that there are no differences between Drug A and Drug B (p ≥ 0.9), or (3) the study will be continued to obtain the total of 42 patients (0.0058 ≤ p ≤ 0.9).p-value: 0.0058t-test, 1 sided
Primary
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.
Time frame: NRS of each patient is measured after each five-week treatment interval with placebo or Neurotropin.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| VAS After Placebo Treatment First in G-1 | Numeric Rating Scale (NRS) of Pain Scores After Administration of Test Drugs (Neurotropin or Placebo) | 3.0 units on a scale | Standard Deviation 1.1 |
| VAS After Neurotropin Treatment Second in G-1 | Numeric Rating Scale (NRS) of Pain Scores After Administration of Test Drugs (Neurotropin or Placebo) | 3.3 units on a scale | Standard Deviation 0.9 |
| VAS After Neurotropin Treatment First in G-2 | Numeric Rating Scale (NRS) of Pain Scores After Administration of Test Drugs (Neurotropin or Placebo) | 4.0 units on a scale | Standard Deviation 0.8 |
| VAS After Placebo Treatment Second in G-2 | Numeric Rating Scale (NRS) of Pain Scores After Administration of Test Drugs (Neurotropin or Placebo) | 3.1 units on a scale | Standard Deviation 0.8 |
Comparison: Data from 16 patients is analyzed using one-sided paired t-test without breaking treatment code (Drug A or B) to determine if (1) the study should be terminated (if 0.0058 ≤ p), (2) the study should be terminated with rejection of the null hypothesis that there are no differences between Drug A and Drug B (p ≥ 0.9), or (3) the study will be continued to obtain the total of 42 patients (0.0058 ≤ p ≤ 0.9).p-value: 0.0058t-test, 1 sided
Primary
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.
Time frame: VAS of each patient is measured after each 5-week treatment interval with placebo or Neurotropin.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| VAS After Placebo Treatment First in G-1 | Visual Analogue Scale (VAS) of Pain Scores After Administration of Test Drugs (Placebo or Neurotropin ) | 33.6 mm | Standard Error 11.1 |
| VAS After Neurotropin Treatment Second in G-1 | Visual Analogue Scale (VAS) of Pain Scores After Administration of Test Drugs (Placebo or Neurotropin ) | 38.3 mm | Standard Error 8.8 |
| VAS After Neurotropin Treatment First in G-2 | Visual Analogue Scale (VAS) of Pain Scores After Administration of Test Drugs (Placebo or Neurotropin ) | 36.0 mm | Standard Error 7.6 |
| VAS After Placebo Treatment Second in G-2 | Visual Analogue Scale (VAS) of Pain Scores After Administration of Test Drugs (Placebo or Neurotropin ) | 31.1 mm | Standard Error 7.7 |
Comparison: Data from 16 patients is analyzed using one-sided paired t-test without breaking treatment code (Drug A or B, without knowing which drug is Neurotropin or Placebo) to determine if (1) the study should be terminated (if 0.0058 ≤ p), (2) the study should be terminated with rejection of the null hypothesis that there are no differences between Drug A and Drug B (p ≥ 0.9), or (3) the study will be continued to obtain the total of 42 patients (0.0058 ≤ p ≤ 0.9).p-value: 0.0058t-test, 1 sided