title: Disambiguating Pharmacodynamic Efficacy from Behavior with Neuroimaging: Implications for Analgesic Drug Development.
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.
authors.affiliation: 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.
authors.forename: Vishvarani
authors.initials: V
authors.lastname: Wanigasekera
authors.forename: Melvin
authors.initials: M
authors.lastname: Mezue
authors.forename: Jesper
authors.initials: J
authors.lastname: Andersson
authors.forename: Yazhuo
authors.initials: Y
authors.lastname: Kong
authors.forename: Irene
authors.initials: I
authors.lastname: Tracey
mesh_terms: D000328:Adult; D000588:Amines / Q000494:pharmacology*; D000700:Analgesics / Q000494:pharmacology*; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D001921:Brain / Q000187:drug effects*; D002211:Capsaicin; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology*; D004311:Double-Blind Method; D005260:Female; D000077206:Gabapentin; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy*; D007052:Ibuprofen / Q000494:pharmacology; D008279:Magnetic Resonance Imaging; D008297:Male; D059906:Neuroimaging; D015203:Reproducibility of Results; D016896:Treatment Outcome; D055815:Young Adult; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
chemical_list: D000588:Amines; D000700:Analgesics; D018712:Analgesics, Non-Narcotic; D003509:Cyclohexanecarboxylic Acids; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D002211:Capsaicin; D007052:Ibuprofen