Disambiguating pharmacological mechanisms from placebo in neuropathic pain using functional neuroimaging

Background: A lack of objective outcome measures and overreliance on subjective pain reports in early proof‐of‐concept studies contribute to the high attrition of potentially effective new analgesics. We studied the utility of neuroimaging in providing objective evidence of neural activity related to drug modulation or a placebo effect in a double‐blind, randomized, placebo‐controlled, three‐way crossover trial. Methods: We chronically administered pregabalin or tramadol (first‐line and second‐line analgesics, respectively), recommended for neuropathic pain, in 16 post‐traumatic neuropathic pain patients. We measured subjective pain reports, allodynia‐evoked neural activity, and brain resting state functional connectivity from patients during the three sessions and resting state data at baseline from patients after washout of their current medication. All data were collected using a 3 T MRI scanner. Results: When compared with placebo only, pregabalin significantly suppressed allodynia‐evoked neural activity in several nociceptive and pain‐processing areas of the brain, despite the absence of behavioural analgesia. Furthermore, placebo significantly increased functional connectivity between the rostral anterior cingulate and the brainstem, a core component of the placebo neural network. Conclusions: Functional neuroimaging provided objective evidence of pharmacodynamic efficacy in a proof‐of‐concept study setting where subjective pain outcome measures are often unreliable. Additionally, we provide evidence confirming the neural mechanism underpinning placebo analgesia as identified in acute experimental imaging studies in patients during the placebo arm of a clinical trial. We explore how brain penetrant active drugs potentially interact with this mechanism. Clinical trial registration: NCT0061015