Evaluation of the Added Value of Metamizole to Standard Postoperative Treatment After Ambulant Shoulder Surgery
Condition: Postoperative Pain; Analgesia; Surgery
MeSH terms: Pain, Postoperative
Study type: Interventional

Summary: 
      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: 
      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.
    

Intervention name(s): Metamizole; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 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. .; 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.
Intervention MeSH terms: Dipyrone
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention 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 (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: ambulant shoulder surgery; post-operative pain; recovery