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.
Highlights
Opioids relieve pain, and produce numerous side effects
NFEPP did not induce respiratory depression, sedation, motor impairment, reward, and constipation, even at doses 10-fold higher than the most effective analgesic doses (Spahn et al, 2017) (Table 2). As this compound will not be an option for patients with CNS inflammation, it represents a promising analgesic for pain conditions associated with peripheral tissue damage, which needs to be demonstrated in clinical trials
These studies used naïve mice, without pathological pain, and reported that morphine induced more efficacious and prolonged analgesia in acute heat pain tests, absent or delayed analgesic tolerance, and decreased constipation and respiratory depression in β-arrestin-2 knockout compared to wild-type mice (Bohn et al, 1999, 2000, 2002; Raehal et al, 2005)
Summary
Produce numerous side effects. All actions of opioids are mediated by μ-, δ-, and κ-opioid receptors encoded by the three respective genes (Evans et al, 1992; Kieffer et al, 1992; Mestek et al, 1995; Simonin et al, 1995). Unlike fentanyl, intravenously applied NFEPP produced analgesia by activation of opioid receptors exclusively in peripheral injured tissue in rat models of unilateral hind paw inflammation or surgical incision (Spahn et al, 2017), sciatic nerve injury-induced neuropathy, and abdominal pain (Rodriguez-Gaztelumendi et al, 2018). NFEPP did not induce respiratory depression, sedation, motor impairment, reward (assessed by conditioned place preference; CPP), and constipation, even at doses 10-fold higher than the most effective analgesic doses (Spahn et al, 2017) (Table 2) As this compound will not be an option for patients with CNS inflammation, it represents a promising analgesic for pain conditions associated with peripheral tissue damage, which needs to be demonstrated in clinical trials. These results suggest that a ligand’s pKa should be close to the pH of injured tissue to obtain analgesia without side effects (Spahn et al, 2018)
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