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

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

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.

Study Overview

• Status: Completed
• Conditions: Postoperative Pain; Analgesia; Pain, Acute; Hip Arthropathy
• Intervention / Treatment: Drug: Paracetamol; Drug: Ibuprofen; Drug: Placebo IV; Drug: Dexamethasone; Drug: Placebo oral capsules

• Study Type: Interventional
• Enrollment (Actual): 1060
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Daniel Hägi-Pedersen, MD, PhD; Phone Number: 0045 21517167; Email: dhag@regionsjaelland.dk
• Study Contact Backup: Name: Joakim Steiness, MD; Email: joast@regionsjaelland.dk

Study Locations

• Denmark
  • Copenhagen, Denmark, 2400
    • Bispebjerg Hospital
  • Hellerup, Denmark, 2900
    • Gentofte Hospital
  • Hillerød, Denmark, 3400
    • Hillerød Hospital
  • Køge, Denmark, 4600
    • Køge Hospital
  • Odense, Denmark, 5000
    • Odense University Hospital (OUH)
  • Svendborg, Denmark, 5700
    • Svendborg Hospital
  • Danmark
    • Næstved, Danmark, Denmark, 4700
      • Næstved-Slagelse-Ringsted Hospitals

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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 Names: Acetaminophen; Drug: Ibuprofen; 400mg x 4 p.o.; Drug: Placebo IV; IV x 1
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 Names: Acetaminophen; Drug: Dexamethasone; 24mg IV x 1 after induction om anaesthesia; Drug: Placebo oral capsules; p.o. x 4
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
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 Names: Acetaminophen; Drug: Ibuprofen; 400mg x 4 p.o.; Drug: Dexamethasone; 24mg IV x 1 after induction om anaesthesia

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serious adverse events within one year	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'	Within 90 days
Pain scores during mobilisation 6h	Pain scores (visual analogue scale (VAS 0-100 mm; no pain = 0; worst imaginable pain = 100)) with active 30 degrees flexion of the hip	6 hours after end of surgery
Pain scores at rest 6h	Pain scores at rest (VAS 0-100 mm; no pain = 0; worst imaginable pain = 100)	6 hours after end of surgery
Prevalence of nausea	Prevalence of nausea, 6 and 24 hours after end of surgery	6 and 24 hours after end of surgery
Number of vomiting episodes	The number of productive vomiting events (volume estimated over 10 ml) is recorded corresponding to the period 0-24 hours	0-24 after end of surgery. Reported by interview 24 hours after end of surgery
Consumption of ondansetron and dehydrobenzperidole	Consumption of ondansetron and dehydrobenzperidole in mg	0-24 hours after end of surgery
Incidence of dizziness during 5 meter walk	Incidence of dizziness during 5 meter walk 24 hours after surgery	24 hours after end of surgery
Blood loss	Blood loss in ml during the surgical procedure	Intraoperatively
Quality of sleep	Quality of sleep (VAS 0-100 mm; worst possible sleep = 0; best possible sleep = 100) Worst possible sleep = 0; best possible sleep = 100	24 hours after end of surgery
Days alive and outside hospital within 90 days after surgery	Days alive and outside hospital within 90 days after surgery	Within 90 days after surgery
Oxford Hip Score at 90 days	5-point Lipert-scale (no, mild, moderate, severe and extreme)	At 90 days after surgery
Quality of life (EQ-5D-5L) at 90 days	EuroQol five-dimensions 5 point Lipert scale (EQ-5D-5L)	At 90 days after surgery
Opioid use at 90 days	Consumption of opioids within 90 days after surgery	Within 90 days after surgery
Serious adverse events within 1 year	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')	Within one year after surgery
Oxford Hip Score at one year	5-point Lipert-scale (no, mild, moderate, severe and extreme)	One year after surgery
Quality of life (EQ-5D-5L) at one year	EuroQol five-dimensions 5 point Lipert scale (EQ-5D-5L)	One year after surgery
Opioid use at one year	Consumption of opioids within one year after surgery	Within one year after surgery

Collaborators and Investigators

• Sponsor: Naestved Hospital

Publications and helpful links

General Publications

• Steiness J, Hagi-Pedersen D, Lunn TH, Lindberg-Larsen M, Graungaard BK, Lundstrom LH, Lindholm P, Brorson S, Bieder MJ, Beck T, Skettrup M, von Cappeln AG, Thybo KH, Gasbjerg KS, Overgaard S, Jakobsen JC, Mathiesen O. Paracetamol, ibuprofen and dexamethasone for pain treatment after total hip arthroplasty: protocol for the randomised, placebo-controlled, parallel 4-group, blinded, multicentre RECIPE trial. BMJ Open. 2022 Sep 1;12(9):e058965. doi: 10.1136/bmjopen-2021-058965.

Helpful Links

• Trial website

Study record dates

Study Major Dates

• Study Start (Actual): March 5, 2020
• Primary Completion (Actual): November 15, 2022
• Study Completion (Actual): February 15, 2023

Study Registration Dates

• First Submitted: September 27, 2019
• First Submitted That Met QC Criteria: October 9, 2019
• First Posted (Actual): October 11, 2019

Study Record Updates

• Last Update Posted (Actual): June 1, 2023
• Last Update Submitted That Met QC Criteria: May 31, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Analgesia; Acute pain; Postoperative pain; Hip arthroplasty; Multimodal analgesia; RECIPE; Non-opioid analgesia
• Additional Relevant MeSH Terms: Pathologic Processes; Postoperative Complications; Pain; Neurologic Manifestations; Pain, Postoperative; Acute Pain; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Antipyretics; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Dexamethasone; Acetaminophen; Ibuprofen
• Other Study ID Numbers: SM1-JOAST-2019

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No