title: Naproxen effects on brain response to painful pressure stimulation in patients with knee osteoarthritis: a double-blind, randomized, placebo-controlled, single-dose study.
abstract: OBJECTIVE
  The aim of our study was to investigate the effects of naproxen, an antiinflammatory analgesic drug, on brain response to painful stimulation on the affected knee in chronic osteoarthritis (OA) using functional magnetic resonance imaging (fMRI) in a double-blind, placebo-controlled study.
  
  
  METHODS
  A sample of 25 patients with knee OA received naproxen (500 mg), placebo, or no treatment in 3 separate sessions in a randomized manner. Pressure stimulation was applied to the medial articular interline of the knee during the fMRI pain sequence. We evaluated subjective pain ratings at every session and their association with brain responses to pain. An fMRI control paradigm was included to discard global brain vascular effects of naproxen.
  
  
  RESULTS
  We found brain activation reductions under naproxen compared to no treatment in different cortical and subcortical core pain processing regions (p≤0.001). Compared to placebo, naproxen triggered an attenuation of amygdala activation (p=0.001). Placebo extended its attenuation effects beyond the classical pain processing network (p≤0.001). Subjective pain scores during the fMRI painful task differed between naproxen and no treatment (p=0.037). Activation attenuation under naproxen in different regions (i.e., ventral brain, cingulate gyrus) was accompanied by an improvement in the subjective pain complaints (p≤0.002).
  
  
  CONCLUSIONS
  Naproxen effectively reduces pain-related brain responses involving different regions and the attenuation is related to subjective pain changes. Our current work yields further support to the utility of fMRI to objectify the acute analgesic effects of a single naproxen dose in patients affected by knee OA. The trial was registered at the EuropeanClinicalTrials Database, "EudraCT Number 2008-004501-33".
authors.affiliation: From the MRI Research Unit, CRC Mar; Rheumatology Department, Hospital del Mar; Centro Investigación Biomédica en Red de Salud Mental, CIBERSAM G21; Department of Clinical and Health Psychology, Autonomous University of Barcelona; Bellvitge Biomedical Research Institute, Psychiatry Department, Bellvitge University Hospital, CYBERSAM; Cell Research Group in Inflammation and Cartilage, Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain; Neurosciences Centers of Excellence for Drug Discovery (CEDD), GlaxoSmithKline, London, UK; Pfizer, Neusentis, Cambridge, UK; Department of Psychology and Neuroscience, University of Colorado, Boulder, Colorado, USA.M. Giménez, PhD; O. Contreras-Rodríguez, PhD; H. Ortiz, MsC, MRI Research Unit, CRC Mar, Hospital del Mar; J. Pujol, MD, MRI Research Unit, CRC Mar, Hospital del Mar, Centro Investigación Biomédica en Red de Salud Mental, CIBERSAM G21; Z. Ali, PhD, Neurosciences CEDD, GlaxoSmithKline; M. López-Solà, PhD, MRI Research Unit, CRC Mar, Hospital del Mar, Department of Psychology and Neuroscience, University of Colorado; J. Deus, PhD, MRI Research Unit, CRC Mar, Hospital del Mar, Department of Clinical and Health Psychology, Autonomous University of Barcelona; C. Soriano-Mas, PhD, Bellvitge Biomedical Research Institute-IDIBELL, Psychiatry Department, Bellvitge University Hospital, CIBERSAM; J. Llorente-Onaindia, MsC; J. Monfort, MD, PhD, Rheumatology Department, Hospital del Mar, Cell Research Group in Inflammation and Cartilage, Institut Hospital del Mar d'Investigacions Mèdiques.
authors.forename: Mónica
authors.initials: M
authors.lastname: Giménez
authors.affiliation: From the MRI Research Unit, CRC Mar; Rheumatology Department, Hospital del Mar; Centro Investigación Biomédica en Red de Salud Mental, CIBERSAM G21; Department of Clinical and Health Psychology, Autonomous University of Barcelona; Bellvitge Biomedical Research Institute, Psychiatry Department, Bellvitge University Hospital, CYBERSAM; Cell Research Group in Inflammation and Cartilage, Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain; Neurosciences Centers of Excellence for Drug Discovery (CEDD), GlaxoSmithKline, London, UK; Pfizer, Neusentis, Cambridge, UK; Department of Psychology and Neuroscience, University of Colorado, Boulder, Colorado, USA.M. Giménez, PhD; O. Contreras-Rodríguez, PhD; H. Ortiz, MsC, MRI Research Unit, CRC Mar, Hospital del Mar; J. Pujol, MD, MRI Research Unit, CRC Mar, Hospital del Mar, Centro Investigación Biomédica en Red de Salud Mental, CIBERSAM G21; Z. Ali, PhD, Neurosciences CEDD, GlaxoSmithKline; M. López-Solà, PhD, MRI Research Unit, CRC Mar, Hospital del Mar, Department of Psychology and Neuroscience, University of Colorado; J. Deus, PhD, MRI Research Unit, CRC Mar, Hospital del Mar, Department of Clinical and Health Psychology, Autonomous University of Barcelona; C. Soriano-Mas, PhD, Bellvitge Biomedical Research Institute-IDIBELL, Psychiatry Department, Bellvitge University Hospital, CIBERSAM; J. Llorente-Onaindia, MsC; J. Monfort, MD, PhD, Rheumatology Department, Hospital del Mar, Cell Research Group in Inflammation and Cartilage, Institut Hospital del Mar d'Investigacions Mèdiques. 21404jpn@comb.cat.
authors.forename: Jesús
authors.initials: J
authors.lastname: Pujol
authors.affiliation: From the MRI Research Unit, CRC Mar; Rheumatology Department, Hospital del Mar; Centro Investigación Biomédica en Red de Salud Mental, CIBERSAM G21; Department of Clinical and Health Psychology, Autonomous University of Barcelona; Bellvitge Biomedical Research Institute, Psychiatry Department, Bellvitge University Hospital, CYBERSAM; Cell Research Group in Inflammation and Cartilage, Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain; Neurosciences Centers of Excellence for Drug Discovery (CEDD), GlaxoSmithKline, London, UK; Pfizer, Neusentis, Cambridge, UK; Department of Psychology and Neuroscience, University of Colorado, Boulder, Colorado, USA.M. Giménez, PhD; O. Contreras-Rodríguez, PhD; H. Ortiz, MsC, MRI Research Unit, CRC Mar, Hospital del Mar; J. Pujol, MD, MRI Research Unit, CRC Mar, Hospital del Mar, Centro Investigación Biomédica en Red de Salud Mental, CIBERSAM G21; Z. Ali, PhD, Neurosciences CEDD, GlaxoSmithKline; M. López-Solà, PhD, MRI Research Unit, CRC Mar, Hospital del Mar, Department of Psychology and Neuroscience, University of Colorado; J. Deus, PhD, MRI Research Unit, CRC Mar, Hospital del Mar, Department of Clinical and Health Psychology, Autonomous University of Barcelona; C. Soriano-Mas, PhD, Bellvitge Biomedical Research Institute-IDIBELL, Psychiatry Department, Bellvitge University Hospital, CIBERSAM; J. Llorente-Onaindia, MsC; J. Monfort, MD, PhD, Rheumatology Department, Hospital del Mar, Cell Research Group in Inflammation and Cartilage, Institut Hospital del Mar d'Investigacions Mèdiques.
authors.forename: Zahid
authors.initials: Z
authors.lastname: Ali
authors.affiliation: From the MRI Research Unit, CRC Mar; Rheumatology Department, Hospital del Mar; Centro Investigación Biomédica en Red de Salud Mental, CIBERSAM G21; Department of Clinical and Health Psychology, Autonomous University of Barcelona; Bellvitge Biomedical Research Institute, Psychiatry Department, Bellvitge University Hospital, CYBERSAM; Cell Research Group in Inflammation and Cartilage, Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain; Neurosciences Centers of Excellence for Drug Discovery (CEDD), GlaxoSmithKline, London, UK; Pfizer, Neusentis, Cambridge, UK; Department of Psychology and Neuroscience, University of Colorado, Boulder, Colorado, USA.M. Giménez, PhD; O. Contreras-Rodríguez, PhD; H. Ortiz, MsC, MRI Research Unit, CRC Mar, Hospital del Mar; J. Pujol, MD, MRI Research Unit, CRC Mar, Hospital del Mar, Centro Investigación Biomédica en Red de Salud Mental, CIBERSAM G21; Z. Ali, PhD, Neurosciences CEDD, GlaxoSmithKline; M. López-Solà, PhD, MRI Research Unit, CRC Mar, Hospital del Mar, Department of Psychology and Neuroscience, University of Colorado; J. Deus, PhD, MRI Research Unit, CRC Mar, Hospital del Mar, Department of Clinical and Health Psychology, Autonomous University of Barcelona; C. Soriano-Mas, PhD, Bellvitge Biomedical Research Institute-IDIBELL, Psychiatry Department, Bellvitge University Hospital, CIBERSAM; J. Llorente-Onaindia, MsC; J. Monfort, MD, PhD, Rheumatology Department, Hospital del Mar, Cell Research Group in Inflammation and Cartilage, Institut Hospital del Mar d'Investigacions Mèdiques.
authors.forename: Marina
authors.initials: M
authors.lastname: López-Solà
authors.affiliation: From the MRI Research Unit, CRC Mar; Rheumatology Department, Hospital del Mar; Centro Investigación Biomédica en Red de Salud Mental, CIBERSAM G21; Department of Clinical and Health Psychology, Autonomous University of Barcelona; Bellvitge Biomedical Research Institute, Psychiatry Department, Bellvitge University Hospital, CYBERSAM; Cell Research Group in Inflammation and Cartilage, Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain; Neurosciences Centers of Excellence for Drug Discovery (CEDD), GlaxoSmithKline, London, UK; Pfizer, Neusentis, Cambridge, UK; Department of Psychology and Neuroscience, University of Colorado, Boulder, Colorado, USA.M. Giménez, PhD; O. Contreras-Rodríguez, PhD; H. Ortiz, MsC, MRI Research Unit, CRC Mar, Hospital del Mar; J. Pujol, MD, MRI Research Unit, CRC Mar, Hospital del Mar, Centro Investigación Biomédica en Red de Salud Mental, CIBERSAM G21; Z. Ali, PhD, Neurosciences CEDD, GlaxoSmithKline; M. López-Solà, PhD, MRI Research Unit, CRC Mar, Hospital del Mar, Department of Psychology and Neuroscience, University of Colorado; J. Deus, PhD, MRI Research Unit, CRC Mar, Hospital del Mar, Department of Clinical and Health Psychology, Autonomous University of Barcelona; C. Soriano-Mas, PhD, Bellvitge Biomedical Research Institute-IDIBELL, Psychiatry Department, Bellvitge University Hospital, CIBERSAM; J. Llorente-Onaindia, MsC; J. Monfort, MD, PhD, Rheumatology Department, Hospital del Mar, Cell Research Group in Inflammation and Cartilage, Institut Hospital del Mar d'Investigacions Mèdiques.
authors.forename: Oren
authors.initials: O
authors.lastname: Contreras-Rodríguez
authors.affiliation: From the MRI Research Unit, CRC Mar; Rheumatology Department, Hospital del Mar; Centro Investigación Biomédica en Red de Salud Mental, CIBERSAM G21; Department of Clinical and Health Psychology, Autonomous University of Barcelona; Bellvitge Biomedical Research Institute, Psychiatry Department, Bellvitge University Hospital, CYBERSAM; Cell Research Group in Inflammation and Cartilage, Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain; Neurosciences Centers of Excellence for Drug Discovery (CEDD), GlaxoSmithKline, London, UK; Pfizer, Neusentis, Cambridge, UK; Department of Psychology and Neuroscience, University of Colorado, Boulder, Colorado, USA.M. Giménez, PhD; O. Contreras-Rodríguez, PhD; H. Ortiz, MsC, MRI Research Unit, CRC Mar, Hospital del Mar; J. Pujol, MD, MRI Research Unit, CRC Mar, Hospital del Mar, Centro Investigación Biomédica en Red de Salud Mental, CIBERSAM G21; Z. Ali, PhD, Neurosciences CEDD, GlaxoSmithKline; M. López-Solà, PhD, MRI Research Unit, CRC Mar, Hospital del Mar, Department of Psychology and Neuroscience, University of Colorado; J. Deus, PhD, MRI Research Unit, CRC Mar, Hospital del Mar, Department of Clinical and Health Psychology, Autonomous University of Barcelona; C. Soriano-Mas, PhD, Bellvitge Biomedical Research Institute-IDIBELL, Psychiatry Department, Bellvitge University Hospital, CIBERSAM; J. Llorente-Onaindia, MsC; J. Monfort, MD, PhD, Rheumatology Department, Hospital del Mar, Cell Research Group in Inflammation and Cartilage, Institut Hospital del Mar d'Investigacions Mèdiques.
authors.forename: Joan
authors.initials: J
authors.lastname: Deus
authors.affiliation: From the MRI Research Unit, CRC Mar; Rheumatology Department, Hospital del Mar; Centro Investigación Biomédica en Red de Salud Mental, CIBERSAM G21; Department of Clinical and Health Psychology, Autonomous University of Barcelona; Bellvitge Biomedical Research Institute, Psychiatry Department, Bellvitge University Hospital, CYBERSAM; Cell Research Group in Inflammation and Cartilage, Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain; Neurosciences Centers of Excellence for Drug Discovery (CEDD), GlaxoSmithKline, London, UK; Pfizer, Neusentis, Cambridge, UK; Department of Psychology and Neuroscience, University of Colorado, Boulder, Colorado, USA.M. Giménez, PhD; O. Contreras-Rodríguez, PhD; H. Ortiz, MsC, MRI Research Unit, CRC Mar, Hospital del Mar; J. Pujol, MD, MRI Research Unit, CRC Mar, Hospital del Mar, Centro Investigación Biomédica en Red de Salud Mental, CIBERSAM G21; Z. Ali, PhD, Neurosciences CEDD, GlaxoSmithKline; M. López-Solà, PhD, MRI Research Unit, CRC Mar, Hospital del Mar, Department of Psychology and Neuroscience, University of Colorado; J. Deus, PhD, MRI Research Unit, CRC Mar, Hospital del Mar, Department of Clinical and Health Psychology, Autonomous University of Barcelona; C. Soriano-Mas, PhD, Bellvitge Biomedical Research Institute-IDIBELL, Psychiatry Department, Bellvitge University Hospital, CIBERSAM; J. Llorente-Onaindia, MsC; J. Monfort, MD, PhD, Rheumatology Department, Hospital del Mar, Cell Research Group in Inflammation and Cartilage, Institut Hospital del Mar d'Investigacions Mèdiques.
authors.forename: Héctor
authors.initials: H
authors.lastname: Ortiz
authors.affiliation: From the MRI Research Unit, CRC Mar; Rheumatology Department, Hospital del Mar; Centro Investigación Biomédica en Red de Salud Mental, CIBERSAM G21; Department of Clinical and Health Psychology, Autonomous University of Barcelona; Bellvitge Biomedical Research Institute, Psychiatry Department, Bellvitge University Hospital, CYBERSAM; Cell Research Group in Inflammation and Cartilage, Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain; Neurosciences Centers of Excellence for Drug Discovery (CEDD), GlaxoSmithKline, London, UK; Pfizer, Neusentis, Cambridge, UK; Department of Psychology and Neuroscience, University of Colorado, Boulder, Colorado, USA.M. Giménez, PhD; O. Contreras-Rodríguez, PhD; H. Ortiz, MsC, MRI Research Unit, CRC Mar, Hospital del Mar; J. Pujol, MD, MRI Research Unit, CRC Mar, Hospital del Mar, Centro Investigación Biomédica en Red de Salud Mental, CIBERSAM G21; Z. Ali, PhD, Neurosciences CEDD, GlaxoSmithKline; M. López-Solà, PhD, MRI Research Unit, CRC Mar, Hospital del Mar, Department of Psychology and Neuroscience, University of Colorado; J. Deus, PhD, MRI Research Unit, CRC Mar, Hospital del Mar, Department of Clinical and Health Psychology, Autonomous University of Barcelona; C. Soriano-Mas, PhD, Bellvitge Biomedical Research Institute-IDIBELL, Psychiatry Department, Bellvitge University Hospital, CIBERSAM; J. Llorente-Onaindia, MsC; J. Monfort, MD, PhD, Rheumatology Department, Hospital del Mar, Cell Research Group in Inflammation and Cartilage, Institut Hospital del Mar d'Investigacions Mèdiques.
authors.forename: Carles
authors.initials: C
authors.lastname: Soriano-Mas
authors.affiliation: From the MRI Research Unit, CRC Mar; Rheumatology Department, Hospital del Mar; Centro Investigación Biomédica en Red de Salud Mental, CIBERSAM G21; Department of Clinical and Health Psychology, Autonomous University of Barcelona; Bellvitge Biomedical Research Institute, Psychiatry Department, Bellvitge University Hospital, CYBERSAM; Cell Research Group in Inflammation and Cartilage, Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain; Neurosciences Centers of Excellence for Drug Discovery (CEDD), GlaxoSmithKline, London, UK; Pfizer, Neusentis, Cambridge, UK; Department of Psychology and Neuroscience, University of Colorado, Boulder, Colorado, USA.M. Giménez, PhD; O. Contreras-Rodríguez, PhD; H. Ortiz, MsC, MRI Research Unit, CRC Mar, Hospital del Mar; J. Pujol, MD, MRI Research Unit, CRC Mar, Hospital del Mar, Centro Investigación Biomédica en Red de Salud Mental, CIBERSAM G21; Z. Ali, PhD, Neurosciences CEDD, GlaxoSmithKline; M. López-Solà, PhD, MRI Research Unit, CRC Mar, Hospital del Mar, Department of Psychology and Neuroscience, University of Colorado; J. Deus, PhD, MRI Research Unit, CRC Mar, Hospital del Mar, Department of Clinical and Health Psychology, Autonomous University of Barcelona; C. Soriano-Mas, PhD, Bellvitge Biomedical Research Institute-IDIBELL, Psychiatry Department, Bellvitge University Hospital, CIBERSAM; J. Llorente-Onaindia, MsC; J. Monfort, MD, PhD, Rheumatology Department, Hospital del Mar, Cell Research Group in Inflammation and Cartilage, Institut Hospital del Mar d'Investigacions Mèdiques.
authors.forename: Jone
authors.initials: J
authors.lastname: Llorente-Onaindia
authors.affiliation: From the MRI Research Unit, CRC Mar; Rheumatology Department, Hospital del Mar; Centro Investigación Biomédica en Red de Salud Mental, CIBERSAM G21; Department of Clinical and Health Psychology, Autonomous University of Barcelona; Bellvitge Biomedical Research Institute, Psychiatry Department, Bellvitge University Hospital, CYBERSAM; Cell Research Group in Inflammation and Cartilage, Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain; Neurosciences Centers of Excellence for Drug Discovery (CEDD), GlaxoSmithKline, London, UK; Pfizer, Neusentis, Cambridge, UK; Department of Psychology and Neuroscience, University of Colorado, Boulder, Colorado, USA.M. Giménez, PhD; O. Contreras-Rodríguez, PhD; H. Ortiz, MsC, MRI Research Unit, CRC Mar, Hospital del Mar; J. Pujol, MD, MRI Research Unit, CRC Mar, Hospital del Mar, Centro Investigación Biomédica en Red de Salud Mental, CIBERSAM G21; Z. Ali, PhD, Neurosciences CEDD, GlaxoSmithKline; M. López-Solà, PhD, MRI Research Unit, CRC Mar, Hospital del Mar, Department of Psychology and Neuroscience, University of Colorado; J. Deus, PhD, MRI Research Unit, CRC Mar, Hospital del Mar, Department of Clinical and Health Psychology, Autonomous University of Barcelona; C. Soriano-Mas, PhD, Bellvitge Biomedical Research Institute-IDIBELL, Psychiatry Department, Bellvitge University Hospital, CIBERSAM; J. Llorente-Onaindia, MsC; J. Monfort, MD, PhD, Rheumatology Department, Hospital del Mar, Cell Research Group in Inflammation and Cartilage, Institut Hospital del Mar d'Investigacions Mèdiques.
authors.forename: Jordi
authors.initials: J
authors.lastname: Monfort
mesh_terms: D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage*; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D009288:Naproxen / Q000008:administration & dosage*; D020370:Osteoarthritis, Knee / Q000175:diagnosis* / Q000188:drug therapy*; D010146:Pain / Q000503:physiopathology / Q000517:prevention & control*; D017288:Pain Threshold / Q000502:physiology; D010812:Physical Stimulation / Q000379:methods; D012016:Reference Values; D012720:Severity of Illness Index
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D009288:Naproxen
keywords: MAGNETIC RESONANCE IMAGING; NAPROXEN; OSTEOARTHRITIS; PAIN