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Original Investigation
December 22/29, 2015

Effect of Opioids vs NSAIDs and Larger vs Smaller Chest Tube Size on Pain Control and Pleurodesis Efficacy Among Patients With Malignant Pleural Effusion: The TIME1 Randomized Clinical Trial

Author Affiliations
  • 1Oxford Respiratory Trials Unit and Oxford Pleural Diseases Unit, Churchill Hospital, Oxford, England
  • 2National Institute for Health Research Oxford Biomedical Research Centre, University of Oxford, Oxford, England
  • 3Somerset Lung Centre, Musgrove Park Hospital, Taunton, England
  • 4Medical Research Council Clinical Trials Unit at University College London, London, England
  • 5Blackpool Teaching Hospitals NHS Foundation Trust, Blackpool, England
  • 6King’s Mill Hospital, Mansfield, England
  • 7Medway Maritime Hospital, Gillingham, England
  • 8Basildon University Hospital, Basildon, England
  • 9University Hospital of South Manchester NHS Foundation Trust, Manchester, England
  • 10Royal Wolverhampton Hospital NHS Trust, Wolverhampton, England
  • 11Rotherham General Hospital, Rotherham, England
  • 12Vancouver Coastal Health, Vancouver, British Columbia, Canada
  • 13University of California, Davis, Medical Center, Sacramento
  • 14Queen Alexandra Hospital, Portsmouth, England
  • 15Cardiff and Vale University Health Board, Cardiff, Wales
  • 16School of Medicine and Centre for Asthma, Allergy, and Respiratory Research, University of Western Australia, Crawley, Australia
  • 17Department of Respiratory Medicine, Ipswich Hospital, Ipswich, England
  • 18Academic Respiratory Unit, Department of Clinical Sciences, Southmead Hospital, University of Bristol, Bristol, England
  • 19Research Department of Infection and Population Health, Institute of Epidemiology and Healthcare, University College London, London, England
    † Deceased.
JAMA. 2015;314(24):2641-2653. doi:10.1001/jama.2015.16840
Abstract

Importance  For treatment of malignant pleural effusion, nonsteroidal anti-inflammatory drugs (NSAIDs) are avoided because they may reduce pleurodesis efficacy. Smaller chest tubes may be less painful than larger tubes, but efficacy in pleurodesis has not been proven.

Objective  To assess the effect of chest tube size and analgesia (NSAIDs vs opiates) on pain and clinical efficacy related to pleurodesis in patients with malignant pleural effusion.

Design, Setting, and Participants  A 2×2 factorial phase 3 randomized clinical trial among 320 patients requiring pleurodesis in 16 UK hospitals from 2007 to 2013.

Interventions  Patients undergoing thoracoscopy (n = 206; clinical decision if biopsy was required) received a 24F chest tube and were randomized to receive opiates (n = 103) vs NSAIDs (n = 103), and those not undergoing thoracoscopy (n = 114) were randomized to 1 of 4 groups (24F chest tube and opioids [n = 28]; 24F chest tube and NSAIDs [n = 29]; 12F chest tube and opioids [n = 29]; or 12F chest tube and NSAIDs [n = 28]).

Main Outcomes and Measures  Pain while chest tube was in place (0- to 100-mm visual analog scale [VAS] 4 times/d; superiority comparison) and pleurodesis efficacy at 3 months (failure defined as need for further pleural intervention; noninferiority comparison; margin, 15%).

Results  Pain scores in the opiate group (n = 150) vs the NSAID group (n = 144) were not significantly different (mean VAS score, 23.8 mm vs 22.1 mm; adjusted difference, −1.5 mm; 95% CI, −5.0 to 2.0 mm; P = .40), but the NSAID group required more rescue analgesia (26.3% vs 38.1%; rate ratio, 2.1; 95% CI, 1.3-3.4; P = .003). Pleurodesis failure occurred in 30 patients (20%) in the opiate group and 33 (23%) in the NSAID group, meeting criteria for noninferiority (difference, −3%; 1-sided 95% CI, −10% to ∞; P = .004 for noninferiority). Pain scores were lower among patients in the 12F chest tube group (n = 54) vs the 24F group (n = 56) (mean VAS score, 22.0 mm vs 26.8 mm; adjusted difference, −6.0 mm; 95% CI, −11.7 to −0.2 mm; P = .04) and 12F chest tubes vs 24F chest tubes were associated with higher pleurodesis failure (30% vs 24%), failing to meet noninferiority criteria (difference, −6%; 1-sided 95% CI, −20% to ∞; P = .14 for noninferiority). Complications during chest tube insertion occurred more commonly with 12F tubes (14% vs 24%; odds ratio, 1.91; P = .20).

Conclusions and Relevance  Use of NSAIDs vs opiates resulted in no significant difference in pain scores but was associated with more rescue medication. NSAID use resulted in noninferior rates of pleurodesis efficacy at 3 months. Placement of 12F chest tubes vs 24F chest tubes was associated with a statistically significant but clinically modest reduction in pain but failed to meet noninferiority criteria for pleurodesis efficacy.

Trial Registration  isrctn.org Identifier: ISRCTN33288337

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