[Skip to Content]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address Please contact the publisher to request reinstatement.
[Skip to Content Landing]
Cancer Statistics Registrations, England (Series MB1). Newport, Wales: Office of National Statistics, Stationary Office; 2010.
American Thoracic Society.  Management of malignant pleural effusions.  Am J Respir Crit Care Med. 2000;162(5):1987-2001.PubMedGoogle ScholarCrossref
Roberts  ME, Neville  E, Berrisford  RG, Antunes  G, Ali  NJ; BTS Pleural Disease Guideline Group.  Management of a malignant pleural effusion: British Thoracic Society Pleural Disease Guideline 2010.  Thorax. 2010;65(suppl 2):ii32-ii40.PubMedGoogle ScholarCrossref
Shaw  P, Agarwal  R.  Pleurodesis for malignant pleural effusions.  Cochrane Database Syst Rev. 2004;(1):CD002916.PubMedGoogle Scholar
Luketich  JD, Kiss  M, Hershey  J,  et al.  Chest tube insertion: a prospective evaluation of pain management.  Clin J Pain. 1998;14(2):152-154.PubMedGoogle ScholarCrossref
Horsley  A, Jones  L, White  J, Henry  M.  Efficacy and complications of small-bore, wire-guided chest drains.  Chest. 2006;130(6):1857-1863.PubMedGoogle ScholarCrossref
Rahman  NM, Maskell  NA, Davies  CW,  et al.  The relationship between chest tube size and clinical outcome in pleural infection.  Chest. 2010;137(3):536-543.PubMedGoogle ScholarCrossref
Lee  YC, Baumann  MH, Maskell  NA,  et al.  Pleurodesis practice for malignant pleural effusions in five English-speaking countries: survey of pulmonologists.  Chest. 2003;124(6):2229-2238.PubMedGoogle ScholarCrossref
Bandolier. Acute pain meta-analysis. 2003. http://www.medicine.ox.ac.uk/bandolier/booth/painpag/acute.html. Accessed November 26, 2015.
Hunt  I, Teh  E, Southon  R, Treasure  T.  Using non-steroidal anti-inflammatory drugs (NSAIDs) following pleurodesis.  Interact Cardiovasc Thorac Surg. 2007;6(1):102-104.PubMedGoogle ScholarCrossref
Ben-Nun  A, Golan  N, Faibishenko  I, Simansky  D, Soudack  M.  Nonsteroidal antiinflammatory medications: efficient and safe treatment following video-assisted pleurodesis for spontaneous pneumothorax.  World J Surg. 2011;35(11):2563-2567.PubMedGoogle ScholarCrossref
Parulekar  W, Di Primio  G, Matzinger  F, Dennie  C, Bociek  G.  Use of small-bore vs large-bore chest tubes for treatment of malignant pleural effusions.  Chest. 2001;120(1):19-25.PubMedGoogle ScholarCrossref
Clementsen  P, Evald  T, Grode  G, Hansen  M, Krag Jacobsen  G, Faurschou  P.  Treatment of malignant pleural effusion: pleurodesis using a small percutaneous catheter: a prospective randomized study.  Respir Med. 1998;92(3):593-596.PubMedGoogle ScholarCrossref
Parker  LA, Charnock  GC, Delany  DJ.  Small bore catheter drainage and sclerotherapy for malignant pleural effusions.  Cancer. 1989;64(6):1218-1221.PubMedGoogle ScholarCrossref
Collop  NA, Kim  S, Sahn  SA.  Analysis of tube thoracostomy performed by pulmonologists at a teaching hospital.  Chest. 1997;112(3):709-713.PubMedGoogle ScholarCrossref
Altman  DG, Bland  JM.  Treatment allocation by minimisation.  BMJ. 2005;330(7495):843.PubMedGoogle ScholarCrossref
Gallagher  EJ, Liebman  M, Bijur  PE.  Prospective validation of clinically important changes in pain severity measured on a visual analog scale.  Ann Emerg Med. 2001;38(6):633-638.PubMedGoogle ScholarCrossref
Nørholt  SE, Sindet-Pedersen  S, Larsen  U,  et al.  Pain control after dental surgery: a double-blind, randomised trial of lornoxicam vs morphine.  Pain. 1996;67(2-3):335-343.PubMedGoogle ScholarCrossref
Kahan  BC, Morris  TP.  Improper analysis of trials randomised using stratified blocks or minimisation.  Stat Med. 2012;31(4):328-340.PubMedGoogle ScholarCrossref
Rahman  NM, Maskell  NA, West  A,  et al.  Intrapleural use of tissue plasminogen activator and DNase in pleural infection.  N Engl J Med. 2011;365(6):518-526.PubMedGoogle ScholarCrossref
Bhatnagar  R, Laskawiec-Szkonter  M, Piotrowska  HE,  et al.  Evaluating the efficacy of thoracoscopy and talc poudrage vs pleurodesis using talc slurry (TAPPS trial): protocol of an open-label randomised controlled trial.  BMJ Open. 2014;4(11):e007045.PubMedGoogle ScholarCrossref
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

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