title: 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.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  A 2×2 factorial phase 3 randomized clinical trial among 320 patients requiring pleurodesis in 16 UK hospitals from 2007 to 2013.
  
  
  METHODS
  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]).
  
  
  METHODS
  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
  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.
  
  
  BACKGROUND
  isrctn.org Identifier: ISRCTN33288337.
authors.affiliation: Oxford Respiratory Trials Unit and Oxford Pleural Diseases Unit, Churchill Hospital, Oxford, England2National Institute for Health Research Oxford Biomedical Research Centre, University of Oxford, Oxford, England.
authors.forename: Najib M
authors.initials: NM
authors.lastname: Rahman
authors.affiliation: Somerset Lung Centre, Musgrove Park Hospital, Taunton, England.
authors.forename: Justin
authors.initials: J
authors.lastname: Pepperell
authors.affiliation: Medical Research Council Clinical Trials Unit at University College London, London, England.
authors.forename: Sunita
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authors.lastname: Rehal
authors.affiliation: Blackpool Teaching Hospitals NHS Foundation Trust, Blackpool, England.
authors.forename: Tarek
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authors.lastname: Saba
authors.affiliation: Blackpool Teaching Hospitals NHS Foundation Trust, Blackpool, England.
authors.forename: Augustine
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authors.affiliation: King's Mill Hospital, Mansfield, England.
authors.forename: Nabeel
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authors.affiliation: Medway Maritime Hospital, Gillingham, England.
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authors.affiliation: Medway Maritime Hospital, Gillingham, England.
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authors.affiliation: Basildon University Hospital, Basildon, England.
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authors.affiliation: Basildon University Hospital, Basildon, England.
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authors.lastname: Samuel
authors.affiliation: University Hospital of South Manchester NHS Foundation Trust, Manchester, England.
authors.forename: Andrew
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authors.affiliation: Royal Wolverhampton Hospital NHS Trust, Wolverhampton, England.
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authors.affiliation: Rotherham General Hospital, Rotherham, England.
authors.forename: Jonathan
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authors.affiliation: Vancouver Coastal Health, Vancouver, British Columbia, Canada.
authors.forename: C Frank
authors.initials: CF
authors.lastname: Ryan
authors.affiliation: University of California, Davis, Medical Center, Sacramento.
authors.forename: Ken Y
authors.initials: KY
authors.lastname: Yoneda
authors.affiliation: Queen Alexandra Hospital, Portsmouth, England.
authors.forename: Anoop
authors.initials: A
authors.lastname: Chauhan
authors.affiliation: Oxford Respiratory Trials Unit and Oxford Pleural Diseases Unit, Churchill Hospital, Oxford, England.
authors.forename: John P
authors.initials: JP
authors.lastname: Corcoran
authors.affiliation: Oxford Respiratory Trials Unit and Oxford Pleural Diseases Unit, Churchill Hospital, Oxford, England.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Psallidas
authors.affiliation: Oxford Respiratory Trials Unit and Oxford Pleural Diseases Unit, Churchill Hospital, Oxford, England2National Institute for Health Research Oxford Biomedical Research Centre, University of Oxford, Oxford, England.
authors.forename: John M
authors.initials: JM
authors.lastname: Wrightson
authors.affiliation: Oxford Respiratory Trials Unit and Oxford Pleural Diseases Unit, Churchill Hospital, Oxford, England.
authors.forename: Rob
authors.initials: R
authors.lastname: Hallifax
authors.affiliation: Cardiff and Vale University Health Board, Cardiff, Wales.
authors.forename: Helen E
authors.initials: HE
authors.lastname: Davies
authors.affiliation: School of Medicine and Centre for Asthma, Allergy, and Respiratory Research, University of Western Australia, Crawley, Australia.
authors.forename: Y C Gary
authors.initials: YC
authors.lastname: Lee
authors.affiliation: Oxford Respiratory Trials Unit and Oxford Pleural Diseases Unit, Churchill Hospital, Oxford, England.
authors.forename: Melissa
authors.initials: M
authors.lastname: Dobson
authors.affiliation: Oxford Respiratory Trials Unit and Oxford Pleural Diseases Unit, Churchill Hospital, Oxford, England.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Hedley
authors.affiliation: Department of Respiratory Medicine, Ipswich Hospital, Ipswich, England.
authors.forename: Douglas
authors.initials: D
authors.lastname: Seaton
authors.affiliation: Oxford Respiratory Trials Unit and Oxford Pleural Diseases Unit, Churchill Hospital, Oxford, England.
authors.forename: Nicky
authors.initials: N
authors.lastname: Russell
authors.affiliation: Oxford Respiratory Trials Unit and Oxford Pleural Diseases Unit, Churchill Hospital, Oxford, England.
authors.forename: Margaret
authors.initials: M
authors.lastname: Chapman
authors.affiliation: Oxford Respiratory Trials Unit and Oxford Pleural Diseases Unit, Churchill Hospital, Oxford, England.
authors.forename: Bethan M
authors.initials: BM
authors.lastname: McFadyen
authors.affiliation: Oxford Respiratory Trials Unit and Oxford Pleural Diseases Unit, Churchill Hospital, Oxford, England.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Shaw
authors.affiliation: Oxford Respiratory Trials Unit and Oxford Pleural Diseases Unit, Churchill Hospital, Oxford, England.
authors.forename: Robert J O
authors.initials: RJ
authors.lastname: Davies
authors.affiliation: Academic Respiratory Unit, Department of Clinical Sciences, Southmead Hospital, University of Bristol, Bristol, England.
authors.forename: Nick A
authors.initials: NA
authors.lastname: Maskell
authors.affiliation: Medical Research Council Clinical Trials Unit at University College London, London, England.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Nunn
authors.affiliation: Research Department of Infection and Population Health, Institute of Epidemiology and Healthcare, University College London, London, England.
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authors.lastname: Miller
mesh_terms: D000368:Aged; D000465:Algorithms; D000698:Analgesia / Q000379:methods; D000701:Analgesics, Opioid / Q000009:adverse effects / Q000627:therapeutic use*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000627:therapeutic use*; D015505:Chest Tubes / Q000009:adverse effects*; D016001:Confidence Intervals; D004867:Equipment Design; D005260:Female; D006801:Humans; D008297:Male; D059408:Pain Management / Q000379:methods*; D010147:Pain Measurement / Q000379:methods; D016066:Pleural Effusion, Malignant / Q000150:complications / Q000628:therapy*; D018700:Pleurodesis / Q000379:methods*; D016879:Salvage Therapy / Q000379:methods / Q000706:statistics & numerical data; D013906:Thoracoscopy / Q000295:instrumentation; D017211:Treatment Failure
chemical_list: D000701:Analgesics, Opioid; D000894:Anti-Inflammatory Agents, Non-Steroidal