<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/NCT03781544</url>
  </required_header>
  <id_info>
    <org_study_id>OPIOVASC</org_study_id>
    <nct_id>NCT03781544</nct_id>
  </id_info>
  <brief_title>Effects of Opioids and NSAIDs on Sympathetic Nervous System and Vascular Function</brief_title>
  <acronym>OPIOVASC</acronym>
  <official_title>Effect of Opioids and NSAIDs on Sympathetic Nervous System and Vascular Function in Healthy Subjects and Patients With Osteoarthritis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Zurich</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Zurich</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>
      Evaluation of the effect of different analgesic treatments (Tramadol, Paracetamol,&#xD;
      Diclofenac) on sympathetic nerve activity, blood pressure, heart rate, heart rate, and&#xD;
      vascular function in osteoarthritis patients and healthy subjects.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Hundreds of millions of patients worldwide require pain-relieving therapy to maintain an&#xD;
      acceptable quality of life. Pain relievers, including non-steroidal anti-inflammatory drugs&#xD;
      (NSAIDs) and opioids, however, exert unwanted potent adverse systemic off-target effects and&#xD;
      their use is associated with a well-documented excess of cerebrovascular and cardiovascular&#xD;
      events. This of particular concern for the one fourth of the world's population aged over 35&#xD;
      years suffering from chronic pain, particularly with arthritis of whom half also present with&#xD;
      established or at high risk of cardiovascular disease. This uncertainty around the&#xD;
      cardiovascular safety of pain relieving drugs leaves practitioners and their patients with&#xD;
      difficult management decisions and underscores the need to investigate potential differential&#xD;
      cardiovascular effects of NSAIDs and opioids and to better delineate the underlying&#xD;
      mechanisms involved. Indeed, currently available NSAIDs invariably disrupt the balance&#xD;
      between prostacyclin and thromboxane, but may also exert multiple and opposing cardiovascular&#xD;
      effects on endothelial factors, including nitric oxide and reactive oxygen species, the&#xD;
      sympathetic nervous system and vascular inflammation. Intriguingly, the net effect of pain&#xD;
      relieving drugs on vascular function and sympathetic nerve activity and its resulting&#xD;
      deterioration of blood pressure control is increasingly recognized as a major possible&#xD;
      determinant in explaining the cardiovascular side effects of NSAIDs. As a result of the&#xD;
      ongoing concerns around the cardiovascular safety of NSAIDs and coxibs many patients are&#xD;
      being withheld effective pain relieve or switched to opioids and/or paracetamol under the&#xD;
      assumption of their yet unproven greater cardiovascular safety. The absence of evidence about&#xD;
      the cardiovascular safety of these drugs presents a major dilemma for patients and&#xD;
      physicians, who have been warned about the toxicity of NSAIDs.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">January 1, 2019</start_date>
  <completion_date type="Anticipated">December 31, 2023</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2023</primary_completion_date>
  <phase>Phase 4</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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>resting MSNA (sympathetic nervous activity )</measure>
    <time_frame>1day (110 min)</time_frame>
    <description>Effect of different single analgesic treatments (Tramadol, Paracetamol, Diclofenac) on resting muscle sympathetic nerve activity (MSNA) in osteoarthritis patients (post 2 days of analgesic therapy washout phase) and in healthy subjects.&#xD;
Tramadol treatment will be compared to diclofenac and paracetamol (3 treatment arms).&#xD;
90 participants (45 osteoarthritis patients, 45 healthy subjects);&#xD;
Single infusion of Tramadol (50 mg i.v.) Single infusion of Paracetamol (1000 mg i.v.) Single infusion of Diclofenac (75 mg i.v.)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>changes in FMD (Flow mediated vasodilation)</measure>
    <time_frame>1 day (210min)</time_frame>
    <description>Effect of a single acute intravenous analgesic treatment with tramadol versus paracetamol on changes in flow mediated dilatation (FMD) in osteoarthritis patients and in healthy subjects.&#xD;
Tramadol treatment will be compared with paracetamol as we previously demonstrated that paracetamol exerts no significant effects on endothelial function as measured by flow mediated dilatation.&#xD;
80 participants (40 osteoarthritis patients, 40 healthy subjects);&#xD;
Single infusion of Tramadol (50 mg i.v.) Single infusion of Paracetamol (1000 mg i.v.)</description>
  </primary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">90</enrollment>
  <condition>Osteoarthritis of Multiple Joints of Ankle or Foot</condition>
  <condition>Healthy</condition>
  <arm_group>
    <arm_group_label>Diclofenac</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Diclofenac (Diclofenacum natricum) A single i.v. infusion of Diclofenac (dose: 75mg/100ml) will be administered to the participants (treatment arm).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Paracetamol</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Paracetamol (Paracetamol Sintetica):&#xD;
A single i.v. infusion of Paracetamol (dose: 1g/100ml) will be administered to the participants (control arm).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Tramadol</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Tramadol (Tramadol-Mepha):&#xD;
A single i.v. infusion of Tramadol (dose: 400mg/100ml) will be administered to the participants (treatment arm).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tramadol</intervention_name>
    <description>A single i.v. infusion of Tramadol (dose: 400mg/100ml) will be administered to the participants (treatment arm).</description>
    <arm_group_label>Tramadol</arm_group_label>
    <other_name>Tramadol-Mepha</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Paracetamol</intervention_name>
    <description>A single i.v. infusion of Paracetamol (dose: 1g/100ml) will be administered to the participants (control arm).</description>
    <arm_group_label>Paracetamol</arm_group_label>
    <other_name>PARACETAMOL Sintetica</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Diclofenac</intervention_name>
    <description>A single i.v. infusion of Diclofenac (dose: 75mg/100ml) will be administered to the participants (treatment arm).</description>
    <arm_group_label>Diclofenac</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Patients ≥ 18 years of age, male or female, with a diagnosis of osteoarthritis or&#xD;
             healthy subjects ≥ 18 years of age;&#xD;
&#xD;
          2. Written informed consent;&#xD;
&#xD;
        Exclusion criteria:&#xD;
&#xD;
          1. History of hypersensitivity or allergy to any of the study drugs&#xD;
&#xD;
          2. Acute coronary syndrome, stroke, transient ischemic attack, cardiac, carotid or other&#xD;
             major CV surgery, percutaneous coronary intervention (PCI) or carotid angioplasty&#xD;
             within the 3 months prior to Visit 1;&#xD;
&#xD;
          3. Coronary or carotid artery disease likely to require surgical or percutaneous&#xD;
             intervention within the 3 months after Visit 1;&#xD;
&#xD;
          4. Presence of significant endocrine diseases;&#xD;
&#xD;
          5. Presence of active acute infectious diseases;&#xD;
&#xD;
          6. Known narrow-angle glaucoma;&#xD;
&#xD;
          7. Known epilepsy;&#xD;
&#xD;
          8. Cimino-shunt operation on both arms;&#xD;
&#xD;
          9. Pregnancy, intention thereof during study, lack of sufficient contraception,&#xD;
             breastfeeding;&#xD;
&#xD;
         10. Drug or alcohol abuse;&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Frank Ruschitzka, MD</last_name>
    <role>Study Director</role>
    <affiliation>Cardiology, University Heart Center Zurich</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Isabella Sudano, MD</last_name>
    <phone>+41442555841</phone>
    <email>Isabella.Sudano@usz.ch</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Anne-Marieke Vegter</last_name>
    <phone>+41442552280</phone>
    <email>Anne-Marieke.Vegter@usz.ch</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>University Heart Center Zurich</name>
      <address>
        <city>Zurich</city>
        <zip>8091</zip>
        <country>Switzerland</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Frank Ruschitzka, MD</last_name>
      <phone>+41442553353</phone>
      <email>frank.ruschitzka@usz.ch</email>
    </contact>
  </location>
  <location_countries>
    <country>Switzerland</country>
  </location_countries>
  <verification_date>November 2022</verification_date>
  <study_first_submitted>December 3, 2018</study_first_submitted>
  <study_first_submitted_qc>December 17, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 20, 2018</study_first_posted>
  <last_update_submitted>November 28, 2022</last_update_submitted>
  <last_update_submitted_qc>November 28, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">November 29, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Osteoarthritis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Acetaminophen</mesh_term>
    <mesh_term>Diclofenac</mesh_term>
    <mesh_term>Tramadol</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</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/NCT03781544
org study id: OPIOVASC
nct id: NCT03781544
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Evaluation of the effect of different analgesic treatments (Tramadol, Paracetamol,
      Diclofenac) on sympathetic nerve activity, blood pressure, heart rate, heart rate, and
      vascular function in osteoarthritis patients and healthy subjects.
Hundreds of millions of patients worldwide require pain-relieving therapy to maintain an
      acceptable quality of life. Pain relievers, including non-steroidal anti-inflammatory drugs
      (NSAIDs) and opioids, however, exert unwanted potent adverse systemic off-target effects and
      their use is associated with a well-documented excess of cerebrovascular and cardiovascular
      events. This of particular concern for the one fourth of the world's population aged over 35
      years suffering from chronic pain, particularly with arthritis of whom half also present with
      established or at high risk of cardiovascular disease. This uncertainty around the
      cardiovascular safety of pain relieving drugs leaves practitioners and their patients with
      difficult management decisions and underscores the need to investigate potential differential
      cardiovascular effects of NSAIDs and opioids and to better delineate the underlying
      mechanisms involved. Indeed, currently available NSAIDs invariably disrupt the balance
      between prostacyclin and thromboxane, but may also exert multiple and opposing cardiovascular
      effects on endothelial factors, including nitric oxide and reactive oxygen species, the
      sympathetic nervous system and vascular inflammation. Intriguingly, the net effect of pain
      relieving drugs on vascular function and sympathetic nerve activity and its resulting
      deterioration of blood pressure control is increasingly recognized as a major possible
      determinant in explaining the cardiovascular side effects of NSAIDs. As a result of the
      ongoing concerns around the cardiovascular safety of NSAIDs and coxibs many patients are
      being withheld effective pain relieve or switched to opioids and/or paracetamol under the
      assumption of their yet unproven greater cardiovascular safety. The absence of evidence about
      the cardiovascular safety of these drugs presents a major dilemma for patients and
      physicians, who have been warned about the toxicity of NSAIDs.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: resting MSNA (sympathetic nervous activity )
time frame: 1day (110 min)
description: Effect of different single analgesic treatments (Tramadol, Paracetamol, Diclofenac) on resting muscle sympathetic nerve activity (MSNA) in osteoarthritis patients (post 2 days of analgesic therapy washout phase) and in healthy subjects.
Tramadol treatment will be compared to diclofenac and paracetamol (3 treatment arms).
90 participants (45 osteoarthritis patients, 45 healthy subjects);
Single infusion of Tramadol (50 mg i.v.) Single infusion of Paracetamol (1000 mg i.v.) Single infusion of Diclofenac (75 mg i.v.)
measure: changes in FMD (Flow mediated vasodilation)
time frame: 1 day (210min)
description: Effect of a single acute intravenous analgesic treatment with tramadol versus paracetamol on changes in flow mediated dilatation (FMD) in osteoarthritis patients and in healthy subjects.
Tramadol treatment will be compared with paracetamol as we previously demonstrated that paracetamol exerts no significant effects on endothelial function as measured by flow mediated dilatation.
80 participants (40 osteoarthritis patients, 40 healthy subjects);
Single infusion of Tramadol (50 mg i.v.) Single infusion of Paracetamol (1000 mg i.v.)
arm group label: Diclofenac
arm group type: Experimental
description: Diclofenac (Diclofenacum natricum) A single i.v. infusion of Diclofenac (dose: 75mg/100ml) will be administered to the participants (treatment arm).
arm group label: Paracetamol
arm group type: Active Comparator
description: Paracetamol (Paracetamol Sintetica):
A single i.v. infusion of Paracetamol (dose: 1g/100ml) will be administered to the participants (control arm).
arm group label: Tramadol
arm group type: Experimental
description: Tramadol (Tramadol-Mepha):
A single i.v. infusion of Tramadol (dose: 400mg/100ml) will be administered to the participants (treatment arm).
intervention type: Drug
intervention name: Tramadol
description: A single i.v. infusion of Tramadol (dose: 400mg/100ml) will be administered to the participants (treatment arm).
arm group label: Tramadol
other name: Tramadol-Mepha
intervention type: Drug
intervention name: Paracetamol
description: A single i.v. infusion of Paracetamol (dose: 1g/100ml) will be administered to the participants (control arm).
arm group label: Paracetamol
other name: PARACETAMOL Sintetica
intervention type: Drug
intervention name: Diclofenac
description: A single i.v. infusion of Diclofenac (dose: 75mg/100ml) will be administered to the participants (treatment arm).
arm group label: Diclofenac
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Frank Ruschitzka, MD
role: Study Director
affiliation: Cardiology, University Heart Center Zurich
last name: Isabella Sudano, MD
phone: +41442555841
email: Isabella.Sudano@usz.ch
last name: Anne-Marieke Vegter
phone: +41442552280
email: Anne-Marieke.Vegter@usz.ch
facility: 
status: Recruiting
contact: 
country: Switzerland
responsible party type: Sponsor
mesh term: Osteoarthritis
mesh term: Acetaminophen
mesh term: Diclofenac
mesh term: Tramadol
sharing ipd: No