Opioid Use Disorder Treatment Gaps and Emerging Therapeutics to Address Them

Despite the availability of three effective opioid use disorder (OUD) medications, the ongoing opioid crisis now in its third decade continues to present global public health challenges. Thus, there is a need for basic and applied research to develop safer and more effective OUD medications to address current treatment gaps. Current OUD medications are clinically deployed based on the level of opioid dependence of the patient with the high intrinsic efficacy mu-opioid receptor (MOR) agonist methadone utilized in high opioid-dependent patients, the partial intrinsic efficacy MOR agonist buprenorphine utilized in moderate-to-low opioid-dependent patients, and the MOR antagonist naltrexone utilized exclusively in nonopioid-dependent patients. Thus, the degree of opioid dependence is an important consideration for both current OUD medications and candidate OUD medication preclinical research. Preclinical experimental design attributes that facilitate preclinical-to-clinical translation will be briefly reviewed before highlighting activity within each of three main categories of candidate OUD medication research targets: (1) medications that target addictive opioid distribution and pharmacokinetic factors such as opioid-targeted vaccines and monoclonal antibodies, (2) medications that directly target MORs such as novel low-efficacy MOR agonists or long-acting formulations, and (3) medications that target post-MOR signaling effects that include both reinforcing effects and non-reinforcing effects such as glucagon-like peptide 1 agonists and dopamine D3 receptor ligands. Future directions for continued OUD medication development are proposed to address the evolving illicit opioid environment that includes both ultrapotent MOR agonists and non-opioid adulterants.