Impact of NSAIDs on delayed fracture healing

BRIEF NAME: Non-steroidal anti-inflammatory drugs (NSAIDs) WHY: Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed following musculoskeletal injuries and fractures as an effective method of pain relief, and are thought to offer a safer alternative to prescription opioids which are associated with an epidemic of abuse and secondary harm. However, there is some evidence that NSAIDs may impair bone formation, and therefore impact upon fracture healing, creating delayed union or non-union. Recent high-quality systematic reviews on the association between NSAID use and fracture non-union have concluded that, owing to a lack of clear evidence for impaired bone healing due to NSAID use, randomised controlled trials (RCTs) and high-quality prospective cohort studies are still needed. Given the frequency and use of NSAIDs, it is essential that we have solid evidence to inform clinical guidelines on the use of safe and appropriate analgesia to improve patient care. In order to conduct a large multi-site RCT to draw more definitive conclusions about the effects of NSAIDs on bone healing, it is important to firstly ascertain the safety and feasibility of conducting such a study via a pilot RCT. Therefore, the aims of this study are: 1. To determine the feasibility of using a prescribed treatment regime of NSAIDs versus a placebo in people with tibial shaft or femoral shaft limb fractures; and 2. To inform the design of a definitive multi-site trial that aims to determine the effect of NSAIDs on rates of non-union in people with tibial or femoral shaft limb fractures WHAT: NSAID: Parecoxib - Dose: 40mg - Frequency/Duration: Single dose, intra-operative - Mode: intravenous NSAID: Celecoxib - Dose: 200mg - Frequency/Duration: twice daily, commencing 24 hours after surgery and in the two weeks post-surgery - Mode: Oral Procedure: Participants in the intervention group will receive standard care* plus intervention NSAIDs (parecoxib and celecoxib). Parecoxib will be intravenously administered to patients peri-operatively. Celecoxib will be prescribed to be taken twice daily, 24 hours after surgery for a duration of 2 weeks. *According to local analgesic ladder. This includes regular paracetamol, regular and as required opioid, and if necessary, other non-opioids (e.g. gabapentinoids, clonidine) or Acute Pain Service consultation in those with difficult pain control. WHO: Randomisation and preparation of study drugs will be prepared by the Clinical Trials Pharmacists at the Alfred Pharmacy Department. Upon receipt of a completed clinical trials prescription by an authorised study prescriber, designated research personal will collect the study drug from Clinical Trials and deliver to the appropriate location, theatres or ward. Receipt and dispensing of study drugs will occur per Clinical Trials Pharmacy procedures. ADHERENCE: • Patient adherence will be determined in the two weeks post-surgery. Participants will complete a daily medication diary, and participate in a face-to-face or telephone call follow-up at two weeks, where participants will be asked questions about medication adherence and any barriers to medication adherence. • Physician adherence will be determined by reviewing the medications prescribed in the first three days post-surgery. Anaesthetic charts, preoperative medication orders, post-operative orders, medication administration records, medication reconciliation forms, and discharge summaries are potential sources for information. A pharmacist working on the orthopaedic ward will conduct the medication monitoring. The type of information collected will be informed by the Alfred Health Guidelines for Pharmacological Management of Acute Pain in Adults and include; name/type of drug, dosage, route of administration, date and time(s) of administration, length of exposure (in-hospital) and details of treatment and any co-morbidities. Additionally, participants will be provided with a letter to give to their GP to inform them about their participation in the study. The GP will be asked to refrain from prescribing any non-steroidal anti-inflammatory medications during the first two weeks following surgery.