V Wanigasekera1, K Wartolowska2, J P Huggins3, E P Duff4, W Vennart5, M Whitlock6, N Massat7, L Pauer8, P Rogers9, B Hoggart10, I Tracey11. 1. Nuffield Division of Anaesthetics, Nuffield Department of Clinical Neurosciences, Oxford Centre for Functional Magnetic Resonance Imaging of the Brain, University of Oxford, Oxford, UK. Electronic address: vishvarani.wanigasekera@ndcn.ox.ac.uk. 2. Nuffield Division of Anaesthetics, Nuffield Department of Clinical Neurosciences, Oxford Centre for Functional Magnetic Resonance Imaging of the Brain, University of Oxford, Oxford, UK; Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Institute of Musculoskeletal Sciences, University of Oxford, Oxford, UK. 3. Clinical Research, Pfizer, Sandwich, UK. 4. Nuffield Division of Anaesthetics, Nuffield Department of Clinical Neurosciences, Oxford Centre for Functional Magnetic Resonance Imaging of the Brain, University of Oxford, Oxford, UK. 5. Clinical Sciences, Pfizer, Sandwich, UK. 6. Statistics, Early Clinical Development, Pfizer, Sandwich, UK. 7. Research Statistics Department, Pfizer, Sandwich, UK. 8. Global Product Development, Pfizer, Groton, CT. 9. Queen Alexandra Hospital, Department of Pain Medicine, Portsmouth, Hampshire, UK. 10. Department of Anaesthetics, Heartlands Hospital, Bordesley Green East, Birmingham, UK. 11. Nuffield Division of Anaesthetics, Nuffield Department of Clinical Neurosciences, Oxford Centre for Functional Magnetic Resonance Imaging of the Brain, University of Oxford, Oxford, UK. Electronic address: irene.tracey@ndcn.ox.ac.uk.
Abstract
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.
RCT Entities:
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 painpatients. 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.
Authors: Ángel Ortega; Juan Salazar; Néstor Galban; Milagros Rojas; Daniela Ariza; Mervin Chávez-Castillo; Manuel Nava; Manuel E Riaño-Garzón; Edgar Alexis Díaz-Camargo; Oscar Medina-Ortiz; Valmore Bermúdez Journal: Int J Mol Sci Date: 2022-04-11 Impact factor: 6.208
Authors: Etienne Vachon-Presseau; Sara E Berger; Taha B Abdullah; Lejian Huang; Guillermo A Cecchi; James W Griffith; Thomas J Schnitzer; A Vania Apkarian Journal: Nat Commun Date: 2018-09-12 Impact factor: 14.919