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 Methods Published and unpublished literature, websites and other sources were searched for basic science and clinical information related to the potential benefits and development of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.

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