Louisiana Anesthesia Group

Strategies for Safer Opioid Analgesics

Despite affecting over 100 million Americans and costing at least $600 billion annually, chronic pain lacks universally effective treatments. This is especially true for neuropathic pain, one of the most common forms of chronic pain, which is caused by dysfunction or damage to the somatosensory nervous system and can result from stroke, diabetes, multiple sclerosis, spinal cord injury, or peripheral nerve damage. First-line treatments, such as calcium channel inhibitors (e.g., gabapentin, pregabalin), antidepressants, and anticonvulsants, often do not provide complete pain relief due to incontrollable side effects. Additionally, second-line treatments, such as opioids (e.g., morphine, fentanyl, tramadol) can pose serious risks, including addiction and overdose.1 There is an urgent need for safer, more effective therapies. A promising direction in the past decade involves targeting multiple μ opioid receptors simultaneously to separate pain relief from side effects. Combined with novel strategies like receptor heterodimers and negative feedback loops, these approaches may allow for the development of safer opioid analgesics with fewer limitations and risks.

To reduce opioid-related side effects, one strategy for developing safer opioid analgesics involves developing mixed opioid receptor agonists and agonist–antagonists that target multiple receptor subtypes simultaneously. The three members of the opioid receptor family are the μ, κ and δ opioid receptors; all three have been shown to modulate pain. Dual μ and κ opioid receptor agonists show promise for providing effective pain relief (i.e., analgesia) while minimizing side effects such as respiratory depression and addiction, as κ receptor activation lacks these adverse effects and may counterbalance μ receptor liabilities.1 New and existing mixed agonists like nalbuphine,2 dezocine,3 PPL-101, PPL-103,4 MP1207, and MP12085 demonstrate synergistic analgesia with reduced side effect profiles, likely due to partial agonism and signaling bias. Simultaneous κ and δ opioid receptor agonists offer promising pain relief with reduced side effects, as δ receptor activation may mitigate the dysphoria typically associated with κ receptor agonists, while κ activation provides anti-convulsant and anti-addiction benefits.6 Compounds like MP1104 demonstrate anti-nociceptive effects in a radiant heat tail flick assay, as assessed in a murine study.7

Heterodimers are complexes formed of two different receptor proteins, with the μ–δ opioid receptor heterodimer (MDORH) being perhaps the most studied example. Evidence suggests MDORH expression could decrease the anti-nociceptive potency of opioid drugs, suggesting MDORH acts as an anti-opioid negative feedback loop, potentially limiting analgesia and contributing to tolerance.8 While selective ligands like CYM51010,9 MP135, MDAN21, and D24M have provided some support for the MDORH’s inhibiting role, their pharmacology is not always clearly defined, highlighting the need for more specific tools.1 Another promising heterodimer, the κ–δ receptor heterodimer (KDORH), may offer analgesia without central side effects, but selective pharmacological tools are still lacking. Overall, heterodimers such as MDORH and KDORH present exciting therapeutic targets for improved pain relief with fewer side effects, but further research is needed to validate their roles and assess potential abuse liability.

Current treatments for chronic and neuropathic pain are often ineffective or carry significant risks; however, recent research reveals novel strategies that target multiple opioid receptors to provide analgesia without the negative side effects. Mixed agonists and receptor heterodimers like MDORH and KDORH offer promising paths toward safer and more effective opioid analgesics for pain management. Continued research into the pharmacology, selectivity, and clinical impact of these mechanisms is essential to fully realizing their therapeutic potential and addressing the pressing need for better pain management solutions.

References

  1. Varga, Balazs R., et al. “Strategies towards Safer Opioid Analgesics—A Review of Old and Upcoming Targets.” British Journal of Pharmacology, 180(7), 2023, 975–993. https://doi.org/10.1111/bph.15760
  2. Schmidt, William K., et al. “Nalbuphine.” Drug and Alcohol Dependence, 14(3), 1985, 339–362. https://doi.org/10.1016/0376-8716(85)90066-3
  3. Wang, Yu-Hua, et al. “Pharmacological Characterization of Dezocine, a Potent Analgesic Acting as a κ Partial Agonist and μ Partial Agonist.” Scientific Reports, 8(1), 2018, 14087. https://doi.org/10.1038/s41598-018-32568-y
  4. Khroyan, Taline V., et al. “In Vitro and In Vivo Profile of PPL-101 and PPL-103: Mixed Opioid Partial Agonist Analgesics with Low Abuse Potential.” Frontiers in Psychiatry, 8, 2017. https://doi.org/10.3389/fpsyt.2017.00052
  5. Uprety, Rajendra, et al. “Controlling Opioid Receptor Functional Selectivity by Targeting Distinct Subpockets of the Orthosteric Site.” eLife, 10, 2021, e56519. https://doi.org/10.7554/eLife.56519
  6. Zangrandi, Luca, et al. “The G‐protein Biased Partial κ Opioid Receptor Agonist 6′‐GNTI Blocks Hippocampal Paroxysmal Discharges without Inducing Aversion.” British Journal of Pharmacology, 173(11), 2016, 1756–1767 https://doi.org/10.1111/bph.13474
  7. Váradi, András, et al. “Synthesis and Characterization of a Dual Kappa-Delta Opioid Receptor Agonist Analgesic Blocking Cocaine Reward Behavior.” ACS Chemical Neuroscience, 6(11), 2015, 1813–1824. https://doi.org/10.1021/acschemneuro.5b00153
  8. Whistler, Jennifer, et al., “Anti-Analgesic Effect of the Mu/Delta Opioid Receptor Heteromer Revealed by Ligand-Biased Antagonism,” 2013. https://escholarship.org/uc/item/2dr2999q
  9. Gomes, Ivone, et al. “Identification of a μ-δ Opioid Receptor Heteromer-Biased Agonist with Antinociceptive Activity.” Proceedings of the National Academy of Sciences, 110(29), 2013, 12072–12077. https://doi.org/10.1073/pnas.1222044110