Measuring the Immeasurable: Biomarkers for Anaesthesia and Pain

Christian S. Guay, MD

Chronic pain has become a major public health issue, with an incidence of around 20% and risk factors including female sex and increasing age. The underlying mechanisms are still unclear, though evidence is growing for the constant firing of “pain nerves,” central sensitization and maladaptive plasticity. Studying chronic pain is difficult in part because nociception does not directly map to perception. This relationship is nonlinear, and the perception of pain is subject to the amplifying and dampening influences of mood, cognition and context. Therefore, it’s no surprise that self-reports of pain perception and analgesic effect sizes are notoriously variable. Reliable pain biomarkers combined into a composite pain signature for individuals could help overcome these limitations. To kickoff Saturday, April 15 at the IARS 2023 Annual Meeting, this year’s T.H. Seldon Memorial Lecturer Professor Irene Tracey, Vice-Chancellor of the University of Oxford and Professor of Anaesthetic Neuroscience in the Nuffield Department of Clinical Neurosciences, focused on the development of biomarkers for pain and pain relief and the findings from her extensive research on the topic during her presentation, “Imaging Pain, Pain Relief and Altered-States of Anaesthesia-induced Consciousness.” 

The descending pain modulation system (DPMS), a network of widely distributed cortical and subcortical brain regions whose integrated function is essential for modulation of sensory pain input, has emerged as a strong candidate for a pain biomarker. Acting as a gatekeeper for ascending pain stimuli, the DPMS can act as a “good cop” by blocking pain signals, or as a “bad cop” by amplifying them. Placebo effects are an example of the DPMS acting as a good cop. Expectations set during physician-patient interactions can also influence this system to induce placebo and nocebo effects. Using fMRI of the DPMS, it is possible to identify patients likely to develop persistent postsurgical pain and diabetic neuropathic pain. Perhaps even more exciting, fMRI of the DPMS provides a biomarker for the dose-response effect of analgesics that is resistant to contextual factors, making it ideal for analgesic drug discovery and development.

Following her presentation on pain biomarkers, Dr. Tracey transitioned to her work on anesthesia and consciousness. There exists a strong need and desire for robust, brain-based individualized measures of perception to enable titration of multimodal anesthesia and improved recovery. In the UK, only 1.8% of anesthetists use “depth of anesthesia” monitors, but 70% think that they can be helpful. To help bridge this gap, Dr. Tracey and Catherine Warnaby, PhD, MPhys, have been investigating what they termed “slow wave activity saturation” (SWAS).

In a landmark article published in 2013, their team administered propofol to 16 volunteers while monitoring their electroencephalograms (EEG). Slow wave activity (SWA), measured as the EEG power in the 0.5 – 1.5 Hz frequency band, was already known to increase in parallel with increasing anesthetic concentrations. However, the team discovered a plateau after which increasing propofol concentrations could no longer increase SWA, thus, SWAS. Every participant in the study exhibited SWAS, and an individual’s SWA plateau correlated with the grey matter volume in their prefrontal cortex. Considering the effects of aging on prefrontal grey matter, SWAS plateaus correlate negatively with age.

Follow-up investigations have revealed that SWAS tracks local GABA_A receptor density (i.e., brain regions with fewer receptors have higher anesthetic requirements) can be measured at most electrodes across the scalp, and is reproducible within subjects. Clinical studies have revealed that SWAS occurs during the induction phase for more than 90% of general anesthetics, and double the dose required to achieve SWAS is administered in 50% of cases. An ongoing trial in collaboration with Professor Jamie Sleigh, PhD, at University of Auckland in New Zealand is investigating the integration of a SWAS graphical user interface in clinical practice. The trial aims to limit positive responses on the isolated forearm technique to less than 5% and awareness with recall after general anesthesia to nil. Interim results from the first 100 patients are promising: SWAS can easily be identified during surgical anesthesia and no patients have tested positive for awareness with recall or responded to the isolated forearm test.

Dr. Tracey concluded her lecture by emphasizing the importance of EEG education for clinicians and noted that decades from now, anesthesiologists will likely be astonished to learn that brain monitoring was not routinely employed during general anesthesia. She remains hopeful that ongoing education efforts and continued development of tools such as SWAS will help anesthesiologists improve intraoperative care and recovery of our patients’ brains.