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

NCT04123873 | Completed Phase 4

• 1 other identifier: SM1-JOAST-2019
• Study Type: interventional
• Target: 1,060
• Locations: 1 country
• Sites: 7

Brief Summary

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.

Conditions

Pain, Acute; Hip Arthropathy; Analgesia; Postoperative Pain

Keywords

RECIPE; Hip arthroplasty; Postoperative pain; Analgesia; Multimodal analgesia; Non-opioid analgesia; Acute pain

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (4)

• Pain scores during mobilisation 24h

  24 hours after end of surgery

• Pain scores at rest 24h

  24 hours after end of surgery

• Maximum level of pain

  24 hours after end of surgery

• Adverse events in the intervention period

  From end of surgery + 24 hours

Other Outcomes (17)

• Serious adverse events within one year

  Within 90 days

• Pain scores during mobilisation 6h

  6 hours after end of surgery

• Pain scores at rest 6h

  6 hours after end of surgery

Study Arms (4)

Group A

EXPERIMENTAL

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; Drug: Ibuprofen; Drug: Placebo IV

Group B

EXPERIMENTAL

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; Drug: Dexamethasone; Drug: Placebo oral capsules

Group C

EXPERIMENTAL

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; Drug: Dexamethasone; Drug: Placebo oral capsules

Group D

EXPERIMENTAL

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; Drug: Ibuprofen; Drug: Dexamethasone

Interventions

Paracetamol DRUG

1g x 4 p.o.

Also known as: Acetaminophen

Group A; Group B; Group D

Ibuprofen DRUG

400mg x 4 p.o.

Group A; Group C; Group D

Dexamethasone DRUG

24mg IV x 1 after induction om anaesthesia

Group B; Group C; Group D

Placebo oral capsules DRUG

p.o. x 4

Group B; Group C

Placebo IV DRUG

IV x 1

Group A

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Naestved Hospital: lead

Study Sites (7)

Næstved-Slagelse-Ringsted Hospitals

Næstved, Danmark, 4700, Denmark

Location

Bispebjerg Hospital

Copenhagen, 2400, Denmark

Location

Gentofte Hospital

Hellerup, 2900, Denmark

Location

Hillerød Hospital

Hillerød, 3400, Denmark

Location

Køge Hospital

Køge, 4600, Denmark

Location

Odense University Hospital (OUH)

Odense, 5000, Denmark

Location

Svendborg Hospital

Svendborg, 5700, Denmark

Location

Related Publications (2)

• Steiness J, Hagi-Pedersen D, Lunn TH, Overgaard S, Brorson S, Graungaard BK, Lindberg-Larsen M, Varnum C, Lundstrom LH, Beck T, Skettrup M, Pedersen NA, Bieder MJ, von Cappeln AG, Pleckaitiene L, Lindholm P, Bukhari SSH, Derby CB, Nielsen MG, Exsteen OW, Vinstrup LO, Thybo KH, Gasbjerg KS, Norskov AK, Jakobsen JC, Mathiesen O; RECIPE trial group. Non-opioid analgesic combinations following total hip arthroplasty (RECIPE): a randomised, placebo-controlled, blinded, multicentre trial. Lancet Rheumatol. 2024 Apr;6(4):e205-e215. doi: 10.1016/S2665-9913(24)00020-1. Epub 2024 Mar 5.

  PMID: 38458208 DERIVED

• 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.

  PMID: 36190737 DERIVED

Related Links

• Trial website

MeSH Terms

Conditions

Acute Pain; Agnosia; Pain, Postoperative

Interventions

Acetaminophen; Ibuprofen; Dexamethasone

Condition Hierarchy (Ancestors)

Pain; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Perceptual Disorders; Neurobehavioral Manifestations; Nervous System Diseases; Postoperative Complications; Pathologic Processes

Intervention Hierarchy (Ancestors)

Acetanilides; Anilides; Amides; Organic Chemicals; Aniline Compounds; Amines; Phenylpropionates; Acids, Carbocyclic; Carboxylic Acids; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: 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
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 27, 2019
• First Posted: October 11, 2019
• Study Start: March 5, 2020
• Primary Completion: November 15, 2022
• Study Completion: February 15, 2023
• Last Updated: June 1, 2023

Record last verified: 2023-05

Locations

DK (7)