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Peripheral opioid receptor agonists for analgesia: A comprehensive review

Nalini Vadivelu, MD, Sukanya Mitra, MD, Roberta L. Hines, MD


Background: It is established that opioid receptors are present in the dorsal root ganglia and the central as well as peripheral terminals of primary afferent neurons. Now, it has been shown that peripheral terminals of afferent nerves can be the sites of the intrinsic modulation of nociception and that opioid analgesia can be mediated by peripheral opioid receptors as well.
Aim: This review focuses on two areas: the first on describing the peripheral opioidergic system, and the second on the review of the current state of development of peripherally active opioid receptor agonists with their potential clinical applications.
Methods: Online and manual search using key words such as peripheral opioid receptors, peripheral (or peripherally restricted) opioid agonists, and peripheral mu-, kappa-, and delta-opioid receptor agonists, followed by full-text access and further cross-referencing.
Results: The obvious theoretical advantage of using these molecules is that analgesia is achieved while avoiding the bothersome-to-dangerous centrally mediated adverse effects of centrally acting opioids. Molecules known for their central action (eg, morphine) have been used in peripheral tissues (joints, bone, teeth) with reasonable but varied success. Over the last 10-15 years, several molecules with peripherally restricted opioid agonist activity have been developed and several more are in the “clinical pipeline.” Although none is available as an approved medication till date, a few (eg, the peripherally restricted kappa-agonist FE200665, also known as CR665) have completed phase I clinical trials and currently in phase II. Others such as loperamide, which is approved for use as an antidiarrheal drug, have been found to be variably useful as a peripherally acting opioid analgesic.
Conclusions: Substantive research is currently underway and this is an exciting research area for both basic and applied clinical fields. Various ways to enhance peripheral opioid analgesia are suggested.


peripheral opioid receptors, peripheral opioid agonists, peripheral mu-/kappa-/delta-opioid, receptor agonists, inflammatory pain, neuropathic pain

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