Safer Nonaddicting and Nonabusable Analgesics: Targeting Truncated 6-Transmembrane Exon 11 Variants of the Oprm1 Gene for Battlefield Pain
Abstract
Morphine and fentanyl, the most commonly prescribed drugs for sufferers of acute and chronic pain, have many problematic side effects. The most common cause of death is respiratory depression caused by activation of the mu opioid receptor, which is the primary target of these drugs. There were 18,893 overdose deaths related to prescription opioid pain relievers and 10,574 overdose deaths related to heroin (a street opioid drug) in 2014. On average, there were 80 overdose deaths a day in 2014 in America. http://www.cdc.gov/nchs/data/health_policy/AADR_drug_poisoning_involving_OA_Heroin_US_2000-2014.pdf. Usage of opioids both as prescription and street drugs also leads to addiction and abuse liability. Opioid abuse in present-day America is an epidemic. The total societal costs of prescription opioid abuse in 2007 were calculated to be $55.7 billion, of which lost workplace productivity contributed $25.6 billion, healthcare costs contributed $25.0 billion, and criminal justice costs accounted for the remaining $5.1 billion (http://www.robindimatteo.com/uploads/3/8/3/4/38344023/societal_costs_opioid_abuse.pdf). Soldiers in the battlefield require opioids to treat the severe pain from combat injuries. Acutely, opioid sedation can impair a Soldier?s attentiveness and judgment, interfering with his/her ability to continue fighting after being wounded. Respiratory depression, particularly in combination with chest wounds or severe head injury, is also problematic and can require additional attention from caregivers on the battlefield. Many injuries lead to prolonged pain issues, opening the Warrior to the potential of physical dependence and addiction liability that can have long-term impact on the mental health of returning Veterans. Finally, many traumatic injuries lead to nerve damage that, in turn, leads to neuropathic pain that is poorly treated with opioids. Clearly safer analgesics are needed without the liabilities of the current clinically used opioid pain medications. Non-pain management is one of the topic areas of the Fiscal Year 2016 Peer Reviewed Medical Research Program that this proposal aims to cover. There are two levels of innovation in this present proposal. The first is a novel drug target distinct from the opioid receptors responsible for drugs such as morphine, fentanyl, and heroin. In addition to lacking respiratory depression, physical dependence, and reward, drugs acting through this new target are potent in a wide range of somatic, neuropathic, and inflammatory pain models. The second level of innovation involves the identification of a natural product scaffold unrelated to morphine. About 50% of approved medications in human use today are either natural products or there derivatives suggesting an excellent starting point for discovering novel drugs. In the present proposal, we utilize 7-OH mitragynine as our lead compound. Our group has developed a synthetic strategy to synthesize 7-OH mitragynine from mitragynine and to generate a range of analogs. 7-OH mitragynine is a potent pain killer -- about 10 times more potent than morphine -- that has no respiratory depression or constipation and that acts through the novel drug target. The central hypothesis of this proposal is that syntheses of 7-OH mitragynine and analogs will lead to greater understanding of the mechanism of action of compounds acting through a novel drug target unrelated to classical opioids such as morphine and the potential development of safer, effective analgesics.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710256
Entities
People
- Susruta Majumdar
Organizations
- Memorial Sloan Kettering Cancer Center
- United States Army