<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03239938</url>
  </required_header>
  <id_info>
    <org_study_id>G007217N</org_study_id>
    <nct_id>NCT03239938</nct_id>
  </id_info>
  <brief_title>Modern Pain Neuroscience Applied to Chronic Pain in Patients With Chronic Whiplash Associated Disorders</brief_title>
  <official_title>Contemporary Pain Neuroscience Compared to Usual Care Evidence-based Physiotherapy Applied to Chronic Pain in Patients With Chronic Whiplash Associated Disorders: Can we Decrease Central Sensitization?</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Vrije Universiteit Brussel</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University Hospital, Ghent</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University Ghent</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Research Foundation Flanders</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Universitair Ziekenhuis Brussel</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Vrije Universiteit Brussel</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Modern pain neuroscience has advanced our understanding of chronic whiplash associated&#xD;
      disorders (WAD). Previous studies have shown the importance of central sensitization,&#xD;
      characterized by hypersensitivity of the somatosensory system, in explaining poor treatment&#xD;
      outcome. Therefore, and to address the need for a better treatment of chronic WAD, we&#xD;
      recently proposed a modern neuroscience approach to chronic WAD. Such approach includes two&#xD;
      specific parts: therapeutic pain neuroscience education followed by dynamic and functional&#xD;
      cognition-targeted exercise therapy and stress management techniques.&#xD;
&#xD;
      The primary scientific objective of the study entails examining the effectiveness of a modern&#xD;
      neuroscience approach versus usual care evidence-based physiotherapy for reducing&#xD;
      dysfunctioning in patients with chronic WAD. The secondary scientific objective of the study&#xD;
      entails examining the effectiveness of a modern neuroscience approach versus usual care&#xD;
      evidence-based physiotherapy for reducing pain, central sensitization, psychosocial problems,&#xD;
      and socio-economic burden in patients with chronic WAD. The trial will randomize 120 patients&#xD;
      with chronic WAD, aged between 18 and 65 years, to the experimental (modern pain neuroscience&#xD;
      approach including 3 sessions of therapeutic pain neuroscience education followed by 15&#xD;
      sessions of dynamic and functional cognition-targeted exercise therapy and stress management&#xD;
      techniques (n = 60)) or the control treatment (usual care physiotherapy including 3 sessions&#xD;
      of neck school followed by 15 sessions of graded and active exercise therapy focusing on&#xD;
      strength, flexibility, endurance, and ergonomic principles (n= 60)). The primary outcome&#xD;
      measure is self-reported functional status. Secondary outcome measures include pain,&#xD;
      health-related quality of life, psychological correlates, measures of central sensitization,&#xD;
      and socio-economic factors. In addition, quantitative scalp Electroencephalography (EEG) to&#xD;
      measure various parameters of brain activation will be performed during a conditioned pain&#xD;
      modulation paradigm. Baseline assessment of all outcome measures will be performed.&#xD;
&#xD;
      Follow-up assessments will be performed immediately after 16 weeks of therapy (all tests),&#xD;
      and 6 months (all tests) and 12 months (only questionnaires) after finishing the therapeutic&#xD;
      intervention.&#xD;
&#xD;
      To investigate these objectives, a multi-center triple-blind randomized, controlled trial&#xD;
      with 1 year follow up will be performed.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Modern pain neuroscience has advanced our understanding of chronic whiplash associated&#xD;
      disorders (WAD). Previous studies have shown the importance of central sensitization,&#xD;
      characterized by hypersensitivity of the somatosensory system, in explaining poor treatment&#xD;
      outcome. Therefore, and to address the need for a better treatment of chronic WAD, we&#xD;
      recently proposed a modern neuroscience approach to chronic WAD. Such approach includes two&#xD;
      specific parts: 3 sessions of therapeutic pain neuroscience education followed by 15 sessions&#xD;
      of dynamic and functional cognition-targeted exercise therapy and stress management&#xD;
      techniques. The main principles of cognition-targeted are the following: All exercises should&#xD;
      be performed in a time-contingent (&quot;Perform this exercise 10 times, regardless of the pain&quot;)&#xD;
      rather than in a symptom-contingent way (&quot;Stop or adjust the exercise when it hurts&quot;). Goal&#xD;
      setting is essentially done together with the patient, focussing on functionality. The&#xD;
      treating physical therapist should continuously assess and challenge the patients' cognitions&#xD;
      and perceptions about the pain and the anticipated outcome of each exercise, to change&#xD;
      maladaptive cognitions and perceptions into positive ones.&#xD;
&#xD;
      The primary scientific objective of the study entails examining the effectiveness of a modern&#xD;
      pain neuroscience approach versus usual care evidence-based physiotherapy for reducing&#xD;
      dysfunctioning in patients with chronic WAD. The secondary scientific objective of the study&#xD;
      entails examining the effectiveness of a modern neuroscience approach versus usual care&#xD;
      evidence-based physiotherapy for reducing pain, central sensitization, psychological&#xD;
      problems, and socio-economic burden in patients with chronic WAD. The trial will randomize&#xD;
      120 patients with chronic WAD, aged between 18 and 65 years, to the experimental (modern pain&#xD;
      neuroscience approach (n = 60)) or control treatment (usual care evidence-based&#xD;
      physiotherapy: 3 sessions of neck school followed by 15 sessions of graded and active&#xD;
      exercise therapy focusing on strength, flexibility, endurance, and ergonomic principles (n=&#xD;
      60)). The primary outcome measure is functional status. Secondary outcome measures include&#xD;
      pain, health-related quality of life, psychological correlates, socio-economic factors, and&#xD;
      measures of central sensitization, including electrical detection and electrical pain&#xD;
      thresholds measured with a constant current electrical stimulator, endogenous pain&#xD;
      facilitation (temporal summation of electrical pain), endogenous pain inhibition assessed by&#xD;
      the conditioned pain modulation paradigm (electrical stimulation as test stimulus and the&#xD;
      cold pressor test (immersion of one hand in cold water of 12°C) as conditioning stimulus). In&#xD;
      addition, quantitative scalp Electroencephalography (EEG) to measure various parameters of&#xD;
      brain activation will be performed during the conditioned pain modulation paradigm.&#xD;
&#xD;
      To comply with these scientific objectives, the 120 chronic WAD patients will be subjected to&#xD;
      the baseline assessment of all outcome measures.&#xD;
&#xD;
      Follow-up assessments will be performed immediately after 16 weeks of therapy (all tests),&#xD;
      and 6 months (all tests) and 12 months (only questionnaires) after finishing the therapeutic&#xD;
      intervention.&#xD;
&#xD;
      To investigate these objectives, a muli-center triple-blind randomized, controlled trial with&#xD;
      1 year follow up will be performed.&#xD;
&#xD;
      Appropriate statistical analyses will be performed to evaluate and compare treatment effects.&#xD;
      Statistical, as well as clinical significant differences will be defined and the effect size&#xD;
      will be determined. Relations between functional status, pain, psychological correlates and&#xD;
      central sensitization will be investigated. Furthermore, prediction of pain and functional&#xD;
      status by central sensitization and psychological correlates will be performed in chronic WAD&#xD;
      patients. Also, factors associated with clinically important changes in the outcome measures&#xD;
      will be unraveled. In addition, factors associated with poor outcome following treatment will&#xD;
      be assessed.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">August 17, 2017</start_date>
  <completion_date type="Actual">June 13, 2022</completion_date>
  <primary_completion_date type="Actual">June 13, 2022</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>The trial will randomize 120 patients with chronic WAD, aged between 18 and 65 years, to the experimental (modern neuroscience approach including 3 sessions of therapeutic pain neuroscience education followed by 15 sessions of dynamic and functional cognition-targeted exercise therapy and stress management techniques (n = 60)) or the control treatment (usual care physiotherapy: 3 sessions of neck school followed by 15 sessions of exercise therapy focusing on strength, flexibility, endurance, and ergonomic principles (n= 60)).</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Self-reported functional status or disability</measure>
    <time_frame>The change between the baseline assessment and the 6 months follow-up assessment (6 months after the end of the therapy)</time_frame>
    <description>The Dutch version of the Neck Disability Index (questionnaire)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Self-reported functional status or disability</measure>
    <time_frame>Baseline assessment, T1 follow-up assessment after 16 weeks of therapy, T3 follow-up assessment 12 months after the end of the therapy.</time_frame>
    <description>The Dutch version of the Neck Disability Index (questionnaire)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Self-reported health-related quality of life</measure>
    <time_frame>Baseline assessment, T1 follow-up assessment after 16 weeks of therapy, T2 follow-up assessment 6 months after the end of the therapy, T3 assessment 12 months after the end of the therapy.</time_frame>
    <description>The Dutch version of the Short Form Health Survey-36 items (questionnaire)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Self-reported pain assessment</measure>
    <time_frame>Baseline assessment, T1 follow-up assessment after 16 weeks of therapy, T2 follow-up assessment 6 months after the end of the therapy, T3 follow-up assessment 12 months after the end of the therapy.</time_frame>
    <description>A 0-10 Numeric Rating Scale for pain (questionnaire). Patients fill out the Numeric Rating Scale (0 no pain - 10 worst pain imaginable) for their perceived neck pain.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Self-reported central sensitization symptoms</measure>
    <time_frame>Baseline assessment, T1 follow-up assessment after 16 weeks of therapy, T2 follow-up assessment 6 months after the end of the therapy, T3 follow-up assessment 12 months after the end of the therapy.</time_frame>
    <description>The Dutch version of the Central Sensitization Inventory (questionnaire)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Electrical detection and electrical pain thresholds with a constant current electrical stimulator (DS7A Digitimer)</measure>
    <time_frame>Baseline assessment, T1 follow-up assessment after 16 weeks of therapy, T2 follow-up assessment 6 months after the end of the therapy</time_frame>
    <description>Determination of the electrical detection and electrical pain threshold with the electrical stimulator will be performed at the sural nerve of the dominant leg and at the median nerve of the dominant arm.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Endogenous pain facilitation assessed by a temporal summation paradigm</measure>
    <time_frame>Baseline assessment, T1 follow-up assessment after 16 weeks of therapy, T2 follow-up assessment 6 months after the end of the therapy</time_frame>
    <description>Temporal summation of electrical pain will be assessed by delivering 20 electrical stimuli at the intensity of the electrical pain threshold.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Endogenous pain inhibition assessed by a conditioned pain modulation paradigm</measure>
    <time_frame>Baseline assessment, T1 follow-up assessment after 16 weeks of therapy, T2 follow-up assessment 6 months after the end of the therapy</time_frame>
    <description>Conditioned pain modulation will be tested with electrical stimulation as test stimulus and the cold pressor test (immersion the hand up to the wrist in cold water of 12°C) as conditioning stimulus.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quantitative Electroencephalography (QEEG) (Sienna digital EEG, EMS Biomedical, Korneuburg, Austria) will be recorded from 32 Sn surface electrodes using an electrode cap (Headcap, Expertise in Medical Solutions Biomedical, Korneuburg, Austria).</measure>
    <time_frame>Baseline assessment, T1 follow-up assessment after 16 weeks of therapy, T2 follow-up assessment 6 months after the end of the therapy</time_frame>
    <description>During the condition pain modulation paradigm a QEEG will be administered to examine various brain activity parameters.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Self-reported psychological correlates: Pain catastrophizing</measure>
    <time_frame>Baseline assessment, T1 follow-up assessment after 16 weeks of therapy, T2 follow-up assessment 6 months after the end of the therapy, T3 follow-up assessment 12 months after the end of the therapy.</time_frame>
    <description>The Dutch version of the Pain Catastrophizing Scale (questionnaire)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Self-reported psychological correlates: Illness perceptions</measure>
    <time_frame>Baseline assessment, T1 follow-up assessment after 16 weeks of therapy, T2 follow-up assessment 6 months after the end of the therapy, T3 follow-up assessment 12 months after the end of the therapy.</time_frame>
    <description>The Dutch version of the illness perception questionnaire-revised (questionnaire)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Self-reported psychological correlates: Post-traumatic stress</measure>
    <time_frame>Baseline assessment, T1 follow-up assessment after 16 weeks of therapy, T2 follow-up assessment 6 months after the end of the therapy, T3 follow-up assessment 12 months after the end of the therapy.</time_frame>
    <description>The Dutch version of the Impact of Event Scale revised (questionnaire)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Self-reported psychological correlates: Pain-related fear and fear-avoidance behaviour</measure>
    <time_frame>Baseline assessment, T1 follow-up assessment after 16 weeks of therapy, T2 follow-up assessment 6 months after the end of the therapy, T3 follow-up assessment 12 months after the end of the therapy.</time_frame>
    <description>The Dutch version of the Pain anxiety symptoms scale (PASS-20) (questionnaire)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Socio-economic factors</measure>
    <time_frame>Baseline assessment, T2 follow-up assessment 6 months after the end of the therapy, T3 follow-up assessment 12 months after the end of the therapy, 1 year before enrollment in the study</time_frame>
    <description>Self-reported questionnaire and data including health-care expenditure from publicly funded healthcare organizations.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">120</enrollment>
  <condition>Whiplash</condition>
  <arm_group>
    <arm_group_label>Modern pain neuroscience approach</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Modern pain neuroscience approach</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Usual care evidence-based physiotherapy</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Usual care physiotherapy</description>
  </arm_group>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>Modern pain neuroscience approach</intervention_name>
    <description>The modern pain neuroscience approach includes 3 sessions (1 group and 2 individual sessions) of therapeutic pain neuroscience education followed by 15 individual sessions of dynamic and functional cognition-targeted exercise therapy and stress management techniques. In addition, participants will be instructed to perform a daily set of home exercises. The exercises will be performed in a time-contingent way. The 18 sessions will be spread over a period of 16 weeks.</description>
    <arm_group_label>Modern pain neuroscience approach</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>Usual care evidence-based physiotherapy</intervention_name>
    <description>The usual care evidence-based physiotherapy includes 3 sessions (1 group and 2 individual sessions) of neck school followed by 15 individual sessions of graded and active exercise therapy focusing on strength, flexibility, endurance, and ergonomic principles. In addition, participants will be instructed to perform a daily set of home exercises. The exercises will be performed in a symptom-contingent way. The 18 sessions will be spread over a period of 16 weeks.</description>
    <arm_group_label>Usual care evidence-based physiotherapy</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Experienced a whiplash trauma which is at least 3 months old and causes pain since at&#xD;
             least 3 months, with pain experience with a mean pain frequency of 3 or more days per&#xD;
             week, and with self-reported moderate to severe pain-related disability, established&#xD;
             by a score of 15 or more of a maximum of 50 on the Neck Disability Index&#xD;
&#xD;
          -  Patients classified as WAD II or WAD III on the modified Quebec Task Force Scale&#xD;
&#xD;
          -  Native Dutch speaker&#xD;
&#xD;
          -  Not starting new treatments or medication and continuing their usual care 6 weeks&#xD;
             prior to and during study participation (to obtain a steady state)&#xD;
&#xD;
          -  Refraining from non-opioid analgesics in the previous 48h of the assessments&#xD;
&#xD;
          -  Refraining from caffeine, alcohol, and nicotine in the previous 24h of the assessments&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Neuropathic pain&#xD;
&#xD;
          -  Being pregnant or having given birth in the preceding year&#xD;
&#xD;
          -  Chronic fatigue syndrome&#xD;
&#xD;
          -  Fibromyalgia&#xD;
&#xD;
          -  Cardiovascular disorders&#xD;
&#xD;
          -  Epilepsy&#xD;
&#xD;
          -  Endocrinological disorders&#xD;
&#xD;
          -  Rheumatic disorders&#xD;
&#xD;
          -  Psychiatric disorders&#xD;
&#xD;
          -  History of neck surgery&#xD;
&#xD;
          -  Loss of consciousness during/after the whiplash trauma&#xD;
&#xD;
          -  Post-traumatic amnesia&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Iris Coppieters, PhD</last_name>
    <role>Study Director</role>
    <affiliation>Vrije Universiteit Brussel</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Jo Nijs, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Vrije Universiteit Brussel</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Sint-jozefkliniek Campus Bornem (AZ Rivierenland)</name>
      <address>
        <city>Bornem</city>
        <state>Antwerpen</state>
        <zip>2880</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ghent University</name>
      <address>
        <city>Ghent</city>
        <state>Oost-Vlaanderen</state>
        <zip>9000</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Vrije Universiteit Brussel</name>
      <address>
        <city>Brussels</city>
        <zip>1000</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Belgium</country>
  </location_countries>
  <reference>
    <citation>Michaleff ZA, Maher CG, Lin CW, Rebbeck T, Jull G, Latimer J, Connelly L, Sterling M. Comprehensive physiotherapy exercise programme or advice for chronic whiplash (PROMISE): a pragmatic randomised controlled trial. Lancet. 2014 Jul 12;384(9938):133-41. doi: 10.1016/S0140-6736(14)60457-8. Epub 2014 Apr 4.</citation>
    <PMID>24703832</PMID>
  </reference>
  <reference>
    <citation>Pinheiro ES, de Queiros FC, Montoya P, Santos CL, do Nascimento MA, Ito CH, Silva M, Nunes Santos DB, Benevides S, Miranda JG, Sa KN, Baptista AF. Electroencephalographic Patterns in Chronic Pain: A Systematic Review of the Literature. PLoS One. 2016 Feb 25;11(2):e0149085. doi: 10.1371/journal.pone.0149085. eCollection 2016.</citation>
    <PMID>26914356</PMID>
  </reference>
  <reference>
    <citation>Van Oosterwijck J, Nijs J, Meeus M, Paul L. Evidence for central sensitization in chronic whiplash: a systematic literature review. Eur J Pain. 2013 Mar;17(3):299-312. doi: 10.1002/j.1532-2149.2012.00193.x. Epub 2012 Sep 25.</citation>
    <PMID>23008191</PMID>
  </reference>
  <reference>
    <citation>Sterling M, Kenardy J. Physical and psychological aspects of whiplash: Important considerations for primary care assessment. Man Ther. 2008 May;13(2):93-102. doi: 10.1016/j.math.2007.11.003. Epub 2008 Jan 24.</citation>
    <PMID>18221907</PMID>
  </reference>
  <reference>
    <citation>Van Oosterwijck J, Nijs J, Meeus M, Truijen S, Craps J, Van den Keybus N, Paul L. Pain neurophysiology education improves cognitions, pain thresholds, and movement performance in people with chronic whiplash: a pilot study. J Rehabil Res Dev. 2011;48(1):43-58. doi: 10.1682/jrrd.2009.12.0206.</citation>
    <PMID>21328162</PMID>
  </reference>
  <reference>
    <citation>Nijs J, Ickmans K. Chronic whiplash-associated disorders: to exercise or not? Lancet. 2014 Jul 12;384(9938):109-11. doi: 10.1016/S0140-6736(14)60130-6. Epub 2014 Apr 4. No abstract available.</citation>
    <PMID>24703833</PMID>
  </reference>
  <reference>
    <citation>Dolphens M, Nijs J, Cagnie B, Meeus M, Roussel N, Kregel J, Malfliet A, Vanderstraeten G, Danneels L. Efficacy of a modern neuroscience approach versus usual care evidence-based physiotherapy on pain, disability and brain characteristics in chronic spinal pain patients: protocol of a randomized clinical trial. BMC Musculoskelet Disord. 2014 May 8;15:149. doi: 10.1186/1471-2474-15-149.</citation>
    <PMID>24885889</PMID>
  </reference>
  <reference>
    <citation>Moseley L. Combined physiotherapy and education is efficacious for chronic low back pain. Aust J Physiother. 2002;48(4):297-302. doi: 10.1016/s0004-9514(14)60169-0.</citation>
    <PMID>12443524</PMID>
  </reference>
  <reference>
    <citation>Meeus M, Nijs J, Hamers V, Ickmans K, Oosterwijck JV. The efficacy of patient education in whiplash associated disorders: a systematic review. Pain Physician. 2012 Sep-Oct;15(5):351-61.</citation>
    <PMID>22996847</PMID>
  </reference>
  <reference>
    <citation>Nijs J, Lluch Girbes E, Lundberg M, Malfliet A, Sterling M. Exercise therapy for chronic musculoskeletal pain: Innovation by altering pain memories. Man Ther. 2015 Feb;20(1):216-20. doi: 10.1016/j.math.2014.07.004. Epub 2014 Jul 18.</citation>
    <PMID>25090974</PMID>
  </reference>
  <reference>
    <citation>Southerst D, Nordin MC, Cote P, Shearer HM, Varatharajan S, Yu H, Wong JJ, Sutton DA, Randhawa KA, van der Velde GM, Mior SA, Carroll LJ, Jacobs CL, Taylor-Vaisey AL. Is exercise effective for the management of neck pain and associated disorders or whiplash-associated disorders? A systematic review by the Ontario Protocol for Traffic Injury Management (OPTIMa) Collaboration. Spine J. 2016 Dec;16(12):1503-1523. doi: 10.1016/j.spinee.2014.02.014. Epub 2014 Feb 15.</citation>
    <PMID>24534390</PMID>
  </reference>
  <reference>
    <citation>Nijs J, Meeus M, Cagnie B, Roussel NA, Dolphens M, Van Oosterwijck J, Danneels L. A modern neuroscience approach to chronic spinal pain: combining pain neuroscience education with cognition-targeted motor control training. Phys Ther. 2014 May;94(5):730-8. doi: 10.2522/ptj.20130258. Epub 2014 Jan 30.</citation>
    <PMID>24481595</PMID>
  </reference>
  <reference>
    <citation>Nijs J, Paul van Wilgen C, Van Oosterwijck J, van Ittersum M, Meeus M. How to explain central sensitization to patients with 'unexplained' chronic musculoskeletal pain: practice guidelines. Man Ther. 2011 Oct;16(5):413-8. doi: 10.1016/j.math.2011.04.005. Epub 2011 May 31.</citation>
    <PMID>21632273</PMID>
  </reference>
  <verification_date>November 2022</verification_date>
  <study_first_submitted>August 1, 2017</study_first_submitted>
  <study_first_submitted_qc>August 1, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 4, 2017</study_first_posted>
  <last_update_submitted>November 24, 2022</last_update_submitted>
  <last_update_submitted_qc>November 24, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">November 28, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Vrije Universiteit Brussel</investigator_affiliation>
    <investigator_full_name>Iris Coppieters</investigator_full_name>
    <investigator_title>dr. Iris Coppieters (principal investigator)</investigator_title>
  </responsible_party>
  <keyword>chronic whiplash associated disorders</keyword>
  <keyword>central sensitization</keyword>
  <keyword>electroencephalography</keyword>
  <keyword>physiotherapy</keyword>
  <keyword>chronic pain</keyword>
  <keyword>functionality</keyword>
  <keyword>quality of life</keyword>
  <keyword>stress management</keyword>
  <keyword>randomized controlled trial</keyword>
  <keyword>modern neuroscience approach</keyword>
  <keyword>pain neuroscience education</keyword>
  <keyword>neck school</keyword>
  <keyword>exercise therapy</keyword>
  <keyword>pain cognitions</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Chronic Pain</mesh_term>
    <mesh_term>Whiplash Injuries</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03239938
org study id: G007217N
nct id: NCT03239938
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Modern pain neuroscience has advanced our understanding of chronic whiplash associated
      disorders (WAD). Previous studies have shown the importance of central sensitization,
      characterized by hypersensitivity of the somatosensory system, in explaining poor treatment
      outcome. Therefore, and to address the need for a better treatment of chronic WAD, we
      recently proposed a modern neuroscience approach to chronic WAD. Such approach includes two
      specific parts: therapeutic pain neuroscience education followed by dynamic and functional
      cognition-targeted exercise therapy and stress management techniques.

      The primary scientific objective of the study entails examining the effectiveness of a modern
      neuroscience approach versus usual care evidence-based physiotherapy for reducing
      dysfunctioning in patients with chronic WAD. The secondary scientific objective of the study
      entails examining the effectiveness of a modern neuroscience approach versus usual care
      evidence-based physiotherapy for reducing pain, central sensitization, psychosocial problems,
      and socio-economic burden in patients with chronic WAD. The trial will randomize 120 patients
      with chronic WAD, aged between 18 and 65 years, to the experimental (modern pain neuroscience
      approach including 3 sessions of therapeutic pain neuroscience education followed by 15
      sessions of dynamic and functional cognition-targeted exercise therapy and stress management
      techniques (n = 60)) or the control treatment (usual care physiotherapy including 3 sessions
      of neck school followed by 15 sessions of graded and active exercise therapy focusing on
      strength, flexibility, endurance, and ergonomic principles (n= 60)). The primary outcome
      measure is self-reported functional status. Secondary outcome measures include pain,
      health-related quality of life, psychological correlates, measures of central sensitization,
      and socio-economic factors. In addition, quantitative scalp Electroencephalography (EEG) to
      measure various parameters of brain activation will be performed during a conditioned pain
      modulation paradigm. Baseline assessment of all outcome measures will be performed.

      Follow-up assessments will be performed immediately after 16 weeks of therapy (all tests),
      and 6 months (all tests) and 12 months (only questionnaires) after finishing the therapeutic
      intervention.

      To investigate these objectives, a multi-center triple-blind randomized, controlled trial
      with 1 year follow up will be performed.
Modern pain neuroscience has advanced our understanding of chronic whiplash associated
      disorders (WAD). Previous studies have shown the importance of central sensitization,
      characterized by hypersensitivity of the somatosensory system, in explaining poor treatment
      outcome. Therefore, and to address the need for a better treatment of chronic WAD, we
      recently proposed a modern neuroscience approach to chronic WAD. Such approach includes two
      specific parts: 3 sessions of therapeutic pain neuroscience education followed by 15 sessions
      of dynamic and functional cognition-targeted exercise therapy and stress management
      techniques. The main principles of cognition-targeted are the following: All exercises should
      be performed in a time-contingent ("Perform this exercise 10 times, regardless of the pain")
      rather than in a symptom-contingent way ("Stop or adjust the exercise when it hurts"). Goal
      setting is essentially done together with the patient, focussing on functionality. The
      treating physical therapist should continuously assess and challenge the patients' cognitions
      and perceptions about the pain and the anticipated outcome of each exercise, to change
      maladaptive cognitions and perceptions into positive ones.

      The primary scientific objective of the study entails examining the effectiveness of a modern
      pain neuroscience approach versus usual care evidence-based physiotherapy for reducing
      dysfunctioning in patients with chronic WAD. The secondary scientific objective of the study
      entails examining the effectiveness of a modern neuroscience approach versus usual care
      evidence-based physiotherapy for reducing pain, central sensitization, psychological
      problems, and socio-economic burden in patients with chronic WAD. The trial will randomize
      120 patients with chronic WAD, aged between 18 and 65 years, to the experimental (modern pain
      neuroscience approach (n = 60)) or control treatment (usual care evidence-based
      physiotherapy: 3 sessions of neck school followed by 15 sessions of graded and active
      exercise therapy focusing on strength, flexibility, endurance, and ergonomic principles (n=
      60)). The primary outcome measure is functional status. Secondary outcome measures include
      pain, health-related quality of life, psychological correlates, socio-economic factors, and
      measures of central sensitization, including electrical detection and electrical pain
      thresholds measured with a constant current electrical stimulator, endogenous pain
      facilitation (temporal summation of electrical pain), endogenous pain inhibition assessed by
      the conditioned pain modulation paradigm (electrical stimulation as test stimulus and the
      cold pressor test (immersion of one hand in cold water of 12°C) as conditioning stimulus). In
      addition, quantitative scalp Electroencephalography (EEG) to measure various parameters of
      brain activation will be performed during the conditioned pain modulation paradigm.

      To comply with these scientific objectives, the 120 chronic WAD patients will be subjected to
      the baseline assessment of all outcome measures.

      Follow-up assessments will be performed immediately after 16 weeks of therapy (all tests),
      and 6 months (all tests) and 12 months (only questionnaires) after finishing the therapeutic
      intervention.

      To investigate these objectives, a muli-center triple-blind randomized, controlled trial with
      1 year follow up will be performed.

      Appropriate statistical analyses will be performed to evaluate and compare treatment effects.
      Statistical, as well as clinical significant differences will be defined and the effect size
      will be determined. Relations between functional status, pain, psychological correlates and
      central sensitization will be investigated. Furthermore, prediction of pain and functional
      status by central sensitization and psychological correlates will be performed in chronic WAD
      patients. Also, factors associated with clinically important changes in the outcome measures
      will be unraveled. In addition, factors associated with poor outcome following treatment will
      be assessed.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: The trial will randomize 120 patients with chronic WAD, aged between 18 and 65 years, to the experimental (modern neuroscience approach including 3 sessions of therapeutic pain neuroscience education followed by 15 sessions of dynamic and functional cognition-targeted exercise therapy and stress management techniques (n = 60)) or the control treatment (usual care physiotherapy: 3 sessions of neck school followed by 15 sessions of exercise therapy focusing on strength, flexibility, endurance, and ergonomic principles (n= 60)).
primary purpose: Treatment
masking: Triple (Participant, Investigator, Outcomes Assessor)
measure: Self-reported functional status or disability
time frame: The change between the baseline assessment and the 6 months follow-up assessment (6 months after the end of the therapy)
description: The Dutch version of the Neck Disability Index (questionnaire)
measure: Self-reported functional status or disability
time frame: Baseline assessment, T1 follow-up assessment after 16 weeks of therapy, T3 follow-up assessment 12 months after the end of the therapy.
description: The Dutch version of the Neck Disability Index (questionnaire)
measure: Self-reported health-related quality of life
time frame: Baseline assessment, T1 follow-up assessment after 16 weeks of therapy, T2 follow-up assessment 6 months after the end of the therapy, T3 assessment 12 months after the end of the therapy.
description: The Dutch version of the Short Form Health Survey-36 items (questionnaire)
measure: Self-reported pain assessment
time frame: Baseline assessment, T1 follow-up assessment after 16 weeks of therapy, T2 follow-up assessment 6 months after the end of the therapy, T3 follow-up assessment 12 months after the end of the therapy.
description: A 0-10 Numeric Rating Scale for pain (questionnaire). Patients fill out the Numeric Rating Scale (0 no pain - 10 worst pain imaginable) for their perceived neck pain.
measure: Self-reported central sensitization symptoms
time frame: Baseline assessment, T1 follow-up assessment after 16 weeks of therapy, T2 follow-up assessment 6 months after the end of the therapy, T3 follow-up assessment 12 months after the end of the therapy.
description: The Dutch version of the Central Sensitization Inventory (questionnaire)
measure: Electrical detection and electrical pain thresholds with a constant current electrical stimulator (DS7A Digitimer)
time frame: Baseline assessment, T1 follow-up assessment after 16 weeks of therapy, T2 follow-up assessment 6 months after the end of the therapy
description: Determination of the electrical detection and electrical pain threshold with the electrical stimulator will be performed at the sural nerve of the dominant leg and at the median nerve of the dominant arm.
measure: Endogenous pain facilitation assessed by a temporal summation paradigm
time frame: Baseline assessment, T1 follow-up assessment after 16 weeks of therapy, T2 follow-up assessment 6 months after the end of the therapy
description: Temporal summation of electrical pain will be assessed by delivering 20 electrical stimuli at the intensity of the electrical pain threshold.
measure: Endogenous pain inhibition assessed by a conditioned pain modulation paradigm
time frame: Baseline assessment, T1 follow-up assessment after 16 weeks of therapy, T2 follow-up assessment 6 months after the end of the therapy
description: Conditioned pain modulation will be tested with electrical stimulation as test stimulus and the cold pressor test (immersion the hand up to the wrist in cold water of 12°C) as conditioning stimulus.
measure: Quantitative Electroencephalography (QEEG) (Sienna digital EEG, EMS Biomedical, Korneuburg, Austria) will be recorded from 32 Sn surface electrodes using an electrode cap (Headcap, Expertise in Medical Solutions Biomedical, Korneuburg, Austria).
time frame: Baseline assessment, T1 follow-up assessment after 16 weeks of therapy, T2 follow-up assessment 6 months after the end of the therapy
description: During the condition pain modulation paradigm a QEEG will be administered to examine various brain activity parameters.
measure: Self-reported psychological correlates: Pain catastrophizing
time frame: Baseline assessment, T1 follow-up assessment after 16 weeks of therapy, T2 follow-up assessment 6 months after the end of the therapy, T3 follow-up assessment 12 months after the end of the therapy.
description: The Dutch version of the Pain Catastrophizing Scale (questionnaire)
measure: Self-reported psychological correlates: Illness perceptions
time frame: Baseline assessment, T1 follow-up assessment after 16 weeks of therapy, T2 follow-up assessment 6 months after the end of the therapy, T3 follow-up assessment 12 months after the end of the therapy.
description: The Dutch version of the illness perception questionnaire-revised (questionnaire)
measure: Self-reported psychological correlates: Post-traumatic stress
time frame: Baseline assessment, T1 follow-up assessment after 16 weeks of therapy, T2 follow-up assessment 6 months after the end of the therapy, T3 follow-up assessment 12 months after the end of the therapy.
description: The Dutch version of the Impact of Event Scale revised (questionnaire)
measure: Self-reported psychological correlates: Pain-related fear and fear-avoidance behaviour
time frame: Baseline assessment, T1 follow-up assessment after 16 weeks of therapy, T2 follow-up assessment 6 months after the end of the therapy, T3 follow-up assessment 12 months after the end of the therapy.
description: The Dutch version of the Pain anxiety symptoms scale (PASS-20) (questionnaire)
measure: Socio-economic factors
time frame: Baseline assessment, T2 follow-up assessment 6 months after the end of the therapy, T3 follow-up assessment 12 months after the end of the therapy, 1 year before enrollment in the study
description: Self-reported questionnaire and data including health-care expenditure from publicly funded healthcare organizations.
arm group label: Modern pain neuroscience approach
arm group type: Experimental
description: Modern pain neuroscience approach
arm group label: Usual care evidence-based physiotherapy
arm group type: Active Comparator
description: Usual care physiotherapy
intervention type: Behavioral
intervention name: Modern pain neuroscience approach
description: The modern pain neuroscience approach includes 3 sessions (1 group and 2 individual sessions) of therapeutic pain neuroscience education followed by 15 individual sessions of dynamic and functional cognition-targeted exercise therapy and stress management techniques. In addition, participants will be instructed to perform a daily set of home exercises. The exercises will be performed in a time-contingent way. The 18 sessions will be spread over a period of 16 weeks.
arm group label: Modern pain neuroscience approach
intervention type: Behavioral
intervention name: Usual care evidence-based physiotherapy
description: The usual care evidence-based physiotherapy includes 3 sessions (1 group and 2 individual sessions) of neck school followed by 15 individual sessions of graded and active exercise therapy focusing on strength, flexibility, endurance, and ergonomic principles. In addition, participants will be instructed to perform a daily set of home exercises. The exercises will be performed in a symptom-contingent way. The 18 sessions will be spread over a period of 16 weeks.
arm group label: Usual care evidence-based physiotherapy
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Iris Coppieters, PhD
role: Study Director
affiliation: Vrije Universiteit Brussel
last name: Jo Nijs, PhD
role: Principal Investigator
affiliation: Vrije Universiteit Brussel
facility: 
facility: 
facility: 
country: Belgium
citation: Michaleff ZA, Maher CG, Lin CW, Rebbeck T, Jull G, Latimer J, Connelly L, Sterling M. Comprehensive physiotherapy exercise programme or advice for chronic whiplash (PROMISE): a pragmatic randomised controlled trial. Lancet. 2014 Jul 12;384(9938):133-41. doi: 10.1016/S0140-6736(14)60457-8. Epub 2014 Apr 4.
PMID: 24703832
citation: Pinheiro ES, de Queiros FC, Montoya P, Santos CL, do Nascimento MA, Ito CH, Silva M, Nunes Santos DB, Benevides S, Miranda JG, Sa KN, Baptista AF. Electroencephalographic Patterns in Chronic Pain: A Systematic Review of the Literature. PLoS One. 2016 Feb 25;11(2):e0149085. doi: 10.1371/journal.pone.0149085. eCollection 2016.
PMID: 26914356
citation: Van Oosterwijck J, Nijs J, Meeus M, Paul L. Evidence for central sensitization in chronic whiplash: a systematic literature review. Eur J Pain. 2013 Mar;17(3):299-312. doi: 10.1002/j.1532-2149.2012.00193.x. Epub 2012 Sep 25.
PMID: 23008191
citation: Sterling M, Kenardy J. Physical and psychological aspects of whiplash: Important considerations for primary care assessment. Man Ther. 2008 May;13(2):93-102. doi: 10.1016/j.math.2007.11.003. Epub 2008 Jan 24.
PMID: 18221907
citation: Van Oosterwijck J, Nijs J, Meeus M, Truijen S, Craps J, Van den Keybus N, Paul L. Pain neurophysiology education improves cognitions, pain thresholds, and movement performance in people with chronic whiplash: a pilot study. J Rehabil Res Dev. 2011;48(1):43-58. doi: 10.1682/jrrd.2009.12.0206.
PMID: 21328162
citation: Nijs J, Ickmans K. Chronic whiplash-associated disorders: to exercise or not? Lancet. 2014 Jul 12;384(9938):109-11. doi: 10.1016/S0140-6736(14)60130-6. Epub 2014 Apr 4. No abstract available.
PMID: 24703833
citation: Dolphens M, Nijs J, Cagnie B, Meeus M, Roussel N, Kregel J, Malfliet A, Vanderstraeten G, Danneels L. Efficacy of a modern neuroscience approach versus usual care evidence-based physiotherapy on pain, disability and brain characteristics in chronic spinal pain patients: protocol of a randomized clinical trial. BMC Musculoskelet Disord. 2014 May 8;15:149. doi: 10.1186/1471-2474-15-149.
PMID: 24885889
citation: Moseley L. Combined physiotherapy and education is efficacious for chronic low back pain. Aust J Physiother. 2002;48(4):297-302. doi: 10.1016/s0004-9514(14)60169-0.
PMID: 12443524
citation: Meeus M, Nijs J, Hamers V, Ickmans K, Oosterwijck JV. The efficacy of patient education in whiplash associated disorders: a systematic review. Pain Physician. 2012 Sep-Oct;15(5):351-61.
PMID: 22996847
citation: Nijs J, Lluch Girbes E, Lundberg M, Malfliet A, Sterling M. Exercise therapy for chronic musculoskeletal pain: Innovation by altering pain memories. Man Ther. 2015 Feb;20(1):216-20. doi: 10.1016/j.math.2014.07.004. Epub 2014 Jul 18.
PMID: 25090974
citation: Southerst D, Nordin MC, Cote P, Shearer HM, Varatharajan S, Yu H, Wong JJ, Sutton DA, Randhawa KA, van der Velde GM, Mior SA, Carroll LJ, Jacobs CL, Taylor-Vaisey AL. Is exercise effective for the management of neck pain and associated disorders or whiplash-associated disorders? A systematic review by the Ontario Protocol for Traffic Injury Management (OPTIMa) Collaboration. Spine J. 2016 Dec;16(12):1503-1523. doi: 10.1016/j.spinee.2014.02.014. Epub 2014 Feb 15.
PMID: 24534390
citation: Nijs J, Meeus M, Cagnie B, Roussel NA, Dolphens M, Van Oosterwijck J, Danneels L. A modern neuroscience approach to chronic spinal pain: combining pain neuroscience education with cognition-targeted motor control training. Phys Ther. 2014 May;94(5):730-8. doi: 10.2522/ptj.20130258. Epub 2014 Jan 30.
PMID: 24481595
citation: Nijs J, Paul van Wilgen C, Van Oosterwijck J, van Ittersum M, Meeus M. How to explain central sensitization to patients with 'unexplained' chronic musculoskeletal pain: practice guidelines. Man Ther. 2011 Oct;16(5):413-8. doi: 10.1016/j.math.2011.04.005. Epub 2011 May 31.
PMID: 21632273
responsible party type: Principal Investigator
investigator affiliation: Vrije Universiteit Brussel
investigator full name: Iris Coppieters
investigator title: dr. Iris Coppieters (principal investigator)
mesh term: Chronic Pain
mesh term: Whiplash Injuries
sharing ipd: Undecided