Pre-clinical assessments of dose-sparing and anti-addictive adjuvants to prevent the future abuse of opioid analgesics

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Project Abstract Treating acute pain with highly addictive mu opioid receptor (MOR)-targeting analgesic drugs, such as oxycodone, hydrocodone, and hydromorphone, has contributed greatly to the present American opioid overdose epidemic, owing to the inherent euphoria-inducing (“rewarding”) effects of these opioid analgesic drugs. Compounds that activate the kappa opioid receptor (KOR), when co-administered with MOR-targeting opioid analgesic drugs, can not only reduce these rewarding properties, but can also enhance of their painkilling properties. However, conventional (“unbiased”) KOR activators have failed in the clinic due to poor tolerance. Many of the negative side effects that follow the use of unbiased KOR agonists are thought to be associated with engaging G protein-independent signaling pathways. It has therefore been proposed that newer G protein- biased KOR agonists might retain their therapeutic benefits without creating negative side effects by reducing the extent to which they signal through these G protein-independent pathways. My long-term goal is therefore to provide an appropriate level of pre-clinical validation to support future clinical trials of the G protein-biased KOR agonist nalfurafine as an anti-addictive / dose-sparing adjuvant to be administered alongside MOR-targeting opioid analgesic drugs. Nalfurafine is an immediately tangible adjuvant candidate given its current use in Japan for uremic pruritus and its decade-long history of safety and tolerability. In this way, successful pre-clinical testing of the use of nalfurafine as an adjuvant will materially advance a novel (and quickly tractable) strategy to reduce the addictive liability of treating acute pain with conventional opioid analgesic drugs. In the short-term, I will perform key mouse-based effect, side effect, and in vivo signaling studies, pairing nalfurafine with the clinically relevant MOR-targeting analgesic drugs morphine, oxycodone, hydrocodone, and hydromorphone, to support this long-term goal. Aim 1 is to determine, via mouse behavioral assays, the therapeutic efficacy of nalfurafine as an adjuvant that reduces the addictive potential of MOR-targeting analgesic drugs without compromising their anti-nociceptive effects. Aim 2 is to determine the anti-therapeutic liabilities associated with co-administration of nalfurafine with MOR-targeting opioid analgesic drugs via mouse behavioral assays that inform on known side effects of unbiased KOR agonists (namely dysphoria, depression, anxiety, and psychotomimesis). Pre-clinical evidence establishing nalfurafine as an addiction-reducing additive to opioid analgesic drugs should lead to future human trials of such a drug combination in acute pain indications. In this way, my proposal is responsive to NIDA’s Notice of Special Interest NOT-19-048 “Research to Prevent Drug Use, Misuse and Addiction”.