Peripheralization Strategies Applied to Morphinans and Implications for Improved Treatment of Pain

Abstract

Opioids are considered the most effective analgesics for the treatment of moderate to severe acute and chronic pain. However, the inadequate benefit/risk ratio of currently available opioids, together with the current ‘opioid crisis’, warrant consideration on new opioid analgesic discovery strategies. Targeting peripheral opioid receptors as effective means of treating pain and avoiding the centrally mediated side effects represents a research area of substantial and continuous attention. Among clinically used analgesics, opioids from the class of morphinans (i.e., morphine and structurally related analogues) are of utmost clinical importance as analgesic drugs activating the mu-opioid receptor. In this review, we focus on peripheralization strategies applied to N-methylmorphinans to limit their ability to cross the blood–brain barrier, thus minimizing central exposure and the associated undesired side effects. Chemical modifications to the morphinan scaffold to increase hydrophilicity of known and new opioids, and nanocarrier-based approaches to selectively deliver opioids, such as morphine, to the peripheral tissue are discussed. The preclinical and clinical research activities have allowed for the characterization of a variety of compounds that show low central nervous system penetration, and therefore an improved side effect profile, yet maintaining the desired opioid-related antinociceptive activity. Such peripheral opioid analgesics may represent alternatives to presently available drugs for an efficient and safer pain therapy.

Insights into the Current and Possible Future Use of Opioid Antagonists in Relation to Opioid-Induced Constipation and Dysbiosis

“…To achieve adequate opioid analgesia, dose escalation is required, which further aggravates the side effects, including OIC as the main factor altering gut microbiome composition, as reviewed above. In the last four decades, outstanding studies have laid the research foundations for the distribution of functional MORs in the peripheral tissues that mediate antinociceptive effects of systemically or locally administered opioid agonists [3,5,7,25,40,[145][146][147]. In these studies, several opioid agonists with limited CNS penetration have been proven to produce peripheral antinociceptives; however, the central side effects (addiction liability, tolerance) were not fully elucidated.…”

“…Opioid agonists exert their antinociceptive actions through the activation of opioid receptors, particularly µ-opioid receptors (MORs), both peripherally and centrally (spinal and supraspinal MOR activation) [2]. Although the site of action of clinically available analgesics is considered to be central, MOR-mediated peripheral analgesia has also been Molecules 2023, 28, 7766 2 of 25 identified in human and experimental pain models [3][4][5][6][7][8][9][10]. The current consensus is that opioid agonists are the most effective analgesics for treating mild to severe acute and chronic pain types, yet in the case of neuropathic pain, their effect is up for debate [11][12][13].…”

In Vitro and In Vivo Pharmacological Profiles of LENART01, a Dermorphin–Ranatensin Hybrid Peptide

“…Because of the inadequate benefit/risk ratio of currently available opioids, together with the ongoing opioid epidemic, there is a huge quest for strategies to discover new opioid analgesics. Alternative chemical and pharmacological approaches are therefore explored to mitigate the deleterious effects of MOR agonists and to limit their abuse and misuse [9][10][11][12][13][14][15][16][17][18][19], amongst which are multifunctional drugs. The concept of 'one molecule, multiple targets' has received increased attention in opioid drug discovery as a promising strategy to generate new analgesics with enhanced effectiveness and reduced unwanted side effects.…”