Inferring distinct mechanisms in the absence of subjective differences: Placebo and centrally acting analgesic underlie unique brain adaptations

Abstract

Development and maintenance of chronic pain is associated with structural and functional brain reorganization. However, few studies have explored the impact of drug treatments on such changes. The extent to which long-term analgesia is related to brain adaptations and its effects on the reversibility of brain reorganization remain unclear. In a randomized placebo-controlled clinical trial, we contrasted pain relief (3-month treatment period), and anatomical (gray matter density [GMD], assessed by voxel-based morphometry) and functional connectivity (resting state fMRI nodal degree count [DC]) adaptations, in 39 knee osteoarthritis (OA) patients (22 females), randomized to duloxetine (DLX, 60 mg once daily) or placebo. Pain relief was equivalent between treatment types. However, distinct circuitry (GMD and DC) could explain pain relief in each group: up to 85% of variance for placebo analgesia and 49% of variance for DLX analgesia. No behavioral measures (collected at entry into the study) could independently explain observed analgesia. Identified circuitry were outside of nociceptive circuitry and minimally overlapped with OA-abnormal or placebo response predictive brain regions. Mediation analysis revealed that changes in GMD and DC can influence each other across remote brain regions to explain observed analgesia. Therefore, we can conclude that distinct brain mechanisms underlie DLX and placebo analgesia in OA. The results demonstrate that even in the absence of differences in subjective pain relief, pharmacological treatments can be differentiated from placebo based on objective brain biomarkers. This is a crucial step to untangling mechanisms and advancing personalized therapy approaches for chronic pain.

Reduced anterior cingulate grey matter volume in painful hand osteoarthritis

“…Tetrault et al [16] found volumetric (and fMRI) changes that are associated with a reduction in pain for knee OA treated with placebo and duloxetine do not overlap within regions of grey matter that are different between participants with OA and non-OA controls. In their recent study in 39 participants with knee osteoarthritis (OA) patients (22 females), randomised to duloxetine (60 mg once daily) or placebo, Tetrault et al [16] showed that outcomes for pain relief were equivalent between treatment groups. The group suggested that distinct circuitry changes in the brain could explain pain relief in each group in brain measures that included grey matter density and resting state fMRI nodal degree count.…”

“…Recent work by other groups has suggested a significant negative association between the ‘pain score’ component and regional cerebral blood flow to a right temporal lobe cluster, including the amygdala and the parahippocampal cortex in a study of hand OA [ 15 ]. Tetrault et al [ 16 ] found volumetric (and fMRI) changes that are associated with a reduction in pain for knee OA treated with placebo and duloxetine do not overlap within regions of grey matter that are different between participants with OA and non-OA controls. In their recent study in 39 participants with knee osteoarthritis (OA) patients (22 females), randomised to duloxetine (60 mg once daily) or placebo, Tetrault et al [ 16 ] showed that outcomes for pain relief were equivalent between treatment groups.…”

Composite Pain Biomarker Signatures for Objective Assessment and Effective Treatment

“…In a recent study of post-traumatic neuropathic pain patients treated chronically with pregabalin, tramadol, and placebo, Wanigasekera and colleagues were able to differentiate each arm using neuroimaging alone, verify that the placebo mechanism was recruited during the placebo arm by patients, and show that the placebo mechanism was interfered with during the two drug arms (Wanigasekera et al, 2018b). A study in osteoarthritis similarly verifies imaging's ability to infer distinct mechanisms in the absence of subjective differences (Té treault et al, 2018).…”

Can Functional Brain Connectivity Predict Placebo Response in Chronic Pain?

“…If we accept the notion that placebo treatment and individual responses are quantifiable, it is also foreseeable that such treatment induces specific brain adaptations. An idea that was validated recently where we showed that upon completion of a 3‐month period with a placebo or duloxetine treatment, patients with knee osteoarthritis pain underwent differential placebo and active‐drug brain adaptations . More importantly, these different brain adaptations happen despite identical analgesic profile of the two compounds.…”