NIDA’s medication development priorities in response to the Opioid Crisis: ten most wanted

摘要

The United States is in the midst of a horrific problem. The rampant misuse of opioid drugs (both prescribed and illegal), now known as the Opioid Crisis, has had grave effects on both the public health and the well-being of our society. In 1 year, 2017, it is estimated that almost as many Americans died from opioid-related overdose as died in the entire Vietnam War [ 1 ]. In response to the problem, the White House has declared the Opioid Crisis a national Public Health Emergency under federal law [ 2 ]. The causes of the Opioid Crisis are complex and multifaceted and a solution will require a Herculean, integrated effort from disparate components of society. Changes in both the public and private sectors (e.g., revisions in: health care policy; medical education; business regulation; deployment of existing medications; local and state justice systems) will be needed to address this crisis. In an effort to leverage science to help address the problem, the National Institutes of Health (NIH) has launched the HEAL (Helping to End Addiction Long-term) Initiative, an aggressive, trans-agency effort to speed scientific solutions to the Opioid Crisis [ 3 ]. This initiative will nearly double funding for research on opioid misuse/addiction and pain. As part of the NIH, the National Institute on Drug Abuse (NIDA) is devoted to addressing this crisis in multiple ways. NIDA will coordinate four overarching research projects around the country: the Focused Opioid Use Disorder (OUD) Medications Development Research Project; the HEALing Communities Study; the Clinical Trials Network OUD Research Enhancement Project; and the Justice Community Opioid Innovation Network [ 4 ]. The medication development component of this four-pronged effort includes aiding the development of novel pharmacotherapies, behavioral therapies and devices for the treatment of opioid overdose and OUD. Our science can have political, economic and social ramifications. Indeed, the introduction of safe and effective therapeutics, while unlikely to be a panacea, has the potential to transform not only health outcomes for individual patients, but anachronistic societal attitudes towards diseases, especially brain diseases. In this regard, we hope that the introduction of new safe and effective medications for OUD will enlighten the public discourse around opioid addiction and those suffering from it. In an effort to specifically speed the development of pharmacotherapies for the treatment of OUD and reach NIDA’s stated goal of 15 Investigational New Drugs (INDs) and 5 New Drug Applications (NDAs) submitted to the Food and Drug Administration (FDA), NIDA’s Division of Therapeutics and Medical Consequences (DTMC) has created a list of medication development priorities. The mechanisms listed in Table? 1 are NIDA’s DTMC highest priority pharmacological targets for the development of novel therapeutics to treat opioid overdose and OUD in the near term . The list does not include mechanisms of existing OUD medications and the mechanisms are listed in no particular order. While the existing medications (e.g., buprenorphine, methadone, naloxone, naltrexone, lofexidine) have demonstrable utility in the treatment of OUD, they are not without limitations. Indeed, problematic residual symptoms and discontinuation rates plague these treatments [ 5 , 6 ], leaving a deceptively cavernous un-met medical need that could be addressed, at least in part, by new medications. Table 1 NIDA's DTMC ten most wanted pharmacological mechanisms for the rapid development of therapeutics in response to the Opioid Crisis NIDA’s DTMC?ten most wanted Orexin-1 or 1/2 antagonists or NAMs [ 17 – 19 ] Kappa opioid antagonists or NAMs [ 20 , 21 ] GABA-B agonists or PAMs [ 22 , 23 ] Muscarinic M5 antagonists or NAMs [ 24 , 25 ] AMPA antagonists, NAMs or PAMs [ 26 – 28 ] NOP/ORL agonists, antagonists, NAMs or PAMs [ 29 – 31 ] mGluR2/3 agonists or PAMs [ 32 – 34 ] Ghrelin antagonists or NAMs [ 35 , 36 ] Dopamine D3 partial agonists, PAMs, antagonists or NAMs [ 37 , 38 ] Cannabinoid CB-1 antagonists or NAMs [ 39 , 40 ] PAM positive allosteric modulator, NAM negative allosteric modulator, AMPA α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, GABA γ-aminobutyric acid, NOP nociceptin opioid peptide receptor, ORL opioid receptor like, mGluR metabotropic glutamate receptor, 5HT 5-hydroxytryptamine, MOP mu opioid protein Other mechanisms of interest: 5HT2C agonists or PAMs, with or without 5HT2A antagonist/NAM activity [ 41 , 42 ] Biased Mu Opioid agonists or PAMs [ 43 , 44 ] NOP/MOP bifunctional agonists or PAMs [ 45 , 46 ] Respiratory stimulants (including nicotinic agonists) [ 47 , 48 ] Our goal is to help deliver new treatment options to the millions of patients and physicians battling OUD. At this point in time, we feel compounds with the mechanisms-of-action listed in Table? 1 have the highest probability of a path to FDA approval for the treatment of some aspect of OUD in the near term