Designing safer analgesics: a focus on μ-opioid receptor pathways

ABSTRACT

Introduction: The recent dramatic increase in intentional and unintentional deaths attributed to opioids has refocused attention on the therapeutic ratio (risk–benefit ratio) of opioid analgesics. Almost all traditional opioid analgesics produce their effects (therapeutic and adverse) via the activation of μ-opioid receptor (MOR) pathways. It is therefore important to examine the question of whether this natural endogenous pathway can still be activated, but with greater safety.

Areas covered: Other comprehensive reviews have focused on pharmacokinetic (e.g. peripheral restriction) and pharmacodynamic (e.g. functional selectivity, biased ligand) approaches. Herein, the authors focus on a different approach, specifically, multi-mechanistic ‘atypical opioids’ that synergistically combines MOR activation plus one or more non-opioid mechanism of analgesic action.

Expert opinion: Four ‘atypical opioid’ analgesics on the market act as μ-opioid receptor pathway agonists but have a non-opioid mechanism of action that significantly contributes to the analgesic effect. The multi-mechanistic action of these products confers particular clinical utility in that they provide effective analgesia with relatively lower opioid load, and they are generally associated with fewer or less severe opioid-related adverse effects and less abuse compared to traditional opioid analgesics.

KEYWORDS:

• Opioid
• analgesic
• opioid pain reliever
• dual mechanism of action
• tapentadol
• tramadol
• buprenorphine
• cebranopadol
• analgesics
• μ-opioid
• efficacy
• adverse effect
• safety

Article highlights

• The newer centrally acting analgesics introduced to market, tramadol and tapentadol, plus buprenorphine and the newest in development, cebranopadol, activate the μ-opioid receptor, but exhibit characteristics atypical of conventional opioids. Indeed, these analgesics are often called ‘atypical opioids.’

• These newer centrally acting analgesics combine at least one additional, non-opioid, usually synergistic, analgesic mechanism of action.

• They thus are able to reduce the amount of opioid administered without sacrificing analgesic efficacy.

• The patient, in effect, consumes less opioid, which might — in theory at least — translate to fewer or less severe adverse events and less potential for abuse and addiction.

• These examples provide a template for one approach for designing safer analgesics that work through μ-opioid receptor pathways.

This box summarizes key points contained in the article.

Declaration of interest

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was not funded.