Will peripherally restricted kappa-opioid receptor agonists (pKORAs) relieve pain with less opioid adverse effects and abuse potential?

Abstract

Summary What is known and objective Optimal utilization of opioid analgesics is significantly limited by the central nervous system adverse effects and misuse/abuse potential of currently available drugs. It has been postulated that opioid‐associated adverse effects and abuse potential would be greatly reduced if opioids could be excluded from reaching the brain. We review the basic science and clinical evidence of one such approach – peripherally restricted kappa‐opioid receptor (KOR) agonists (pKORAs). Methods Published and unpublished literature, websites and other sources were searched for basic science and clinical information related to the potential benefits and development of peripherally restricted kappa‐opioid receptor agonists. Each source was summarized, reviewed and assessed. Results The historical development of pKORAs can be traced from the design of increasingly KOR‐selective agonists, elucidation of the pharmacologic attributes of such compounds and strategies to restrict passage across the blood–brain barrier. Novel compounds are under development and have progressed to clinical trials. What is new and conclusions The results from recent clinical trials suggest that peripherally restricted opioids can be successfully designed and that they can retain analgesic efficacy with a more favourable adverse effect profile.

Selective κ receptor partial agonist HS666 produces potent antinociception without inducing aversion after i.c.v. administration in mice

“…The μ receptor agonists are efficacious analgesics (Spetea et al, 2013b;Pasternak, 2014) but induce unwanted euphoria, addiction, respiratory depression and gastrointestinal tract inhibition (Benyamin et al, 2008;Atkinson et al, 2014). The κ receptor modulates pain processing at central and peripheral sites, and pain remains a likely indication for κ agonists (Kivell and Prisinzano, 2010;Albert-Vartanian et al, 2016). Moreover, κ agonists do not cause the liabilities of μ receptor activation.…”

Randomized Controlled Trial of Difelikefalin for Chronic Pruritus in Hemodialysis Patients

“…Difelikefalin (CR845) is a peripherally restricted and selective agonist at KORs, with no identified off-target activity. 18 Its unique all D-amino acidÀbased peptide structure is different from small organic heterocycle KOR agonists studied to date, which activate both central and peripheral KORs in addition to other receptors. Preclinical studies demonstrated that due to its physicochemical properties, difelikefalin does not penetrate the blood-brain barrier and thus may not produce the undesirable central nervous system effects related to activation of central KORs (e.g., dysphoria, hallucinations).…”

The dynamic interaction between pain and opioid misuse

“…Likewise, the mechanisms of opioid sparing remain to be elucidated, but are at least partially mediated by overall analgesic requirements, given the self‐tapering nature of patients' opioid dosing after the initiation of cannabis therapy (Boehnke et al, ; Haroutounian et al, ). Peripherally restricted opioid agonists are also undergoing intense investigation, because of their inability to produce the adverse effects mediated by the central nervous system (Albert‐Vartanian et al, ). Although this approach has great potential utility in clinical practice, to date, there is only one peripherally restricted opioid undergoing Phase II clinical trials (κ receptor agonist JNJ‐38488502; Olesen et al, ).…”