Opioid-Sparing and Pain-Reducing Properties of Syntocinon: A Dose-Effect Determination

ABSTRACT Opioid misuse is a major source of morbidity and mortality in the U.S. and represents a pressing public health crisis. Opioid-related overdose deaths have more than quadrupled since 2002. Oxycodone (in Percocet™ and Oxycontin™) is reliably among the medications commonly prescribed for pain, but is also widely abused and involved in overdose deaths. Despite its abuse potential, oxycodone is effective for reducing acute pain. There is an urgent need for interventions that preserve the analgesic properties of oxycodone while curtailing its abuse potential. A promising adjunctive treatment option for pain management, that could simultaneously reduce the abuse liability of opioids, is syntocinon (the intranasal formulation of the neuropeptide oxytocin). Syntocinon may reduce opioid abuse potential, and simultaneously has analgesic properties. Animal models have shown that oxytocin decreases opioid intravenous self- administration and reverses oxycodone conditioned place preference. Rat models of pain show that oxytocin enhances anti-nociception (blocking of painful stimuli), and in humans, syntocinon administration decreases pain sensitivity experimentally. Further, evidence in animals and humans support the shared brain structure and function changes associated with both addiction and chronic pain, which may be modulated by oxytocin administration. Based on the existing literature, we propose that syntocinon will significantly reduce abuse liability of opioids and reduce experimental pain via its effects on brain structure, function and biochemistry. Thirty healthy recreational opioid users will self-administer 48 IUs of intranasal syntocinon (or placebo) shortly after oral oxycodone (0, 2.5, 5.0 mg) in a double-blind, randomized, placebo-controlled, within- subjects laboratory study. Subject-rated abuse liability and cardiovascular and respiratory responses will be assessed before and repeatedly for 5 hours following drug administration. Pain and neurobiological measures will also be collected, including a standardized experimental pain battery (i.e., quantitative sensory testing) and a multi-modal neuroimaging battery (i.e., brain structure, function, and biochemistry). This study has tremendous potential for public health impact in examining intranasal oxytocin as a promising agent for reducing opioid addictive potential, while effectively reducing pain, which could substantially advance the field of pharmacotherapy and carve out a novel treatment option. This study will also advance scientific understanding of neurobiological mechanisms underlying the link between abuse potential and pain. This research will also facilitate the PI’s career goals and path to independence by developing expertise in 1) multi-modal assessments of pain; 2) neuroimaging techniques as they relate to addiction and pain; 3) deepen current expertise in addiction and human behavioral pharmacology in the context of opioid administration and translation; 4) grant and manuscript writing skills; and 5) enhance management and supervision skills. This multidisciplinary team is uniquely suited to mentor the PI in these areas and address the proposed aims.