Methods and compositions using ampk activators for pharmacological prevention of chronic pain

Abstract

Methods and compositions using a combination of adenosine monophosphate protein kinase (AMPK) activators for treating pain such as post-surgical pain or development of chronic pain. The two or more AMPK activators work synergistically and may be administered in individually sub-efficacious doses. The AMPK activators may have different mechanisms of AMPK activation. The AMPK activators may be administered systemically and/or topically in, for example, as a gel, ointment, cream, lotion, suspension, liquid, or transdermal patch.

What is claimed: 
     
         1 . A composition for preventing, reducing, or treating pain in a subject, said composition comprising:
 a. a dosage of a first 5′-adenosine monophosphate-activated protein kinase (AMPK) activator; and   b. a dosage of a second AMPK activator;   wherein the dosage of the first AMPK activator is an individually sub-efficacious dose, and the dosage of the second AMPK activator is an individually sub-efficacious dose,   wherein the first AMPK activator and the second AMPK activator can synergistically prevent, reduce, or treat pain.   
     
     
         2 . The composition of  claim 1 , wherein the pain is neuropathy pain, acute pain, incision-induced hypersensitivity, incision-induced hyperalgesic priming, or incision-induced development of chronic pain. 
     
     
         3 . The composition of  claim 1 , wherein the second AMPK activator has a mechanism of AMPK activation that is different from that of the first AMPK activator. 
     
     
         4 . The composition of  claim 1 , wherein the composition is applied topically. 
     
     
         5 . The composition of  claim 1 , wherein the first AMPK activator comprises a hormone or a natural compound and the second AMPK activator comprises a molecule selected from the group consisting of A769662, salicylate or a derivative thereof, AICAR, PT1, C24, and OSU53. 
     
     
         6 . The composition of  claim 1 , wherein the first AMPK activator is a hormone and the second AMPK activator is a natural compound. 
     
     
         7 . The composition of  claim 6 , wherein the hormone is selected from the group consisting of a salicylate or a derivative thereof, adiponectin, leptin, IL-6, and ciliary neurotrophic factor (CNTF). 
     
     
         8 . The composition of  claim 6 , wherein the natural compound is selected from the group consisting of resveratrol, berberine, galegine, quercetin, ginsenoside, curcumin, epigallocatechin gallate, theaflavin, hispidulin, rooibos, and alpha-lipoic acid. 
     
     
         9 . The composition of  claim 1 , wherein the first and second AMPK activators independently comprise a hormone, a natural compound, a biguinide, or a thiazolidinedione. 
     
     
         10 . A method of preventing, reducing, or treating pain in a subject in need thereof, said method comprising administering to the subject a dosage of a first 5′-adenosine monophosphate-activated protein kinase (AMPK) activator and a dosage of a second AMPK activator, wherein the dosage of the first AMPK activator is an individually sub-efficacious dose, and the dosage of the second AMPK activator is an individually sub-efficacious dose, wherein the first AMPK activator and the second AMPK activator synergistically prevent, reduce, or treat pain. 
     
     
         11 . The method of  claim 10 , wherein the pain is neuropathy pain, acute pain, incision-induced hypersensitivity, incision-induced hyperalgesic priming, or incision-induced development of chronic pain. 
     
     
         12 . The method of  claim 10 , wherein the second AMPK activator has a mechanism of AMPK activation that is different from that of the first AMPK activator. 
     
     
         13 . The method of  claim 10 , wherein the dosages are administered topically. 
     
     
         14 . The method of  claim 10 , wherein the first AMPK activator comprises a hormone or a natural compound and the second AMPK activator comprises a molecule selected from the group consisting of A769662, salicylate or a derivative thereof, AICAR, PT1, C24, and OSU53. 
     
     
         15 . The method of  claim 10 , wherein the first AMPK activator is a hormone and the second AMPK activator is a natural compound. 
     
     
         16 . The method of  claim 15 , wherein the hormone is selected from the group consisting of a salicylate or a derivative thereof, adiponectin, leptin, IL-6, and ciliary neurotrophic factor (CNTF). 
     
     
         17 . The method of  claim 15 , wherein the natural compound is selected from the group consisting of resveratrol, berberine, galegine, quercetin, ginsenoside, curcumin, epigallocatechin gallate, theaflavin, hispidulin, rooibos, and alpha-lipoic acid. 
     
     
         18 . The method of  claim 10 , wherein the first and second AMPK activators independently comprise a hormone, a natural compound, a biguinide, or a thiazolidinedione. 
     
     
         19 . A method of preventing, reducing, or treating pain in a subject in need thereof, said method comprising topically administering to the subject a dosage of a first 5′-adenosine monophosphate-activated protein kinase (AMPK) activator and a dosage of a second AMPK activator, the first AMPK activator is a salicylate or a derivative thereof and the second AMPK activator is resveratrol, wherein the dosage of the first AMPK activator is an individually sub-efficacious dose, and the dosage of the second AMPK activator is an individually sub-efficacious dose, wherein the first AMPK activator and the second AMPK activator synergistically prevent, reduce, or treat pain. 
     
     
         20 . The method of  claim 19 , wherein the pain is neuropathy pain, acute pain, incision-induced hypersensitivity, incision-induced hyperalgesic priming, or incision-induced development of chronic pain.