Neuroimaging pain and analgesia mechanisms in experimental and chronic pain states

Chronic pain is a common and debilitating condition, affecting up to half of the UK population. Despite the use of both pharmacological and psychological/cognitive interventions, it is difficult to treat, and there is a clear need for new, effective therapies. The subjective nature of pain reporting makes the discovery and validation of new treatments challenging, but this could be improved by the presence of an objective biomarker of analgesic efficacy.
In this thesis I looked at the use of functional magnetic resonance imaging (fMRI) as such a biomarker, and as a technique for understanding the mechanisms by which interventions might achieve therapeutic effects. This was achieved through the investigation of two novel treatments for pain, the first being a pharmacological agent, and the second a cognitive therapy.
A randomised controlled trial was set up comparing ABX-1431, a first-in-class pharmacological agent that acts on the endocannabinoid system, with both placebo and nothing. Although it was not possible to show analgesic efficacy using behavioural outcomes, the presence of sedation in the active drug arm indicated a likely pharmacodynamic effect. It was possible to confirm this effect using functional magnetic resonance imaging (fMRI). Since the mechanism of action did not match that of existing analgesic agents, it was not possible to confirm analgesic efficacy, but the presence of altered activity in and connectivity between regions known to have a key role in descending pain modulation, including the lateral prefrontal cortex and right amygdala, indicates that ABX-1431 could impact chronic pain through these mechanisms, and that further trials are warranted.
Next, a prospective study of mindfulness-based cognitive therapy for irritable bowel syndrome (MBCT-IBS) was performed, in which behavioural data showed that it was an effective therapy for chronic visceral pain. Imaging showed that like ABX-1431, MBCT-IBS led to altered activity in regions of the brain known to have a role in descending pain modulation, including the right amygdala and dorsolateral prefrontal cortex. There was evidence of modulated functional connectivity between these regions and other cortical and subcortical regions important for pain perception. Activity and connectivity within the default mode network (DMN) was also affected, as was connectivity between the DMN and sensory cortices, indicating that MBCT-IBS might act by modulating intrinsic attentional networks as well as by influencing the top-down control of pain.
In combination, these studies have shown that fMRI is a valuable tool for elucidating the mechanisms of novel analgesic therapies across both pharmacological and cognitive modalities. The fact that neither intervention produced the imaging pattern seen in classical analgesia meant that fMRI was unable to provide an objective biomarker of efficacy on this occasion, but in both cases it was possible to show clear mediation of neural function in regions relating to descending pain control. It may be that in chronic pain, an objective biomarker of efficacy will look different to that seen in acute pain, and this is something worthy of further investigation.

Keywords: neuroimaging
analgesia
chronic pain
pain
Advisor: Tracey, I
Wanigasekera, V