Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1996-11-06
2001-06-19
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S625000, C514S629000
Reexamination Certificate
active
06248788
ABSTRACT:
FIELD OF THE INVENTION
The present invention generally relates to peripheral neuropathy and more particularly to methods for treating neuropathic pain by use of capsaicin (and/or a capsaicin analog) in high concentration in conjunction with a previously administered anesthetic to the affected areas.
This application claims the benefit of U.S. Provisional Application No. 60/006,385, filed Nov. 8, 1995.
BACKGROUND OF THE INVENTION
Neuropathic pain is thought to occur because of a sensitization in the peripheral and central nervous systems after an initial injury to the peripheral system. Direct injury to the peripheral nerves as well as many systemic diseases including AIDS/HIV, Herpes Zoster, syphilis, diabetes, and various autoimmune diseases, can induce this disorder. Neuropathic pain is typically burning, shooting, and unrelenting in its intensity and can sometimes be more debilitating that the initial injury or the disease process which induced it. Unfortunately, the few remedies that have been reported to alleviate this condition is effective in only a small percentage of patients.
Capsaicin, a pungent substance derived from the plants of the Solanaceae family (hot chili peppers) has long been used as an experimental tool because of its selective action on the small diameter afferent nerve fibers, or C fibers, that are believed to mediate pain. From studies in animals, capsaicin appears to trigger C fiber membrane depolarization by opening cation selective channels for calcium and sodium. Although detailed mechanisms are not yet known, capsaicin mediated effects include: (i) activation of nociceptors in peripheral tissues; (ii) eventual desensitization of peripheral nociceptors to one or more stimulus modalities; (iii) cellular degeneration of sensitive unmyelinated C fiber afferents; (iv) activation of neuronal proteases; (v) blockage of axonal transport; and (vi) the decrease of the absolute number of C fibers without affecting the number of myelinated fibers.
Because of capsaicin's ability to desensitize nociceptors in peripheral tissues, its potential analgesic effects have been assessed in various clinical trials. However, since the capsaicin application itself frequently causes burning pain and hyperalgesia apart from the neuropathic pain being treated, patient compliance has been poor and the drop out rates during clinical trials have exceed fifty percent. The spontaneous burning pain and heat hyperalgesia are believed to be due to intense activation and temporary sensitization of the peripheral nociceptors at the site of capsaicin application (primary hyperalgesia). Mechanical hyperalgesia evident in areas surrounding the site of topical application appears to originate from central sensitization of dorsal horn neurons involved in pain transmission (secondary hyperalgesia). Because of these side effects, the maximal capsaicin concentration used in previous human studies has been limited to 0.075%.
Analogs of capsaicin with similar physiological properties are known. For example, resiniferatoxin is described as a capsaicin analog by inventor Blumberg, U.S. Pat. No. 5,290,816, issued Mar. 1, 1994. Inventor Brand in U.S. Pat. No. 4,812,446, issued Mar. 14, 1989, describes capsaicin analogs and methods for their preparation. Further, inventors LaHann et al. in U.S. Pat. No. 4,424,205, issued Jan. 3, 1984, cite Newman, “Natural and Synthetic Pepper-Flavored Substances” published in 1954 as listing pungency of capsaicin-like analogs. Ton et al.,
British Journal of Pharmacology,
10, pp. 175-182 (1955) discuss pharmacological actions of capsaicin and its analogs.
SUMMARY OF THE INVENTION
One aspect of the present invention comprises administering an anesthetic to a patient suffering neuropathic pain followed by applying a composition including from about 5% to about 10% of capsaicin (and/or a capsaicin analog) by weight to the patient. The capsaicin (and/or capsaicin analog) containing composition preferably is administered topically, is applied more than once, and includes a vehicle with skin penetrating properties. The anesthetic preferably is by means of a somatic or neuraxial block administered prior to application of the capsaicin (and/or capsaicin analog) composition, which can be of any local anesthetic, and can be administered such as by injection in the epidural space adjacent to the spine. The prior administration of a proximal neural block sufficiently desensitizes C fibers to the expected side effects of the subsequent capsaicin application. The administration of the anesthetic along with the subsequent administration of capsaicin appears to alleviate the symptoms of peripheral neuropathy for a prolonged period of time. For example, patients with previously resistant neuropathic pain have experienced pain relief for periods of two weeks to seven weeks following the high dose capsaicin treatment as described in this invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Practice of the invention prevents the burning pain and hyperalgesia to both heat and touch typically occurring after even the relatively low concentration applications of capsaicin ointment known to the art. Such burning pain is avoided by first administering an anesthetic, such as a block (somatic or neuraxial), so as to cause regional anesthesia in the areas to be treated.
It is believed feasible to employ topically active anesthetic cremes in addition to or in lieu of the anesthetic block to prevent the side effects from the application of the high dose capsaicin, thus reducing or obviating the need to perform a somatic block.
A wide variety of suitable anesthetics for the block are known and useful, such as tetracaine hydrochloride and the like. Due to its short action, 2-chloroprocaine hydrochloride is preferred among the suitable local anesthetics. The local anesthetic is administered at an appropriate site, one preference being at the epidural space adjacent the spine for neuropathic pain originating below a patient's waist (such as in a patient's legs or feet).
When the anesthetic administered has taken effect in providing analgesia, then a composition including capsaicin (and/or a capsaicin analog) is administered, preferably by topical application, at least once. This composition preferably is formulated with a vehicle having a skin penetrating and skin absorbing agent. One suitable such vehicle is commercially available as EUCERIN cosmetic skin lotion (Beiersdorf Aktiengesellschaft). The topical application of the capsaicin (and/or capsaicin analog) containing composition delivers the drug through the skin. Because skin is a structurally complex, relatively thick membrane, molecules moving from the environment into and through intact skin must first penetrate the stratum corneum and any material on its surface, then penetrate the viable epidermis, the papillary dermis, and the capillary walls. To be so absorbed, molecules must overcome a different resistance to penetration in the different types of tissue. It is for these reasons that the formulation is prepared so as to increase skin permeability and to increase the permeability in particular of the stratum corneum. Such skin penetrating and absorbing agents are known to the art. For example, the capsaicin composition can include one or more penetration-enhancing agents such as those described by U.S. Pat. No. 4,971,800, issued Nov. 20, 1990, inventors Chess et al.
At present, capsaicin is commercially available in over-the-counter topical preparations at concentrations of 0.025% and 0.075%. However, capsaicin concentrations in the range of 5-10% appear to be necessary to sufficiently desensitize the C fiber population to effectuate prolonged relief from many of the symptoms of peripheral neuropathy. Thus, capsaicin compositions necessary for the practice of this invention must be prepared by mixing pure capsaicin powder to the desired concentration by weight, from about 5% to 10%, more preferably at about 7.5%, in the selected vehicle. Such an admixture of high concentration of capsaicin is a substance that m
Pappagallo Marco
Robbins Wendye R.
Staats Peter S.
Jones Dwayne C.
The Regents of the University of California
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