Therapeutic Development of Non-Opioid Strategically Substituted Agmatines for Chronic Pain Management
Abstract
Topic Area: Chronic pain has been recognized as a significant problem for military personnel. Through establishment of the Pain Management Task Force in 2010, the Department of Defense recognized the critical need to advocate for an integrated approach to improve pain management options to optimize the quality of life for military personnel. The impact of chronic pain in the United States of America as summarized by the Institute of Medicine (IoM) is estimated at 100 million US adults afflicted with chronic pain and that a national economic cost of chronic pain in the US is approximated at $560-$635 billion/year. Improving pain control is a national public health priority as stated through the National Pain Strategy, introduced in 2016 by Office of the Assistant Secretary of Health, and reconfirmed by the Federal Pain Research Strategy launched in 2017. Non-opioid analgesic therapeutics offer the potential to meet the needs of our military and civilian pain patients while mitigating or eliminating the risk of misuse, abuse, and addiction. Area of Encouragement: The area of encouragement this application addresses is neuropathic pain and sensory dysfunction with an emphasis on developing alternatives to current opioid analgesics for severe pain management. Central Critical Problem: Opioids remain a mainstay treatment for chronic pain. However, opioid misuse and abuse has led to a national opioid epidemic. For nearly 20 years, our research group has been looking for non-opioid alternatives to treat pain to avoid the need for opioids or decrease the amount of opioid needed. We have investigated a mechanism in the central nervous system that inhibits the development and persistence of chronic pain and also reduces the development of opioid-induced tolerance, potentially reducing opioid dose requirements. This mechanism takes advantage of the communication system used by the amino acid glutamate, which carries the pain signal forward in the spinal cord. When the glutamate system is inhibited, chronic pain is reduced. There are several well-known clinically used drugs that can inhibit this system including dextromethorphan (an ingredient commonly found in cough syrup) and ketamine (an anesthetic). There have been attempts to develop both of these drugs to treat chronic pain; however, they have other side effects that have limited their utility. Overview of Proposed Research: We have studied the effects of a chemical related to the amino acid Larginine, agmatine. We have shown that agmatine reduces chronic pain through inhibition of the glutamate system discussed above. The difference between agmatine and the compounds mentioned above is that agmatine does not have the same side effects. We have now discovered a way to improve the potential of making agmatine a medication by modifying the structure, creating a new compound we refer to as Strategically Substituted Agmatine (SSA). This new structure allows agmatine to be more directly available in the region where pain is transmitted. In this proposal, we seek to finalize the synthesis and formulation for our lead SSA and conduct safety and toxicology experiments. Additionally, research will be done to confirm that SSA does not have a high likelihood of being addictive. Following the successful completion of these efforts, SSA will be poised to begin clinical trials in people, a significant step for the advancement of this research. Impact: Opioids are currently essential medications for treating severe pain. However, through expanded use of opioids, an addiction crisis in our country has emerged that has increased fatal accidental overdoses. According to the National Institute of Drug Abuse, annual overdose deaths due to the abuse of both prescription and illegal opioids amounted to 53,000 people in 2016, a 32% increase from the previous year. Now is an optimal time to bring our discovery through the development process to develop a new medicati
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910673
Entities
People
- Carolyn A. Fairbanks
Organizations
- United States Army
- University of Minnesota