Safe and effective
pain management is a critical healthcare and societal need. The potential for acute liver injury from
paracetamol (
ApAP) overdose; nephrotoxicity and gastrointestinal damage from chronic non-steroidal anti-inflammatory drug (
NSAID) use; and
opioids' addiction are unresolved challenges. We developed SRP-001, a non-
opioid and non-hepatotoxic small molecule that, unlike
ApAP, does not produce the hepatotoxic metabolite N-acetyl-
p-benzoquinone-
imine (
NAPQI) and preserves hepatic tight junction integrity at high doses. CD-1 mice exposed to SRP-001 showed no mortality, unlike a 70% mortality observed with increasing equimolar doses of
ApAP within 72 h. SRP-001 and
ApAP have comparable antinociceptive effects, including the complete
Freund's adjuvant-induced inflammatory von Frey model. Both induce
analgesia via N-arachidonoylphenolamine (
AM404) formation in the midbrain periaqueductal grey (PAG) nociception region, with SRP-001 generating higher amounts of
AM404 than
ApAP. Single-cell transcriptomics of PAG uncovered that SRP-001 and
ApAP also share modulation of
pain-related gene expression and cell signaling pathways/networks, including
endocannabinoid signaling, genes pertaining to mechanical nociception, and
fatty acid amide hydrolase (FAAH). Both regulate the expression of key genes encoding FAAH,
2-arachidonoylglycerol (2-AG),
cannabinoid receptor 1 (CNR1), CNR2, transient receptor potential vanilloid type 4 (TRPV4), and voltage-gated Ca2+ channel. Phase 1 trial (NCT05484414) (02/08/2022) demonstrates SRP-001's safety, tolerability, and favorable pharmacokinetics, including a half-life from 4.9 to 9.8 h. Given its non-hepatotoxicity and clinically validated
analgesic mechanisms, SRP-001 offers a promising alternative to
ApAP,
NSAIDs, and
opioids for safer
pain treatment.