Pain Medicine  |   January 2016
Disambiguating Pharmacodynamic Efficacy from Behavior with Neuroimaging: Implications for Analgesic Drug Development
Author Notes
  • From the Nuffield Division of Anaesthetics, Nuffield Department of Clinical Neurosciences, Centre for Functional Magnetic Resonance Imaging of the Brain (FMRIB), University of Oxford, John Radcliffe Hospital, Headington, Oxford, United Kingdom.
  • This article is featured in “This Month in Anesthesiology,” page 1A.
    This article is featured in “This Month in Anesthesiology,” page 1A.×
  • Presented at the 14th World Congress on Pain, August 27–31, 2013, Milan, Italy, and 15th World Congress on Pain, October 7–11, 2014, Buenos Aires, Argentina. V.W. and I.T. designed research; V.W. and M.M. performed research; V.W., M.M., J.A., and Y.K. analyzed the data; and V.W., M.M., J.A., Y.K., and I.T. interpreted data and wrote the manuscript.
    Presented at the 14th World Congress on Pain, August 27–31, 2013, Milan, Italy, and 15th World Congress on Pain, October 7–11, 2014, Buenos Aires, Argentina. V.W. and I.T. designed research; V.W. and M.M. performed research; V.W., M.M., J.A., and Y.K. analyzed the data; and V.W., M.M., J.A., Y.K., and I.T. interpreted data and wrote the manuscript.×
  • Submitted for publication November 4, 2014. Accepted for publication September 16, 2015.
    Submitted for publication November 4, 2014. Accepted for publication September 16, 2015.×
  • Address correspondence to Dr. Wanigasekera: Centre for Functional Magnetic Resonance Imaging of the Brain (FMRIB) & Nuffield Division of Anaesthetics, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, United Kingdom. vishvarani.wanigasekera@ndcn.ox.ac.uk. This article may be accessed for personal use at no charge through the Journal Web site, www.anesthsiology.org.
Article Information
Pain Medicine / Clinical Science / Central and Peripheral Nervous Systems / Pain Medicine / Pharmacology
Pain Medicine   |   January 2016
Disambiguating Pharmacodynamic Efficacy from Behavior with Neuroimaging: Implications for Analgesic Drug Development
Anesthesiology 1 2016, Vol.124, 159-168. doi:10.1097/ALN.0000000000000924
Anesthesiology 1 2016, Vol.124, 159-168. doi:10.1097/ALN.0000000000000924
Abstract

Background: Attrition rates of new analgesics during drug development are high; poor assay sensitivity with reliance on subjective outcome measures being a crucial factor.

Methods: The authors assessed the utility of functional magnetic resonance imaging with capsaicin-induced central sensitization, a mechanism relevant in neuropathic pain, for obtaining mechanism-based objective outcome measures that can differentiate an effective analgesic (gabapentin) from an ineffective analgesic (ibuprofen) and both from placebo. The authors used a double-blind, randomized phase I study design (N = 24) with single oral doses.

Results: Only gabapentin suppressed the secondary mechanical hyperalgesia–evoked neural response in a region of the brainstem’s descending pain modulatory system (right nucleus cuneiformis) and left (contralateral) posterior insular cortex and secondary somatosensory cortex. Similarly, only gabapentin suppressed the resting-state functional connectivity during central sensitization between the thalamus and secondary somatosensory cortex, which was plasma gabapentin level dependent. A power analysis showed that with 12 data sets, when using neural activity from the left posterior insula and right nucleus cuneiformis, a statistically significant difference between placebo and gabapentin was detected with probability ≥ 0.8. When using subjective pain ratings, this reduced to less than or equal to 0.6.

Conclusions: Functional imaging with central sensitization can be used as a sensitive mechanism–based assay to guide go/no-go decisions on selecting analgesics effective in neuropathic pain in early human drug development. We also show analgesic modulation of neural activity by using resting-state functional connectivity, a less challenging paradigm that is ideally suited for patient studies because it requires no task or pain provocation.

Abstract

After development of experimental central sensitization, gabapentin reduces the activation of pain-related brain areas as well as functional connectivity between the thalamus and secondary somatosensory cortex, whereas ibuprofen does not when compared with placebo. Functional imaging may be a viable tool for evaluating analgesic efficacy during early stages of drug development.