Anesthetic insights from sham surgeries: Is the future of chronic pain relief hidden in our controls?

We propose that the therapeutic benefits observed in sham surgical trials, particularly for chronic pain conditions, are substantially mediated by the neurobiological effects of anesthetic agents rather than placebo responses alone. This testable hypothesis challenges the traditional interpretation of sham surgery outcomes. It suggests that general anesthetics and their adjuncts play an active therapeutic role through persistent effects on neural plasticity, inflammatory pathways, and nociceptive processing. Multiple classes of anesthetic agents, including GABA receptor modulators, NMDA antagonists, volatile anesthetics, and local anesthetics, demonstrate sustained neural function and immune response modifications beyond their immediate sedative effects. These modifications occur through multiple pathways, including altered synaptic plasticity, reduced neuroinflammation, and modified nociceptive processing. To test this hypothesis, we propose a controlled clinical trial comparing different anesthetic combinations in an ambulatory setting. If supported, our findings would have significant implications for pain medicine, potentially leading to novel therapeutic protocols using targeted anesthetic administration for chronic pain management. This paradigm shift could bridge the gap between conservative treatment and surgery while avoiding the ethical concerns associated with sham procedures. Our framework offers a testable model for investigating the therapeutic potential of anesthetic agents beyond their traditional surgical applications.