Clinical Trial: Neurotropin to Treat Acute Dental and Chronic Neural Pain


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Sponsored by:	National Institute of Dental and Craniofacial Research (NIDCR)
Information provided by:	Warren G Magnuson Clinical Center (CC)

Three groups of patients will participate in this study: 1) dental patients undergoing removal of impacted third molars (wisdom teeth); 2) patients with complex regional pain syndrome type 1, or CRPS-I (also called reflex sympathetic dystrophy); and 3) 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, electrocardiogram and, for dental patients, oral examination and dental X-rays to confirm the need for third molar extraction. Participants will undergo the following tests and procedures:

Dental patients will have oral surgery to remove their upper and lower third molars on one side. Before surgery, they will be given two injections: a local anesthetic (lidocaine) and a sedative (midazolam). They will also receive neurotropin tablets or placebo-look-alike tablets with no active medicine-1 hour before surgery, several hours after surgery and 4 times a day for 2 days. If needed, patients may also take a standard painkiller that will be supplied to them. After 2 days they will be given a different painkiller to use for the rest of the recovery period. After at least one week, patients will return for removal of the third molars on the other side and will repeat the drug regimen described above, except patients who received placebo for the first surgery will receive neurotropin for the second surgery, and vice versa. Neither the patients nor the doctors will know who received placebo and who received neurotropin for each surgery until the study is over.

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 neutropin 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.

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

Condition	Treatment or Intervention	Phase
Causalgia Facial Pain Reflex Sympathetic Dystrophy	Drug: Neurotropin	Phase II

Patients with Reflex Sympathetic Dystrophy, 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 reflex sympathetic dystrophy 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.

INCLUSION CRITERIA
Dental outpatients undergoing elective removal of impacted third molars based on a preoperative diagnosis of the type and number of teeth to be extracted.
Both lower teeth to be extracted should be similarly boney impacted, and the score for each of the two lower teeth should be 3 to 4. Uppers are usually in soft tissue. The diagnosis for each tooth will be confirmed by the oral surgeon after the procedure based on the surgical procedure actually performed.
CRPS patients are referred with CRPS-I or CRPS-II in one limb only, based on pain (1) that is post-traumatic and spread beyond the region of injury; (2) has persisted for more than 2 weeks but less than one year; and (3) is associated with swelling, altered skin color or skin temperature, altered sweating, allodynia or hyperestesia or limitation of active movement.
Both sexes are to be studied.
Children can participate, if they can provide adequate self-ratings.
All ethnic and racial groups can participate.
EXCLUSION CRITERIA
Dental outpatients must not be taking any medications chronically (with the exception of oral contraceptive agents).
Pregnant or 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-tramatic 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.
Subjects with impaired mental capacity that precludes informed consent and children who cannot provide adequate self-ratings are excluded.