title: Pregabalin rectifies aberrant brain chemistry, connectivity, and functional response in chronic pain patients.
abstract: BACKGROUND
  Chronic pain remains a significant challenge for modern health care as its pathologic mechanisms are largely unknown and preclinical animal models suffer from limitations in assessing this complex subjective experience. However, human brain neuroimaging techniques enable the assessment of functional and neurochemical alterations in patients experiencing chronic pain and how these factors may dynamically change with pharmacologic treatment.
  
  
  METHODS
  To identify the clinical action of pregabalin, a proven analgesic, the authors performed three complementary brain neuroimaging procedures: (proton magnetic resonance spectroscopy, functional magnetic resonance imaging, and functional connectivity magnetic resonance imaging) in 17 chronic pain patients diagnosed with fibromyalgia.
  
  
  RESULTS
  The authors found that pregabalin but not placebo reduces combined glutamate + glutamine levels within the posterior insula (pregabalin P = 0.016; placebo P = 0.71). Interestingly, reductions in clinical pain were associated with reductions in brain connectivity of this structure to brain regions within the default mode network during pregabalin (r = 0.82; P = 0.001) but not placebo (r = -0.13; P = 0.63). Response of default mode network regions to experimental pain was also reduced with pregabalin (P = 0.018) but not placebo (P = 0.182). Perhaps most importantly, baseline values for all three neuroimaging markers predicted subsequent analgesic response to pregabalin but not placebo.
  
  
  CONCLUSIONS
  The results of this study suggest that pregabalin works in part by reducing insular glutamatergic activity, leading to a reduction of the increased functional connectivity seen between brain regions in chronic pain states. The study also supports a role for human brain imaging in the development, assessment, and personalized use of central-acting analgesics.
authors.affiliation: * Assistant Professor, # Research Specialist, ‖‖ Professor, Chronic Pain and Fatigue Research Center, Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan. † Assistant Professor, ‖ Research Fellow, Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. ‡ Senior Director, § Director, Pfizer Incorporated, Groton, Connecticut. ** Professor, Department of Radiology, Division of Neuroradiology, University of Michigan, and Department of Diagnostic Radiology, Clinical Sciences Lund, Lund University, Lund, Sweden. †† Assistant Professor, Department of Radiology, Division of Neuroradiology, University of Michigan, and Ann Arbor VA Healthcare System. ‡‡ Assistant Professor, Department of Radiology, Division of Neuroradiology, University of Michigan. §§ Associate Professor, Department of Neurology, Bergmannsheil, Berufsgenossenschaftliche Universitätsklinik, Ruhr Universität Bochum, Bochum, Germany.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Harris
authors.forename: Vitaly
authors.initials: V
authors.lastname: Napadow
authors.forename: John P
authors.initials: JP
authors.lastname: Huggins
authors.forename: Lynne
authors.initials: L
authors.lastname: Pauer
authors.forename: Jieun
authors.initials: J
authors.lastname: Kim
authors.forename: Johnson
authors.initials: J
authors.lastname: Hampson
authors.forename: Pia C
authors.initials: PC
authors.lastname: Sundgren
authors.forename: Bradley
authors.initials: B
authors.lastname: Foerster
authors.forename: Myria
authors.initials: M
authors.lastname: Petrou
authors.forename: Tobias
authors.initials: T
authors.lastname: Schmidt-Wilcke
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Clauw
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000700:Analgesics / Q000627:therapeutic use*; D001923:Brain Chemistry / Q000187:drug effects*; D059350:Chronic Pain / Q000188:drug therapy* / Q000503:physiopathology*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D005356:Fibromyalgia / Q000188:drug therapy; D018698:Glutamic Acid / Q000502:physiology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D009434:Neural Pathways / Q000187:drug effects*; D010147:Pain Measurement; D000069583:Pregabalin; D055815:Young Adult; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D000700:Analgesics; D018698:Glutamic Acid; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid