The Potential Role of Dual Mechanistic Opioids in Combating Opioid Misuse

Coluzzi, Flaminia; Mercadante, Sebastiano

doi:10.1007/s40140-020-00414-5

Cited by 2 publications

(2 citation statements)

References 61 publications

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“…Its activity on MOR is, indeed, 50-fold lower than morphine; however, in clinical trials, its effect was comparable to that of oxycodone [ 13 ]. This evidence led to the hypothesis that dual mechanistic opioids, through a lower activity on MOR, could be also evaluated for their potential in combating opioid misuse [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Current and Future Therapeutic Options in Pain Management: Multi-mechanistic Opioids Involving Both MOR and NOP Receptor Activation

Coluzzi

Rullo

Scerpa³

et al. 2022

CNS Drugs

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Opioids are widely used in chronic pain management, despite major concerns about their risk of adverse events, particularly abuse, misuse, and respiratory depression from overdose. Multi-mechanistic opioids, such as tapentadol and buprenorphine, have been widely studied as a valid alternative to traditional opioids for their safer profile. Special interest was focused on the role of the nociceptin opioid peptide (NOP) receptor in terms of analgesia and improved tolerability. Nociceptin opioid peptide receptor agonists were shown to reinforce the antinociceptive effect of mu opioid receptor (MOR) agonists and modulate some of their adverse effects. Therefore, multi-mechanistic opioids involving both MOR and NOP receptor activation became a major field of pharmaceutical and clinical investigations. Buprenorphine was re-discovered in a new perspective, as an atypical analgesic and as a substitution therapy for opioid use disorders; and buprenorphine derivatives have been tested in animal models of nociceptive and neuropathic pain. Similarly, cebranopadol, a full MOR/NOP receptor agonist, has been clinically evaluated for its potent analgesic efficacy and better tolerability profile, compared with traditional opioids. This review overviews pharmacological mechanisms of the NOP receptor system, including its role in pain management and in the development of opioid tolerance. Clinical data on buprenorphine suggest its role as a safer alternative to traditional opioids, particularly in patients with non-cancer pain; while data on cebranopadol still require phase III study results to approve its introduction on the market. Other bifunctional MOR/NOP receptor ligands, such as BU08028, BU10038, and AT-121, are currently under pharmacological investigations and could represent promising analgesic agents for the future.

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Section: Introductionmentioning

confidence: 99%

Current and Future Therapeutic Options in Pain Management: Multi-mechanistic Opioids Involving Both MOR and NOP Receptor Activation

Coluzzi

Rullo

Scerpa³

et al. 2022

CNS Drugs

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“…The recent development of atypical opioids is a partial response to that challenge [ 1 ]. Borrowing from the principals of multimechanistic analgesia where two or more agents with complementary and synergistic mechanisms of action are utilized, a new category of analgesic agents offers dual mechanisms of action in a single molecule.…”

Section: Introductionmentioning

confidence: 99%

Multimechanistic Single-Entity Combinations for Chronic Pain Control: A Narrative Review

Pergolizzi¹,

Magnusson²,

Coluzzi³

et al. 2022

Cureus

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Atypical opioids such as tramadol, tapentadol, and cebranopadol combine two complementary mechanisms of action into a single molecule, creating novel analgesic agents. These are synthetic small molecules: cebranopadol is not yet market released; tramadol and tapentadol are commercially available and have immediate-release (IR) and extended-release (ER) formulations. Tramadol has been widely used in the United States in recent years and works as a prodrug in that its metabolites are active in inhibiting serotonin and norepinephrine reuptake. Tapentadol is a direct-acting agent with a faster onset of action and is a mu-opioid-receptor agonist and also inhibits noradrenaline reuptake. Cebranopadol is the newest of these drugs, a first-in-class atypical analgesic that combines mu-opioid receptor (MOR) agonism with activity at the nociception/orphanin (NOP) FQ petide receptors. Cebranopadol may be considered a partial kappa-opioid receptor agonist as well. The pharmacology of these unique single-entity agents allows them to offer analgesic benefit with fewer side effects and risks. Clinical studies have demonstrated the safety and efficacy of tramadol and tapentadol, and promising but limited studies for cebranopadol show good analgesic effect and safety. Serotonin toxicity or ‘serotonin syndrome’ may occur with accumulation of serotonin with tramadol. While the misuse of these agents is limited in the United States, tramadol misuse is prevalent in Iran and parts of Africa. Patients have been successfully rotated from one of these agents to another. All three agents show promise in the treatment of cancer and non-cancer pain and their unique formulation in a single molecule reduces the pill burden.

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The Potential Role of Dual Mechanistic Opioids in Combating Opioid Misuse

Cited by 2 publications

References 61 publications

Current and Future Therapeutic Options in Pain Management: Multi-mechanistic Opioids Involving Both MOR and NOP Receptor Activation

Current and Future Therapeutic Options in Pain Management: Multi-mechanistic Opioids Involving Both MOR and NOP Receptor Activation

Multimechanistic Single-Entity Combinations for Chronic Pain Control: A Narrative Review

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