Evaluation of Therapies for Peripheral and Neuraxial Opioid-induced Pruritus based on Molecular and Cellular Discoveries

Abstract

Opioids are a mainstay of treatment for pain worldwide. Pruritus, a common side effect of opioids, is a patient dissatisfier that limits their use in many clinical settings. Both parenteral and neuraxial administration of opioids frequently evoke pruritus. The ability of opioids to suppress pain while causing itch continues to perplex clinicians and researchers alike. Several mechanisms have been proposed to explain how opioids can give rise to pruritus, but specific knowledge gaps perpetuate debate. This review summarizes the clinical burden of opioid-induced pruritus and emphasizes recent discoveries of peripheral and central mechanisms for opioid-induced pruritus, particularly with respect to scientific and conceptual advances in spinal cord circuitry and mast cell biology. The mechanisms and effectiveness of existing medications used for clinical management of pruritus will be evaluated, and we will highlight the emerging preclinical utility of selective κ-opioid receptor agonists, such as nalfurafine, for the management of opioid-induced pruritus.

Role of kappa‐opioid and mu‐opioid receptors in pruritus: Peripheral and central itch circuits

“…10 Recently, the generation of itch by intrathecal morphine was found to be due to disinhibition of spinal dynorphin-expressing interneurons 36 ; in contrast, itch generation by parenterally administered morphine appears to be the result of histamine release caused by morphine-induced mast cell degranulation. 37 In contrast, KOR agonism and MOR antagonism (separately or in combination) have consistently been associated with reduction in itch severity; prophylactic treatment with the combination KOR agonist and MOR antagonist nalbuphine was found to significantly reduce the incidence of intrathecal opioid-induced pruritus. 10 Moreover, in addition to the itch suppression demonstrated by dynorphin treatment of afferent low-threshold mechanoreceptors and of B5-I neurons, treatment with KOR agonists and/or MOR antagonists has consistently demonstrated reductions in pruritus severity.…”

“…The reported incidence of pruritus as an adverse event following neuraxial administration of MOR agonists ranges from 30% to 100% 10 . Recently, the generation of itch by intrathecal morphine was found to be due to disinhibition of spinal dynorphin‐expressing interneurons 36 ; in contrast, itch generation by parenterally administered morphine appears to be the result of histamine release caused by morphine‐induced mast cell degranulation 37 …”

In vitro models for investigating itch

“…One further mechanism contributing to itch in AD may be an imbalance in opioid receptor expression ( Ádám et al, 2022 ). This is because binding of β-endorphin to the μ-opioid receptor (MOR) causes itch, while activation of κ-opioid receptor (KOR) suppresses it; the following review provides a detailed discussion of opioid receptor signaling in relation to itch ( Nguyen E. et al, 2021 ).…”

Autoimmune Connective Tissue Diseases-Related Pruritus: Proper Diagnosis and Possible Mechanisms

“…The British Society for Rheumatology and British Health Professionals in Rheumatology guidelines recommend lanolin-based moisturizer and antihistamine for itch management in patients with SSc [ 49 ]. Opioid signaling plays a part in itch perception by modulation of neuronal sensation [ 50 ]. Three patients with SSc showed improvement in pruritus and gastrointestinal symptoms with low-dose naltrexone, a mu-opioid receptor antagonist [ 51 ].…”