Advances in Achieving Opioid Analgesia Without Side Effects

Abstract

Opioids are the most effective drugs for the treatment of severe pain, but they also cause addiction and overdose deaths, which have led to a worldwide opioid crisis. Therefore, the development of safer opioids is urgently needed. In this article, we provide a critical overview of emerging opioid-based strategies aimed at effective pain relief and improved side effect profiles. These approaches comprise biased agonism, the targeting of (i) opioid receptors in peripheral inflamed tissue (by reducing agonist access to the brain, the use of nanocarriers, or low pH-sensitive agonists); (ii) heteromers or multiple receptors (by monovalent, bivalent, and multifunctional ligands); (iii) receptor splice variants; and (iv) endogenous opioid peptides (by preventing their degradation or enhancing their production by gene transfer). Substantial advancements are underscored by pharmaceutical development of new opioids such as peripheral κ-receptor agonists, and by treatments augmenting the action of endogenous opioids, which have entered clinical trials. Additionally, there are several promising novel opioids comprehensively examined in preclinical studies, but also strategies such as biased agonism, which might require careful rethinking.

IL-4 induces M2 macrophages to produce sustained analgesia via opioids

“…This is in agreement with our previous study, in which heat hypersensitivity was attenuated by perineurally applied exogenous opioids, but not by opioid peptides, including ENK, END, and DYN (53). Even though both exogenous and endogenous opioids activate the same opioid receptors, it is possible that these ligands initiate different downstream mechanisms to interact with various pain modality-dependent ion channels or intracellular pathways (36,53), and further studies are required. Interestingly, other studies found that M2 macrophages polarized by morphine or peroxisome proliferator-activated receptor-γ agonist reduced mechanical but not heat hypersensitivity in models of inflammatory and postoperative pain (28,54).…”

“…Together, our findings may have wide implications, since IL-4 and M2 cells play a role in inflammatory and neurodegenerative diseases (2,9,10,63). The opioid system may be particularly beneficial in peripheral neuroinflammatory conditions, since the activation of peripheral opioid receptors can provide analgesia without centrally mediated adverse effects (35,36). Nonetheless, our study does not preclude the search for strategies targeting other macrophage-derived mediators, including antiinflammatory cytokines and specialized proresolving mediators.…”

“…Additionally, the inhibition of IL-4-induced analgesia by NLXM, an opioid receptor antagonist with limited blood-brain barrier permeability (34), suggests that the effects were mediated by peripheral opioid receptors. This has important implications because in contrast to opioid receptors in the brain, the activation of peripheral opioid receptors is devoid of serious side effects such as respiratory arrest, sedation, and addiction (35,36). Interestingly, all these opioid effects occurred both 24 hours and 5 days after discontinuation of IL-4 treatment; of note, the analgesia was equally efficient and did not diminish even at the latter time point.…”

Opioid Receptors in Immune and Glial Cells—Implications for Pain Control

“…In addition, activation of MOP receptors in the brain activates descending noradrenergic pathways, which leads to increased release of noradrenaline in the spinal cord (54,55). All above described effects underlay the opioid receptorinduced analgesia [reviewed by (26,41,(56)(57)(58)(59)(60)]. Additionally, the activation of NOP receptors in the brain can lead to hyperalgesia or anti-opioid actions in animal models (20,21,61).…”

“…Neuronal opioid receptors also mediate numerous side effects, such as respiratory depression, nausea, vomiting, reward/euphoria, dependence/withdrawal (MOP), convulsions (DOP), aversion/dysphoria, psychotomimesis (KOP), learning and memory impairment, motor disturbance, hypotension, bradycardia (NOP), sedation (MOP, KOP, NOP), constipation (MOP, NOP), and diuresis (KOP, NOP) [reviewed by (56,57,(64)(65)(66)(67)]. The main efforts are currently directed toward the development of novel ligands that exert analgesia with reduced side effects [reviewed by (57,68,69)].…”