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

> **NIH NIH R36** · WEST VIRGINIA UNIVERSITY · 2020 · $54,000

## Abstract

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”.

## Key facts

- **NIH application ID:** 10040041
- **Project number:** 1R36DA051703-01
- **Recipient organization:** WEST VIRGINIA UNIVERSITY
- **Principal Investigator:** Allison White
- **Activity code:** R36 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $54,000
- **Award type:** 1
- **Project period:** 2020-09-30 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10040041

## Citation

> US National Institutes of Health, RePORTER application 10040041, Pre-clinical assessments of dose-sparing and anti-addictive adjuvants to prevent the future abuse of opioid analgesics (1R36DA051703-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10040041. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*