Effects of Opioids and NSAIDs on Sympathetic Nervous System and Vascular Function (OPIOVASC)

Effect of Opioids and NSAIDs on Sympathetic Nervous System and Vascular Function in Healthy Subjects and Patients With Osteoarthritis

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.

Study Overview

• Status: Recruiting
• Conditions: Healthy; Osteoarthritis of Multiple Joints of Ankle or Foot
• Intervention / Treatment: Drug: Diclofenac; Drug: Paracetamol; Drug: Tramadol

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 90
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Isabella Sudano, MD; Phone Number: +41442555841; Email: Isabella.Sudano@usz.ch
• Study Contact Backup: Name: Anne-Marieke Vegter; Phone Number: +41442552280; Email: Anne-Marieke.Vegter@usz.ch

Study Locations

• Switzerland
  • Zurich, Switzerland, 8091
    • Recruiting
    • University Heart Center Zurich
    • Contact: Frank Ruschitzka, MD; Phone Number: +41442553353; Email: frank.ruschitzka@usz.ch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patients ≥ 18 years of age, male or female, with a diagnosis of osteoarthritis or healthy subjects ≥ 18 years of age;
2. Written informed consent;

Exclusion criteria:

1. History of hypersensitivity or allergy to any of the study drugs
2. Acute coronary syndrome, stroke, transient ischemic attack, cardiac, carotid or other major CV surgery, percutaneous coronary intervention (PCI) or carotid angioplasty within the 3 months prior to Visit 1;
3. Coronary or carotid artery disease likely to require surgical or percutaneous intervention within the 3 months after Visit 1;
4. Presence of significant endocrine diseases;
5. Presence of active acute infectious diseases;
6. Known narrow-angle glaucoma;
7. Known epilepsy;
8. Cimino-shunt operation on both arms;
9. Pregnancy, intention thereof during study, lack of sufficient contraception, breastfeeding;
10. Drug or alcohol abuse;

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Diclofenac; Diclofenac (Diclofenacum natricum) A single i.v. infusion of Diclofenac (dose: 75mg/100ml) will be administered to the participants (treatment arm).	Drug: Diclofenac; A single i.v. infusion of Diclofenac (dose: 75mg/100ml) will be administered to the participants (treatment arm).
Active Comparator: Paracetamol; Paracetamol (Paracetamol Sintetica): A single i.v. infusion of Paracetamol (dose: 1g/100ml) will be administered to the participants (control arm).	Drug: Paracetamol; A single i.v. infusion of Paracetamol (dose: 1g/100ml) will be administered to the participants (control arm).; Other Names: PARACETAMOL Sintetica
Experimental: Tramadol; Tramadol (Tramadol-Mepha): A single i.v. infusion of Tramadol (dose: 400mg/100ml) will be administered to the participants (treatment arm).	Drug: Tramadol; A single i.v. infusion of Tramadol (dose: 400mg/100ml) will be administered to the participants (treatment arm).; Other Names: Tramadol-Mepha

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
resting MSNA (sympathetic nervous activity )	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.)	1day (110 min)
changes in FMD (Flow mediated vasodilation)	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.)	1 day (210min)

Collaborators and Investigators

• Sponsor: University of Zurich
• Investigators: Study Director: Frank Ruschitzka, MD, Cardiology, University Heart Center Zurich

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2019
• Primary Completion (Anticipated): December 31, 2023
• Study Completion (Anticipated): December 31, 2023

Study Registration Dates

• First Submitted: December 3, 2018
• First Submitted That Met QC Criteria: December 17, 2018
• First Posted (Actual): December 20, 2018

Study Record Updates

• Last Update Posted (Actual): November 29, 2022
• Last Update Submitted That Met QC Criteria: November 28, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Arthritis; Osteoarthritis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Antipyretics; Analgesics, Opioid; Narcotics; Acetaminophen; Diclofenac; Tramadol
• Other Study ID Numbers: OPIOVASC

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No