Effect of Combinations of Paracetamol, Ibuprofen, and Dexamethasone on Patient-Controlled Morphine Consumption in the First 24 Hours After Total Hip Arthroplasty

Study Overview
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Brief Summary
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Multimodal pain management is essential for recovery after surgery, aiming to target different pain mechanisms to minimize opioid usage and opioid-related adverse effects. Evidence for benefits and harms of various non-opioid analgesic combinations is, however, nearly non-existing, and large-scale trials are urgently needed. Recently, the investigators have demonstrated that combining paracetamol and ibuprofen is superior to each single drug when assessing pain after hip replacement. Further improvement is needed, investigating additional non-opioid analgesics to this combination. Glucocorticoids have anti-emetic and analgesic properties, but evidence for analgesic efficacy in combination with paracetamol and ibuprofen is lacking. The RECIPE trial is an investigator-initiated randomized, placebo-controlled, parallel, 4-group, blinded multicentre trial with 90-day follow-up investigating benefits and harms of different combinations of paracetamol, ibuprofen, and dexamethasone for patients undergoing total hip arthroplasty. The primary outcome is total use of IV morphine 0-24 hours postoperatively. Secondary outcomes are pain (upon mobilisation, at rest, and during 5 m walk), and adverse events. Exploratory outcomes include quality of sleep, opioid-related adverse effects, serious adverse events (< 90 days), and patient reported disability score and quality of life (at 90 days). Based on sample-size calculations, 1060 patients are needed to detect a minimal clinically important difference in 24-hour morphine consumption of 8 mg, using a familywise type 1 error rate of 0.05 and a type 2 error rate of 0.2. The primary analyses will be based on the intention to treat population. More than six Danish university- and regional hospitals will participate in the trial. With this trial the investigators expect to lay the foundation for the best postoperative multimodal analgesic regimen for both total hip arthroplasty and possibly other surgeries, thereby facilitating recovery for millions of future surgical patients worldwide.

Official Title
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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

Conditions
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Pain, Acute, Hip Arthropathy, Analgesia, Postoperative Pain

Intervention / Treatment
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* Drug: Paracetamol
* Drug: Ibuprofen
* Drug: Dexamethasone
* Drug: Placebo oral capsules
* Drug: Placebo IV


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Scheduled for elective, unilateral, primary THA Age ≥ 18 ASA 1-3 BMI > 18 and < 40 Negative urine HCG pregnancy test and use of anti-conception for women in the fertile age Give written informed consent to participate in the trial after having fully understood the contents of the protocol and restrictions Exclusion Criteria: Patients who cannot cooperate with the trial Concomitant participation in another trial involving medication Patients who cannot understand or speak Danish Patients with allergy to medication used in the trial Patients with daily use of high dose opioid (> oral morphine 30 mg/day or oxycodone 30 mg/day or tramadol 150 mg/day) or any use of other opioids including methadone and transdermal opioids. Patients with daily use of systemic glucocorticoids (within 3 months before the trial) Contraindications against ibuprofen or paracetamol, for example previous ulcer, known heart failure, known liver failure, or known renal failure (eGRF < 60 ml/kg/1,73m2), known thrombocytopenia (< 100 x 109/l); or against treatment with glucocorticoids Dysregulated diabetes (investigator's judgement) Patients suffering from alcohol and/or drug abuse - based on the investigator's judgement

Ages Eligible for Study
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Minimum Age: 18 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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A<br>Paracetamol 1000 mg + Ibuprofen 400 mg administered orally 1 hour before surgery and given with 6-hour intervals to a total of 4 times the first postoperative day. Plus placebo (matching DXM) IV administered after induction of anaesthesia | Drug: Paracetamol<br>* 1g x 4 p.o.<br>* Other names: Acetaminophen;Drug: Ibuprofen<br>* 400mg x 4 p.o.<br>Drug: Placebo IV<br>* IV x 1<br>|
| Experimental: Group B<br>Paracetamol 1000 mg and placebo (matching ibuprofen) orally 1 hour before surgery and given with 6-hour intervals to a total of 4 times the first postoperative day. Plus DXM 24 mg IV after induction of anaesthesia | Drug: Paracetamol<br>* 1g x 4 p.o.<br>* Other names: Acetaminophen;Drug: Dexamethasone<br>* 24mg IV x 1 after induction om anaesthesia<br>Drug: Placebo oral capsules<br>* p.o. x 4<br>|
| Experimental: Group C<br>Placebo (matching paracetamol) + ibuprofen 400 mg orally 1 hour before surgery and given with 6-hour intervals to a total of 4 times the first postoperative day. Plus DXM 24 mg IV after induction of anaesthesia | Drug: Ibuprofen<br>* 400mg x 4 p.o.<br>Drug: Dexamethasone<br>* 24mg IV x 1 after induction om anaesthesia<br>Drug: Placebo oral capsules<br>* p.o. x 4<br>|
| Experimental: Group D<br>Paracetamol 1000 mg + ibuprofen 400 mg orally 1 hour before surgery and given with 6-hour intervals to a total of 4 times the first postoperative day. Plus DXM 24 mg IV after induction of anaesthesia | Drug: Paracetamol<br>* 1g x 4 p.o.<br>* Other names: Acetaminophen;Drug: Ibuprofen<br>* 400mg x 4 p.o.<br>Drug: Dexamethasone<br>* 24mg IV x 1 after induction om anaesthesia<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative opioid consumption in the first 24 hours after surgery | Cumulative opioid consumption in units of intravenous morphine equivalents in the first 24 postoperative hours. This includes opioids administered as (a) patient-controlled analgesia (PCA); (b) supplemental opioid administered at the post-anaesthesia care unit the first hour after end of surgery (general anaesthesia) or the first hour after ceasing of spinal anaesthesia; and (c) any supplemental opioid given at the ward | 0-24 hours after end of surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain scores during mobilisation 24h | Pain scores (visual analogue scale (VAS 0-100 mm; no pain = 0; worst imaginable pain = 100)) with active 30 degrees flexion of the hip | 24 hours after end of surgery | 
| Pain scores at rest 24h | Pain scores at rest (VAS 0-100 mm; no pain = 0; worst imaginable pain = 100) | 24 hours after end of surgery | 
| Maximum level of pain | Maximum level of pain (VAS 0-100 mm No pain = 0; worst imaginable pain = 100) during walk of 5 meters | 24 hours after end of surgery | 
| Adverse events in the intervention period | Proportion of patients with one or more AEs in the intervention period | From end of surgery + 24 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Analgesia, Multimodal analgesia, Non-opioid analgesia, Acute pain, RECIPE, Hip arthroplasty, Postoperative pain