Effects of Opioids and NSAIDs on Sympathetic Nervous System and Vascular Function

Phase 4

Recruiting

• Conditions: Osteoarthritis of Multiple Joints of Ankle or Foot; Healthy
• Interventions: Drug: Diclofenac; Drug: Paracetamol; Drug: Tramadol

• Registration Number: NCT03781544
• Lead Sponsor: University of Zurich

Brief Summary

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.

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 Timeline

• Study First Submitted: 2018-12-03
• Study First Submitted QC: 2018-12-17
• Study First Posted: 2018-12-20
• Study Start: 2019-01-01
• Status Verified: 2024-05
• Last Update Submitted: 2024-05-16
• Last Update Posted: 2024-05-17
• Primary Completion: 2025-07-31
• Study Completion: 2025-12-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 90

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;

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Diclofenac	Diclofenac	Diclofenac (Diclofenacum natricum) A single i.v. infusion of Diclofenac (dose: 75mg/100ml) will be administered to the participants (treatment arm).
Paracetamol	Paracetamol	Paracetamol (Paracetamol Sintetica): A single i.v. infusion of Paracetamol (dose: 1g/100ml) will be administered to the participants (control arm).
Tramadol	Tramadol	Tramadol (Tramadol-Mepha): A single i.v. infusion of Tramadol (dose: 400mg/100ml) will be administered to the participants (treatment arm).

Primary Outcome Measures

Name	Time	Method
resting MSNA (sympathetic nervous activity )	1day (110 min)	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.)
changes in FMD (Flow mediated vasodilation)	1 day (210min)	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.)

Trial Locations

Locations (1)

University Heart Center Zurich; 🇨🇭 Zurich, Switzerland