Effect of Combinations of Paracetamol, Ibuprofen, and Dexamethasone on Patient-Controlled Morphine Consumption in the First 24 Hours After Total Hip Arthroplasty.
The RECIPE Randomized Clinical Trial
A brief project description
Objectives and purposes
To assess the benefits and harms of combinations of paracetamol, ibuprofen, and dexamethasone for patients undergoing total hip arthroplasty (THA).
In patients undergoing THA, using the combination of paracetamol, ibuprofen, and dexamethasone provides an increased analgesic effect compared to any combination of two drugs, with reduced opioid consumption and pain levels for the first 24 postoperative hours.
To investigate the analgesic effects, by differences in 24-hour morphine consumption, of different combinations of paracetamol, ibuprofen, and dexamethasone after THA.
To investigate the analgesic effect on pain levels during mobilization and at rest, of different combinations of paracetamol, ibuprofen, and dexamethasone.
To investigate the analgesic effect on pain levels during walk (5 meters) at 24-hours postoperatively, of different combinations of paracetamol, ibuprofen, and dexamethasone.
To investigate number of patients with adverse events of different combinations of paracetamol, ibuprofen, and dexamethasone.
Optimizing postoperative pain treatment is essential for the well-being and rehabilitation of the surgical patient. This includes reduction of the surgical stress-response and facilitation of early mobilisation, resumption of food and fluid intake, and recommencement of daily activities. It is a key element for an early recovery.
Multimodal analgesia is the leading treatment principle for managing acute postoperative pain, and vast amounts of different analgesic approaches are used worldwide. Pain after THA is moderate to severe, but no gold standard for treatment hereof has been determined. Especially, evidence on both benefits and harms of different combined analgesic treatment regimens are sparse.
Paracetamol and ibuprofen are two commonly used drugs with proven analgesic efficacy when administered alone, . In general, they are recommended as a basic part of pain treatment in many surgical and non-surgical settings, but, until recently, without firm evidence of a possible additive or synergistic effect from combining the two. Yet, two previous reviews found increased analgesic efficacy from the combination compared to monotherapy.,  Additionally, this research group recently performed the PANSAID-trial, a 556 patient randomized controlled trial investigating the additive effect of combining paracetamol and ibuprofen after THA. Results showed a statistically significant reduction in 24-hour cumulative dose of morphine from the combination of paracetamol + ibuprofen compared to using each drug separately. The combination also reduced pain levels both at rest and during mobilization, as compared to each individual analgesic.
Thus, prior results shows that combining basic, well-known and thoroughly tested non-opioid analgesics reduces pain, and decreases the need of opioids after THA. However, patients still experience significant pain and use considerably amounts of opioids, meaning that the pain management needs further improvement.
With the RECIPE trial, we therefore aim to investigate the analgesic and opioid-sparing effect of adding a further non-opioid analgesic to this combination. Dexamethasone, a long-acting glucocorticoid is already used during numerous surgeries to prevent postoperative nausea and vomiting, and may at a higher dose have pain-relieving properties. However, only few studies have investigated this, and so far, no previous studies have systematically investigated benefits and harms of dexamethasone in combination with paracetamol and/or ibuprofen for THA.
By performing the RECIPE trial, we expect to deliver high-quality evidence for a better and safer pain treatment after surgery, ultimately leading the way to a postoperative pain-regime free of opioids.
Total hip arthroplasty
THA is a frequently performed procedure with an incidence of primary THAs of 180 per 100.000 inhabitants in Denmark. In the US, incidences of THA surgeries are expected to increase with 174% from 2005 to 2036. The majority of patients having THA are elderly, with 80% > 60 years, and often with significant co-morbidities, including chronic pain, emphasizing the need for an effective management of postoperative pain after this procedure.
We believe that participating in this trial is associated with low risk. Based on the existing literature this trial should not involve adverse effects or risks that exceed those normal for this surgical procedure.
Paracetamol is generally well tolerated and is a standard analgesic drug in postoperative pain treatment. When delivered within recommended dosage limitation, as in this trial, the number of adverse effects is extremely low.
The adverse effects of ibuprofen depend on dose and treatment duration and are more common in the elderly. The most significant adverse effect is gastrointestinal disturbances, and beside this, there is a long list of less frequent adverse effects. In this trial, ibuprofen treatment is short, dosages are within recommended range, and it is expected that adverse effects will be few.
Dexamethasone has proved safe to use during surgery. A single dose of dexamethasone (2-8 mg) is commonly used as anti-emetic treatment and prophylaxis. In this trial patients are given 24 mg dexamethasone after induction of anaesthesia. This single dose is not expected to result in adverse effects or risks that exceed the adverse effects for the surgical procedure alone. This is subsided by large studies and reviews., 
All participating patients will be thoroughly informed both orally and in writing, and investigators must obtain written informed consent from each eligible patient before inclusion can be completed.
RECIPE is a randomized, placebo-controlled, parallel 4-group, blinded multicentre trial with stratification for site.
This trial is initiated from, and anchored in, Næstved-Slagelse-Ringsted Hospitals and Zealand University Hospital, and it will be conducted in collaboration with Departments of Anaesthesiology and Orthopaedic Surgery in hospitals in three different Danish regions.
Selection of participants
All patients scheduled for unilateral, primary THA will be considered for inclusion. Patients will be eligible, if they fulfil all strict inclusion criteria and none of the exclusion criteria.
Randomization and blinding
Patients will be randomized into four groups at a 1:1:1:1 ratio by central randomisation using a computer-generated random sequence list with blocks of varying size (unknown to investigators). Randomization will be stratified for site. The pharmacy will further supply the trial medication in packages with identical tablets and vials, making distinction between active and placebo interventions impossible. This medication will be packed and labelled according to the allocation numbers.
Total need for IV-morphine mg (eqv) for the first 24 hours postoperatively, administered as patient-controlled analgesia (0-24 hours), and supplemental opioid administered at the post-anaesthesia care unit the first hour postoperatively after end of surgery (general anaesthesia) or end of spinal anaesthesia, or any supplemental opioid given at the ward
Pain scores (measured via visual analogue scale (VAS)) with active 30 degrees flexion of the hip at 24 hours postoperatively
Pain scores at rest (VAS) at 24 hours postoperatively
Maximum pain score (VAS) during walk of 5 meters at 24 hours postoperatively.
Number of patients with one or more adverse effects in the intervention period (0-24 hours)
Exploratory outcomes include
Serious adverse events, including death, within 90 days after surgery
Days alive and outside hospital within 90 days after surgery
Opioid use at 90 days
The trial period starts at randomisation and lasts to 90 days postoperatively. The intervention period is from the end of surgery (T = 0) and the next 24 hours. The follow-up period ends on the 90th postoperative day.
Patients will be randomized into one of four groups receiving the experimental interventions, and interventions will be administered as follows:
Paracetamol 1000 mg and ibuprofen 400 mg will be administered orally 1 hour before surgery and given with 6-hour intervals to a total of 4 times the first postoperative day.
Dexamethasone 24 mg administered IV after induction of anaesthesia.
Groups and associated interventions are as listed below
Group paracetamol + ibuprofen + placebo
Group paracetamol + dexamethasone + placebo
Group ibuprofen + dexamethasone + placebo
Group paracetamol + ibuprofen + dexamethasone
Standard postoperative pain management during intervention period
Patient-controlled analgesia pump:
Mixture: Morphine 1mg/ml, bolus: 2,0 mg, lockout time: 10 minutes, no background infusion
If there is a need of morphine additional to the pump, additional bolus doses of 2 mg can be administered on patient request.
Protection of participant data
All information will be treated confidentially and the persons responsible for this trial are bound to confidentiality. When reporting the test results, participants will be anonymized.
Collected data and records will only be made available to third parties in accordance with the act on processing of personal data, which means in connection with monitoring by regional Good Clinical Practice units, or upon inspection by authorized representatives of relevant authorities.
Expected clinical impact
Currently, various combinations of non-opioid analgesics are used for postoperative pain management without firm evidence for efficacy nor safety of these combinations. With the RECIPE trial, and the following systematic review, we will most certainly be able to clarify pros and cons of combining paracetamol, ibuprofen and dexamethasone for postoperative pain management in patients undergoing THA.
 H. Kehlet and J. B. Dahl, “Anaesthesia, surgery, and challenges in postoperative recovery,” Lancet, vol. 362, pp. 1921–1928, 2003.
 R. Chou et al., “Management of Postoperative Pain: A Clinical Practice Guideline From the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists’ Committee on Regional Anesthesia, Executive Commi,” J. Pain, vol. 17, no. 2, pp. 131–157, 2016.
 A. P. Højer Karlsen, A. Geisler, P. L. Petersen, O. Mathiesen, and J. B. Dahl, “Postoperative pain treatment after total hip arthroplasty: a systematic review,” Pain, vol. 156, no. 1, pp. 8–30, 2015.
 J. B. Dahl et al., “Post-operative analgesic effects of paracetamol, NSAIDs, glucocorticoids, gabapentinoids and their combinations: A topical review,” Acta Anaesthesiologica Scandinavica, vol. 58, no. 10. pp. 1165–1181, 2014.
 R. A. Moore, S. Derry, D. Aldington, and P. J. Wiffen, “Single dose oral analgesics for acute postoperative pain in adults - an overview of Cochrane reviews,” Cochrane Database of Systematic Reviews, vol. 2017, no. 10. 2015.
 C. L. Wu and S. N. Raja, “Treatment of acute postoperative pain,” Lancet, vol. 377, no. 9784, pp. 2215–2225, 2011.
 C. J. Derry, S. Derry, and R. A. Moore, “Single dose oral ibuprofen plus paracetamol (acetaminophen) for acute postoperative pain,” Cochrane Database Syst. Rev., vol. 2017, no. 10, Jun. 2013.
 C. K. S. Ong, R. A. Seymour, P. Lirk, and A. F. Merry, “Combining Paracetamol (Acetaminophen) with Nonsteroidal Antiinflammatory Drugs: A Qualitative Systematic Review of Analgesic Efficacy for Acute Postoperative Pain,” Anesth. Analg., vol. 110, no. 4, pp. 1170–1179, 2010.
 “Danish Hip Arthroplasty Register,” 2018.
 D. J. B. Mathiesen O., Wetterslev J., Kontinen V.K., Pommergaard H.-C., Nikolajsen L., Rosenberg J., Hansen M. S., Hamunen K., Kjer J.J., “Adverse effects of perioperative paracetamol, NSAIDs, glucocorticoids, gabapentinoids and their combinations: a topical review,” Acta Anaesthesiol. Scand., vol. 58, pp. 1182–1198, 2014.
 K. H. Thybo et al., “Effect of Combination of Paracetamol (Acetaminophen) and Ibuprofen vs Either Alone on Patient-Controlled Morphine Consumption in the First 24 Hours After Total Hip Arthroplasty The PANSAID Randomized Clinical Trial,” JAMA, vol. 321(6), pp. 562–571, 2019.
 A. J. Toner, V. Ganeshanathan, M. T. Chan, K. M. Ho, and T. B. Corcoran, “Safety of Perioperative Glucocorticoids in Elective Noncardiac Surgery,” Anesthesiology, vol. 126, no. 2, pp. 234–248, Feb. 2017.
 A. Salerno and R. Hermann, “Efficacy and safety of steroid use for postoperative pain relief: Update and review of the medical literature.,” J. Bone Jt. Surg., vol. 88, no. 6, pp. 1361–1372, 2006.
 V. Martinez, H. Beloeil, E. Marret, D. Fletcher, P. Ravaud, and L. Trinquart, “Non-opioid analgesics in adults after major surgery: Systematic review with network meta-analysis of randomized trials,” British Journal of Anaesthesia, vol. 118, no. 1. pp. 22–31, Jan-2017.