State and Future Science of Opioids and Potential of Biased-ligand Technology in the Management of Acute Pain After Burn Injury

Abstract

Pain associated with severe burn injury is one of the most intense and clinically challenging to manage, as the metabolic imbalances associated with the inflammation caused by the injury and treatment interventions (e.g., dressing changes and debridement, excision, and grafting) can further worsen the pain. In the pharmacologic management of a complex, hospitalized patient with burn injuries, opioid therapy remains an efficacious mainstay of treatment. However, the complex nature of pain, injury characteristics, and common demographics after burn injury place patients at high risk of opioid-related adverse events. Thus, guidelines recommend that decisions about choice of opioid be based on physiology, pharmacology, and physician experience, in addition to individualizing initial treatment with subsequent continual adjustments throughout care. Although substantial progress has been made in pain management strategies with utilization of nonopioid medications and nonpharmacologic adjuncts to opioid pharmacotherapy, there is still a need to evaluate new therapies, as an optimal regimen still lacks significant evidential support. Herein, we review the actions of opioids at the cellular level, contributing to both nociception and opioid-related adverse events. We also discuss the most recently approved intravenously administered opioid, oliceridine, developed utilizing biased ligand technology, including a summary of its clinical efficacy and safety in the management of severe acute pain. While oliceridine has been evaluated for the management of moderate-to-severe acute pain, the large phase 3 studies did not include patients with burn injuries. However, potential implications and future study direction for pain associated with burn injury are discussed.

Keywords: Adverse Drug Event; Analgesics; Burns; Opioid; Pain.

Figure 1:

Schematic depiction of pain transduction (left panel) and analgesic mechanism of action of opioids on the pain pathway (right panel). (Left panel) Pain pathway: Following activation of nociceptors, 1) signal transduction in pre-synaptic neurons results in activation of adenylyl cyclase and cyclic adenosine monophosphate (cAMP)-mediated release of neurotransmitters (glutamate, substance P, calcitonin gene-related protein [CGRP]) into the synaptic cleft; 2) released neurotransmitters bind to specific post-synaptic receptors: glutamate to the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors, substance P to the neurokinin-1 (NK-1) receptor, and CGRPs to the CGRP receptors (CGRP-R); 3) Activation of AMCP and NMDA receptors leads to an increase in the flow of positively-charged ions such as Ca2+ and Na2+ and increase in pain signal; another positive ion, Mg2+, is mobilized following NK-1 receptor binding-mediated protein kinase C activation and acts indirectly by unblocking NMDA receptors; 4) Substance P also mediates an increase in the influx of Ca2+ into the presynaptic neuron, contributing to increased neurotransmitter release and signaling; 5) Although the mechanism is not completely clear, activation of CGRP-R(s) is also believed to contribute to neuromodulation in the periphery similar to its involvement in migraine headache pathophysiology. (Right panel) Opioid Analgesic Action: Four subtypes of opioid receptors are present on both pre- and post-synaptic neurons: mu (µ) opioid receptor (mOR), kappa (κ) opioid receptor (kOR), delta (δ) opioid receptor (dOR), and nociception-related G protein-coupled receptor (non-naloxone-binding; not shown in figure). 1) Both endogenous and exogenous opioids bind to the mOR, resulting in a series of actions that inhibit pain signaling; 2) Activation of mOR results in an inhibition of adenylyl cyclase, leading to an inhibition of cAMP release and subsequent inhibition of neurotransmitters; 3) mOR binding also inhibits voltage-gated Ca2* channels and influx of positive ions into the pre-synaptic neuron, contributing to an inhibition of neurotransmitter release; 4) Finally, binding of opioids to the mOR on the post-synaptic neuron results in an opening of G protein-gated K+ channels, facilitating efflux of K+ ions and hyperpolarization leading to decreased sensitization to pain signaling.

Figure 2:

Timeline of Availability of Opioids.

Figure 3:

Hypothesis for the G Protein-Biased Ligands at the Mu-opioid Receptor. Unbiased or non-biased agonists (ligands) can efficiently activate both G protein- and β-arrestin-dependent signaling. In contrast, biased agonists at the mu opioid receptor (mOR) preferentially activate G-protein signaling and may offer increased analgesia with improved safety and tolerability.

Figure 4:

Respiratory Safety of Oliceridine in Phase 3 Randomized Clinical Trials (Adapted from Gan and Wase 2020). Respiratory safety burden (RSB) and respiratory safety events (RSE) in pivotal Phase 3 studies of oliceridine.^, RSB was calculated as the mathematical product of the incidence of respiratory safety events and the mean duration of such events in affected patients. No statistically significant differences for any of the oliceridine treatment groups vs. morphine. RSEs were changes in respiratory rate, oxygen saturation (SpO₂ < 90%), and sedation measured using the Moline-Roberts Pharmacologic Sedation Scale.