Effect of Combinations of Paracetamol, Ibuprofen, and Dexamethasone on Patient-Controlled Morphine Consumption in the First 24 Hours After Total Hip Arthroplasty (RECIPE)
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| ClinicalTrials.gov Identifier: NCT04123873 |
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Recruitment Status :
Recruiting
First Posted : October 11, 2019
Last Update Posted : March 4, 2022
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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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Pain, Acute Hip Arthropathy Analgesia Postoperative Pain | Drug: Paracetamol Drug: Ibuprofen Drug: Dexamethasone Drug: Placebo oral capsules Drug: Placebo IV | Phase 4 |
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 1060 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) |
| Masking Description: | The study medication will be masked by the pharmacy. The experimental medicine will be packed and labelled by Skanderborg Pharmacy in accordance with the Good Manufacturing Practice regulations. The sponsor has a set of sealed, opaque envelopes with the participants' allocation, and these will only be revealed for the investigators when the data has been analysed and abstracts and conclusions covering the different possibilities for interpreting the trial results, have been agreed upon by the steering committee |
| Primary Purpose: | Treatment |
| Official Title: | 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 |
| Actual Study Start Date : | March 5, 2020 |
| Estimated Primary Completion Date : | January 2023 |
| Estimated Study Completion Date : | April 2023 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Group A
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
1g x 4 p.o.
Other Name: Acetaminophen Drug: Ibuprofen 400mg x 4 p.o. Drug: Placebo IV IV x 1 |
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Experimental: Group B
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
1g x 4 p.o.
Other Name: Acetaminophen Drug: Dexamethasone 24mg IV x 1 after induction om anaesthesia Drug: Placebo oral capsules p.o. x 4 |
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Experimental: Group C
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
400mg x 4 p.o. Drug: Dexamethasone 24mg IV x 1 after induction om anaesthesia Drug: Placebo oral capsules p.o. x 4 |
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Experimental: Group D
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
1g x 4 p.o.
Other Name: Acetaminophen Drug: Ibuprofen 400mg x 4 p.o. Drug: Dexamethasone 24mg IV x 1 after induction om anaesthesia |
- Cumulative opioid consumption in the first 24 hours after surgery [ Time Frame: 0-24 hours after end of 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
- Pain scores during mobilisation 24h [ Time Frame: 24 hours after end of surgery ]Pain scores (visual analogue scale (VAS 0-100 mm; no pain = 0; worst imaginable pain = 100)) with active 30 degrees flexion of the hip
- Pain scores at rest 24h [ Time Frame: 24 hours after end of surgery ]Pain scores at rest (VAS 0-100 mm; no pain = 0; worst imaginable pain = 100)
- Maximum level of pain [ Time Frame: 24 hours after end of surgery ]Maximum level of pain (VAS 0-100 mm No pain = 0; worst imaginable pain = 100) during walk of 5 meters
- Adverse events in the intervention period [ Time Frame: From end of surgery + 24 hours ]Proportion of patients with one or more AEs in the intervention period
- Serious adverse events within one year [ Time Frame: Within 90 days ]SAEs, including death, within 90 days after surgery defined as SAE (according to ICH-GCP-guidelines) except 'prolongation of hospitalisation' that has been modified to 'prolongation of hospitalization with ≥4 days'
- Pain scores during mobilisation 6h [ Time Frame: 6 hours after end of surgery ]Pain scores (visual analogue scale (VAS 0-100 mm; no pain = 0; worst imaginable pain = 100)) with active 30 degrees flexion of the hip
- Pain scores at rest 6h [ Time Frame: 6 hours after end of surgery ]Pain scores at rest (VAS 0-100 mm; no pain = 0; worst imaginable pain = 100)
- Prevalence of nausea [ Time Frame: 6 and 24 hours after end of surgery ]Prevalence of nausea, 6 and 24 hours after end of surgery
- Number of vomiting episodes [ Time Frame: 0-24 after end of surgery. Reported by interview 24 hours after end of surgery ]The number of productive vomiting events (volume estimated over 10 ml) is recorded corresponding to the period 0-24 hours
- Consumption of ondansetron and dehydrobenzperidole [ Time Frame: 0-24 hours after end of surgery ]Consumption of ondansetron and dehydrobenzperidole in mg
- Incidence of dizziness during 5 meter walk [ Time Frame: 24 hours after end of surgery ]Incidence of dizziness during 5 meter walk 24 hours after surgery
- Blood loss [ Time Frame: Intraoperatively ]Blood loss in ml during the surgical procedure
- Quality of sleep [ Time Frame: 24 hours after end of surgery ]Quality of sleep (VAS 0-100 mm; worst possible sleep = 0; best possible sleep = 100) Worst possible sleep = 0; best possible sleep = 100
- Days alive and outside hospital within 90 days after surgery [ Time Frame: Within 90 days after surgery ]Days alive and outside hospital within 90 days after surgery
- Oxford Hip Score at 90 days [ Time Frame: At 90 days after surgery ]5-point Lipert-scale (no, mild, moderate, severe and extreme)
- Quality of life (EQ-5D-5L) at 90 days [ Time Frame: At 90 days after surgery ]EuroQol five-dimensions 5 point Lipert scale (EQ-5D-5L)
- Opioid use at 90 days [ Time Frame: Within 90 days after surgery ]Consumption of opioids within 90 days after surgery
- Serious adverse events within 1 year [ Time Frame: Within one year after surgery ]Proportion of participants with one or more serious adverse events, including death, within one year after surgery, according to ICH-GCP guidelines[24] (except for 'prolongation of hospitalization' that has been modified to 'prolongation of hospitalization with ≥4 days')
- Oxford Hip Score at one year [ Time Frame: One year after surgery ]5-point Lipert-scale (no, mild, moderate, severe and extreme)
- Quality of life (EQ-5D-5L) at one year [ Time Frame: One year after surgery ]EuroQol five-dimensions 5 point Lipert scale (EQ-5D-5L)
- Opioid use at one year [ Time Frame: Within one year after surgery ]Consumption of opioids within one year after surgery
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04123873
| Contact: Daniel Hägi-Pedersen, MD, PhD | 0045 21517167 | dhag@regionsjaelland.dk | |
| Contact: Joakim Steiness, MD | joast@regionsjaelland.dk |
| Denmark | |
| Næstved-Slagelse-Ringsted Hospitals | Recruiting |
| Næstved, Danmark, Denmark, 4700 | |
| Contact: Daniel Hägi-Pedersen, Ph.D. +45 21517167 dhag@regionsjaelland.dk | |
| Principal Investigator: Joakim Steiness | |
| Bispebjerg Hospital | Recruiting |
| Copenhagen, Denmark, 2400 | |
| Contact: Troels H Lunn, MD, DMSc +45 26 25 00 06 lunn@dadlnet.dk | |
| Gentofte Hospital | Recruiting |
| Hellerup, Denmark, 2900 | |
| Contact: Ben Kristian Graungaard, MD +45 40 20 20 56 bigben@dadlnet.dk | |
| Hillerød Hospital | Recruiting |
| Hillerød, Denmark, 3400 | |
| Contact: Lars H Lundstrøm, MD, PhD +45 26 85 25 25 lars_hyldborg@hotmail.com | |
| Køge Hospital | Recruiting |
| Køge, Denmark, 4600 | |
| Contact: Ole Matiesen, MD, PhD omat@regionsjaelland.dk | |
| Principal Investigator: Ole Matiesen, MD, PhD | |
| Odense University Hospital (OUH) | Recruiting |
| Odense, Denmark, 5000 | |
| Contact: Martin Lindberg-Larsen, MD, PhD martin.lindberg-larsen@rsyd.dk | |
| Svendborg Hospital | Recruiting |
| Svendborg, Denmark, 5700 | |
| Contact: Martin Lindberg-Larsen, MD, PhD +45 25 21 39 00 martin.lindberg-larsen@rsyd.dk | |
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | Naestved Hospital |
| ClinicalTrials.gov Identifier: | NCT04123873 |
| Other Study ID Numbers: |
SM1-JOAST-2019 |
| First Posted: | October 11, 2019 Key Record Dates |
| Last Update Posted: | March 4, 2022 |
| Last Verified: | February 2022 |
| Studies a U.S. FDA-regulated Drug Product: | No |
| Studies a U.S. FDA-regulated Device Product: | No |
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RECIPE Hip arthroplasty Postoperative pain Analgesia |
Multimodal analgesia Non-opioid analgesia Acute pain |
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Pain, Postoperative Acute Pain Postoperative Complications Pathologic Processes Pain Neurologic Manifestations Acetaminophen Dexamethasone Ibuprofen Anti-Inflammatory Agents Antiemetics Autonomic Agents Peripheral Nervous System Agents Physiological Effects of Drugs Gastrointestinal Agents |
Glucocorticoids Hormones Hormones, Hormone Substitutes, and Hormone Antagonists Antineoplastic Agents, Hormonal Antineoplastic Agents Analgesics, Non-Narcotic Analgesics Sensory System Agents Antipyretics Anti-Inflammatory Agents, Non-Steroidal Antirheumatic Agents Cyclooxygenase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action |