Evidence-Based Approaches in Postoperative Pain Treatment
We spoke to Professor Ole Mathiesen, who is leading the PERISAFE trial—a randomised clinical study exploring the safety and efficacy of ibuprofen for postoperative pain management following hip and knee arthroplasty. This innovative research addresses critical questions about optimising pain relief while minimising risks in the crucial postoperative period.
Surgical interventions cause tissue injury and inflammation. The body’s responses to surgical trauma, both local and systemic, give rise to postoperative pain - a distressing experience for patients who’ve undergone a surgical procedure. Postoperative pain is mediated by the activation of nociceptors in the skin, muscles, and joints, triggered by noxious stimuli and the release of inflammatory mediators. Additionally, the surgical stress response, exacerbates postoperative pain and is associated with nausea, vomiting, cerebral dysfunction, increased infection risk, and potential organ failure. Uncontrolled postoperative pain and surgical stress can prolong hospitalisation, delay recovery, and heighten the risk of perioperative cardiac complications in major noncardiac surgeries. Effective management of postoperative pain is essential for improving surgical outcomes and ensuring a smoother, faster recovery for patients. The current approach to managing acute postoperative
pain emphasises the use of multimodal analgesia. This strategy combines a variety of treatments, including non-opioid analgesics like paracetamol and non-steroidal antiinflammatory drugs (NSAIDs), local anaesthetics, glucocorticoids, and opioids when necessary. Research has shown that this approach not only reduces pain levels but also helps decrease opioid consumption and minimises opioid-related adverse effects. The treatment principle is also the golden standard for the management of postoperative pain following hip and knee replacements, one of the most frequently performed elective surgical procedures. Each year, over 1.5 million hip and knee replacements are performed worldwide, significantly improving pain, quality of life, and functional outcomes for patients with severe osteoarthritis. Hip and knee arthroplasty surgeries are generally considered safe, with a 90-day mortality rate of 0.5% for total hip replacements and 0.4% for total knee replacements. However, older
age, multiple health conditions, and previous heart disease can increase mortality risk. The postoperative pain associated with these procedures is moderate to severe. While most postoperative pain management protocols recommend using both paracetamol and NSAIDs, there is no consensus on which NSAIDs to use, the treatment regimen, or the duration of therapy. Individual preferences or local guidelines typically guide these decisions. A recent survey of NSAID use across all Danish orthopedic departments found that ibuprofen is the most commonly prescribed NSAID after elective hip and knee arthroplasties. Also internationally, ibuprofen is one of the most used NSAIDs. However, long-term ibuprofen use in nonsurgical patients has been linked to several adverse effects, including gastrointestinal bleeding, kidney problems, and increased cardiovascular risks. An important, yet still unanswered question remains: What are the risks to using ibuprofen for short-term pain relief after hip and knee surgery? This
inspired the work of Professor Ole Mathiesen, Zealand University Hospital, who is the primary supervisor of the PERISAFE trial - a randomised clinical multicentre trial that aims to assess the adverse effects of an eightday treatment of postoperative pain with ibuprofen in patients undergoing elective hip or knee arthroplasty surgery.
“One major question that remains is the treatment approach for patients discharged shortly after hip or knee replacement surgeries, often on the same day or the following day. In Denmark, the hospital stay is typically very short, however, patients still need pain management at home, which would generally include NSAIDs like ibuprofen. These drugs are well known in medical practice for treating general and inflammatory pain, such as in rheumatologic diseases. However, they also come with a range of potential adverse effects, especially with long-term use. It was never investigated in a large trial how patients who received a new knee or hip coped with this treatment during the first week or two after being discharged” explains Prof. Mathiesen. “To better understand the potential benefits and risks, we needed a study to investigate the effects of sending
the hospital within the 90-day period. “If the treatment was effective, more patients would be able to stay at home, whereas if it was harmful, more patients would need to return to the hospital.” he continues. Prof. Mathiesen was initially researching postoperative pain back in 2009, as a PhD student at the University of Copenhagen. Throughout his scientific career, he focused on developing evidence-based postoperative pain treatments, authoring many trials and reviews with meta-analyses on the subject. “When we treat patients’ pain after surgery, opioids are nearly always necessary, but they come with various adverse effects. Therefore, we aim to reduce the need for opioids by using other analgesics like paracetamol, NSAIDs, steroids, and so on. While each of these has an analgesic effect, we don’t know the benefits and risks of combining these non-opioid medications for patients. This was the research question driving a series of trials conducted in collaboration with anaesthesia and orthopedic departments, and my core collaborators Professor Janus C Jakobsen (Copenhagen Trial Unit), associate professor Troels H Lunn (Bispebjerg and Frederiksberg Hospital) and associate professor Daniel Hägi-Pedersen (Næstved-
“When we treat patients’ pain after surgery, opioids are nearly always necessary, but they come with various adverse effects. Therefore, we aim to reduce the need for opioids by using other analgesics like paracetamol, NSAIDs, steroids, and so on.”
patients home with NSAID treatment during the first-week post-surgery. The relevance of this research is substantial, as it involves a significant patient population—around 25,000 patients annually in Denmark alone” he elaborates further on the objectives of the PERISAFE trial. The PERISAFE trial will enroll 2,904 participants scheduled for hip and knee arthroplasty who will be randomly assigned to receive either 400 mg of ibuprofen three times per day or an identical placebo tablet for eight days postoperatively, with followup occurring 90 days after surgery. This high number of participants is only achievable due to an extensive national collaboration between orthopedic and anaesthesia researchers at 10 hospitals throughout all five Danish Regions, and an effective central coordinating unit headed by Christina CW Laursen, MD, PhD student and primary investigator on PERISAFE. The trial aims to assess both the benefits and potential harms of the treatment by tracking incidences of ten core serious adverse events in patients participating, and also days spent outside
Slagelse-Ringsted Hospitals).” explains Prof. Mathiesen. In the PANSAID randomised trial conducted across six Danish hospitals, he and his team discovered that combining ibuprofen and paracetamol significantly reduces morphine consumption in the first 24 hours following total hip arthroplasty. Furthermore, the researchers conducted the randomised controlled DEX-2-TKA trial investigating the effects of dexamethasone as an analgesic adjuvant in patients after total knee arthroplasty. They found that two doses of dexamethasone added to a multimodal pain treatment effectively reduced morphine consumption and postoperative pain. More recently, the researchers conducted the RECIPE trial - a randomised controlled trial conducted across nine Danish hospitals, which included 1060 participants. They found that multimodal treatment combining paracetamol, ibuprofen, and dexamethasone in adults undergoing total hip arthroplasty resulted in the lowest morphine consumption and had the most favourable adverse event profile of the possible non-opioid combinations.
PERISAFE
Serious adverse events of ibuprofen after elective primary total hip and knee arthroplasties
Project Objectives
The PERISAFE trial aims to assess the benefits and potential harms of an eightday postoperative ibuprofen regimen in patients undergoing elective hip and knee arthroplasty. This study will provide critical insights into the safety and efficacy of short-term NSAID use for postoperative pain management.
Project Timeline
The trial will conclude in less than two years, ending in April 2025.
Project Funding
The PERISAFE project is funded by grants from Sundhedsdonationer, part of a private Danish health insurance organisation, Independent Research Fund Denmark, The Zealand Region DK, The Danish Medical Association Research fund, and Shipowner Per Henriksen and Wife’s Fund.
Project Partners
The PERISAFE trial is one of the projects in Collaboration for Evidence-based Prctice & Research in Anaesthesia (CEPRA), a national research group with more than 100 researchers and 25+ hospitals.
See more on www.cepra.nu
Contact Details
Professor Ole Mathiesen, PhD Consultant
Centre for Anaesthesiological Research Department of Anaesthesiology, Zealand University Hospital Lykkebækvej 1, 4600 Køge, Denmark Department of Clinical Medicine, Copenhagen University, Copenhagen T: +45 4732 6321
E: omat@regionsjaelland.dk
W: www.perisafe.dk
W: https://anaesthesiaresearch.dk
Ole Mathiesen is a chair professor and consultant at the Department of Clinical Medicine at the University of Copenhagen and the Department of Anaesthesiology at Zealand University Hospital Køge. His research focuses on the optimization of perioperative care, particularly evidencebased postoperative pain management.
Christina Cleveland Westerdahl Laursen is a PhD student and Coordinating Investigator on the trial.
Ole Mathiesen Christina Cleveland