Perineural administration of resiniferatoxin for treatment of maladaptive pain
Disclosed herein are methods of administering resiniferatoxin (RTX) perineurally for treatment of maladaptive pain, and compositions for use in such methods.
1. A method of treating maladaptive pain, comprising peripherally perineurally administering resiniferatoxin (RTX) to a subject in need of treatment of maladaptive pain.
2. The method of claim 1 , wherein the method comprises administering a dose of 0.1 μg to 100 μg of RTX, or a dose of RTX in the range of from 0.1-1 μg, 1-2 μg, 2-5 μg, 5-10 μg, 10-20 μg, 20-30 μg, 30-40 μg, 40-50 μg, 50-60 μg, 60-70 μg, 70-80 μg, 80-90 μg, or 90-100 μg.
3. The method of claim 1 , wherein the RTX is administered perineurally to a single site, to a plurality of sites, to the sciatic nerve, to the saphenous nerve, to the femoral nerve, to the radial nerve, to the ulnar nerve, to the median nerve, to the musculocutaneous nerve, and/or to the palmar digital nerve; or wherein the RTX is administered perineurally to a plurality of sites that collectively correspond to sensory input from one or more digits, a foot or hand, a forelimb, a limb, and/or a joint.
4. The method of claim 1 , wherein the subject is an amputee, or the subject suffers from phantom limb pain or stump pain; or wherein perineural administration targets one or more nerve fibers downstream of an amputation site.
5. The method of claim 1 , wherein perineural administration targets at least two, three, four, or five nerve fibers downstream of an amputation site.
6. The method of claim 1 , wherein the subject has abnormal nerve growth at nerve endings.
7. The method of claim 6 , wherein perineural administration targets one or more nerve fibers downstream of a nerve with abnormal growth at its peripheral ending.
8. The method of claim 1 , wherein perineural administration targets one or more nerve fibers downstream of a neuroma.
9. The method of claim 1 , wherein the method comprises administering a pharmaceutical formulation comprising the RTX and a pharmaceutically acceptable carrier.
10. The method of claim 9 , wherein the pharmaceutically acceptable carrier comprises
a) water;
b) polysorbate 80;
c) polyethylene glycol;
d) a sugar or sugar alcohol;
e) mannitol;
f) dextrose;
g) a pharmaceutically acceptable salt; and/or
h) a pharmaceutically acceptable buffer.
11. The method of claim 10 , wherein the pharmaceutically acceptable carrier comprises a pharmaceutically acceptable buffer, and the pharmaceutically acceptable buffer is a phosphate buffer.
12. The method of claim 10 , wherein the pharmaceutical formulation has a pH in the range of 6 to 7.6; or wherein the pharmaceutical formulation has a pH in the range of 6 to 6.4, 6.3 to 6.7, 6.4 to 6.8, 6.8 to 7.2, 7 to 7.4, or 7.2 to 7.6; or wherein the pharmaceutical formulation has a pH of 6.5 or 7.2.
13. The method of claim 10 , wherein the concentration of RTX in the pharmaceutical formulation is in the range of 0.02-0.1 μg/ml or 0.1 to 300 μg/ml.
14. The method of claim 13 , wherein the concentration of RTX in the pharmaceutical formulation is in the range of 0.02-0.1 μg/ml, 0.1-1 μg/ml, 1-5 μg/ml, 5-10 μg/ml, 10-20 μg/ml, 20-50 μg/ml, 50-100 μg/ml, 100-150 μg/ml, 150-200 μg/ml, 200-250 μg/ml, or 250-300 μg/ml.
15. The method of claim 10 , wherein the concentration of RTX in the pharmaceutical formulation is in the range of 0.1-200 μg/ml, optionally wherein the concentration of RTX in the pharmaceutical formulation is in the range of 0.1-50 μg/ml.
16. The method of claim 1 , wherein the RTX is administered in an injection volume of 0.05-10 ml, optionally wherein the injection volume is in the range of 0.05-0.2 ml, 0.2-0.5 ml, 0.5-1 ml, 1-2 ml, 2-5 ml, or 5-10 ml.
17. The method of claim 1 , wherein the subject is a mammal; or wherein the subject is a cat, dog, horse, pig, ruminant, cow, sheep, goat, or domesticated mammal.
18. The method of claim 17 , wherein the subject is a human.
19. The method of claim 1 , wherein the treatment reduces local and central effects of the maladaptive pain.
20. The method of claim 1 , wherein the subject had one or more behavioral symptoms of maladaptive pain prior to treatment and the treatment reduces or eliminates the one or more behavioral symptoms.