Evaluation of the Added Value of Metamizole to Standard Postoperative Treatment After Ambulant Shoulder Surgery

Study Overview
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Brief Summary
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This study aims to investigate if the combination of metamizole and paracetamol is superior in reducing post-operative pain on day 1 after ambulatory shoulder surgery where the use of NSAIDs is prohibited compared to paracetamol treatment. Therefore, a monocenter, prospective, double-blind, randomized controlled superiority trial will be designed to investigate the superiority of the combination of metamizole and paracetamol compared to paracetamol treatment in patients undergoing arthroscopic shoulder surgery with tendon repair.

Detailed Description
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In an ambulatory setting, good post-operative analgesia is challenging because patients have to control pain at home by themselves, in the absence of hospital staff. Moreover, there is a limit in the type of analgesia that is available (i.e. no strong opioids) as well as in the route of administration (i.e. no epidural, intravenous, subcutaneous, or intramuscular route) at home. Nowadays a multimodal approach based on a combination of paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs) and, if necessary, weak opioids to control pain has been advocated in the ambulatory setting. Local and regional anesthesia also has been advocated in the ambulatory setting to relieve pain for 8 to 24 hours after surgery. Despite this multimodal pain therapy, the prevalence of outpatients suffering from moderate to severe acute postoperative pain at home remains high and varies from 9 to 40%. More specifically, some patients seem to be at high risk to develop moderate to severe pain on the fourth postoperative day, among which patients undergoing arthroscopic shoulder surgery. Besides this high prevalence, recent findings suggest that the use of NSAIDs is detrimental to tendon healing, especially in early stages. This negative impact is due to its effect on both proliferation and migration of tendon cells, as well as the inflammation reaction involved in the healing process and the bone growth necessary for tendon-to-bone healing. Healing of injured tendon proceeds through three phases: inflammation, regeneration, and remodeling/maturation. The initial phase involves an inflammatory response, in which the pro-inflammatory cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE-2) pathway is of major importance. In the regenerative phase of a tendon injury, tendon cells migrate towards a repair site, proliferate and deposit extracellular matrix (ECM) in the tissue. The expression of paxillin, a positive regulator of cell mobility, is downregulated by ibuprofen, resulting in inhibited tendon cell migration. Moreover, treatment decreases DNA synthesis and gene expression in tendon cells, harming proliferation, and interfering with normal processes of ECM remodeling. Furthermore, the resulting p21CYP1 expression and decreased Rb protein phosphorylation are associated with inhibited proliferation. Additionally, the inhibition of COX-enzymes associated with PGE-2 inhibition may lead to impaired osteoblast differentiation, essential for tendon-to-bone healing. On top of that, NSAIDs are not always sufficiently effective, can have numerous contraindications, and are therefore not suitable in up to 25% of all patients. These controversies implicate the need for alternative pain therapy. Metamizole (dipyrone) is a non-opioid compound with strong analgesic, antipyretic, and spasmolytic effects. The analgesic efficacy of intravenous or intramuscular metamizole for pain relief after inpatient surgery is well described. Recently, we showed in a prospective, double-blind, randomized controlled trial that the combination of paracetamol and metamizole is equally effective in the treatment of acute postoperative pain at home after ambulatory surgery compared to paracetamol and ibuprofen. Moreover, patient satisfaction was equal in both groups, as well as the reported side effects. Multiple mechanisms are involved in the antinociceptive effects of metamizole. More particularly, the inhibition of COX-1 and -2 enzymes and the activation of the endocannabinoid and opioidergic system. This seems partly similar to the working mechanism of NSAIDs, suggesting a theoretical presumption that metamizole also harms tendon repair. However, metamizole is not classified as an NSAID and no detrimental effect of metamizole on tendon healing and no link between metamizole and the previously described mechanism has been reported in the literature. The most important advantage of metamizole compared with NSAIDs is its favorable gastro-intestinal and cardiovascular side effect profile. Therefore, replacing NSAIDs with metamizole in the standard approach in surgeries where NSAIDs are contraindicated such as shoulder arthroscopies with tendon repair may increase the overall suitability of postoperative pain therapy.

Official Title
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Evaluation of the Added Value of Metamizole to Standard Postoperative Treatment After Ambulant Shoulder Surgery: a Double-blind, Randomized Controlled Trial

Conditions
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Postoperative Pain, Analgesia, Surgery

Intervention / Treatment
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* Drug: Metamizole
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients aged between 18 and 75 years ASA classification 1, 2 or 3 Bodyweight > 50 kg Undergoing ambulatory arthroscopic shoulder surgery and with a contraindication to NSAID (SAD ± ACJ excision or decompression, decompression + biceps tenodesis, SLAP repair, Bankart repair, rotator cuff repair) Exclusion Criteria: Not meeting inclusion criteria Cognitive impairment or no understanding of the Dutch language Preoperative pharmacological pain treatment and/or a history of chronic pain excluding shoulder pain Allergy to or contraindication for taking the study medication (e.g. paracetamol or metamizole) Porphyria Pregnancy or lactation A history of severe renal, hepatic, pulmonary or cardiac failure A history of substance abuse, or use of medication with a suppressive effect on the central nervous system Hypotension Hematological disease Use of anti-rheumatic drugs Rhinosinusitis or nasal polyposis Glucose-6-phosphate dehydrogenase deficiency Fever or other signs of infection Refusal of an interscalene block

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A monocenter, prospective, double-blind, randomized controlled superiority trial is designed to investigate the superiority of the combination of metamizole and paracetamol compared to paracetamol treatment in patients undergoing arthroscopic shoulder surgery with tendon repair.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Control group<br>Patients in the control group will be instructed to take a placebo tablet three times a day for four days and patients will be instructed to take 1000 mg paracetamol orally four times a day for four days. | Drug: Placebo<br>* Patients in the control group will be instructed to take a placebo tablet three times a day for four days and patients will be instructed to take 1000 mg paracetamol orally four times a day for four days.<br>|
| Active Comparator: Intervention group<br>Patients in the experimental group will be instructed to take metamizole 1000 mg orally three times a day for four days patients will be instructed to take 1000 mg paracetamol orally four times a day for four days. | Drug: Metamizole<br>* Patients in the experimental group will be instructed to take metamizole 1000 mg orally three times a day for four days patients will be instructed to take 1000 mg paracetamol orally four times a day for four days. .<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Postoperative pain at movement | Postoperative pain intensity at movement measured by an 11-point Numeric Rating Scale (NRS), where 0: no pain and 10: worst imaginary pain, on postoperative day 1. | 24 hours after the surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quality of recovery | Quality of Recovery measured by the 1-item Global Surgical Recovery (GSR) index which represents a single question about the extent to which patients consider themselves to be recovered from surgery (0-100%) at baseline and days 7, 14, 28 and 3 months postoperatively. | at baseline and days 7, 14, 28 and 3 months postoperatively | 
| Quality of Recovery | Measured with the EuroQol (EQ5D) questionnaire, which is non-disease specific instrument developed for describing and valuing health-related quality of life, at baseline and days 7, 14, 28 and 3 months postoperatively | at baseline and days 7, 14, 28 and 3 months postoperatively | 
| Postoperative pain | Postoperative pain intensity at rest and at movement measured by an 11-point Numeric Rating Scale (NRS) where 0: no pain and 10: worst imaginary pain) at baseline, at discharge and at day 1, 2, 3, 4, 7, 14, 28 and at 3 months. | at baseline, at discharge, and day 1, 2, 3, 4, 7, 14, 28, and 3 months postoperatively. | 
| Simple shoulder test | Simple shoulder test (SST) measured at baseline and days 7, 14, 28 and 3 months postoperatively. | at baseline and days 7, 14, 28, and 3 months postoperatively. | 
| Adherence | Adherence to studymedication on day 1, 2, 3 and 4 postoperatively | day 1, 2, 3 and 4 postoperatively | 
| Adverse effects | Adverse effects of the studymedication | throughout study completion, e.g. 3 months postoperatively | 
| Piritramide | The total amount of piritramide used in the PACU | after surgery until discharge of PACU (up to 3 hours after surgery) | 
| Rescue medication | The use of rescue medication (tramadol) at home on day 1, 2 ,3 and 4 postoperatively (yes/no) | on day 1, 2, 3 and 4 postoperatively | 
| Satisfaction of the patient | Satisfaction with study medication, surgery and hospital care and telephone follow-up measured at day 7 and 3 months postoperative measured by an 11-point Numeric Rating Scale (NRS) where 0: totally unsatisfied and 10: totally satisfied | at day 7 and 3 months postoperatively | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ambulant shoulder surgery, post-operative pain, recovery