Chronic pain is a world-wide clinical challenge. Response to
analgesic treatment is limited and difficult to predict. Functional MRI has been suggested as a potential
solution. However, while most
analgesics target specific neurotransmission pathways, functional MRI-based
biomarkers are not specific for any
neurotransmitter system, limiting our understanding of how they might contribute to predict treatment response. Here, we sought to bridge this gap by applying Receptor-Enriched Analysis of Functional Connectivity by Targets to investigate whether neurotransmission-enriched functional connectivity mapping can provide insights into the brain mechanisms underlying
chronic pain and inter-individual differences in
analgesic response after a placebo or
duloxetine. We performed secondary analyses of two openly available resting-state functional MRI data sets of 56 patients with chronic
knee osteoarthritis pain who underwent pre-treatment brain scans in two clinical trials. Study 1 (n = 17) was a 2-week single-blinded placebo pill trial. Study 2 (n = 39) was a 3-month double-blinded randomized trial comparing placebo to
duloxetine, a dual
serotonin-
noradrenaline reuptake inhibitor. Across two independent studies, we found that patients with
chronic pain present alterations in the functional circuit related to the
serotonin transporter, when compared with age-matched healthy controls. Placebo responders in Study 1 presented with higher pre-treatment functional connectivity enriched by the
dopamine transporter compared to non-responders.
Duloxetine responders presented with higher pre-treatment functional connectivity enriched by the
serotonin and
noradrenaline transporters when compared with non-responders. Neurotransmission-enriched functional connectivity mapping might hold promise as a new mechanistic-informed
biomarker for functional brain alterations and prediction of response to pharmacological
analgesia in
chronic pain.