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

Najib M. Rahman, Justin Pepperell, Sunita Rehal, Tarek Saba, Augustine Tang, Nabeel Ali, Alex West, Gihan Hettiarachchi, Dipak Mukherjee, Johnson Samuel, Andrew Bentley, Lee Dowson, Jonathan Miles, C. Frank Ryan, Ken Y Yoneda, Anoop Chauhan, John P. Corcoran, Ioannis Psallidas, John M. Wrightson, Rob HallifaxHelen E. Davies, Y. C. Gary Lee, Melissa Dobson, Emma L. Hedley, Douglas Seaton, Nicky Russell, Margaret Chapman, Bethan M. McFadyen, Rachel A. Shaw, Robert J O Davies, Nick A. Maskell, Andrew J. Nunn, Robert F. Miller

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Abstract

Importance For treatment of malignant pleural effusion, nonsteroidal anti-inflammatory drugs (NSAIDs) are avoided because theymay reduce pleurodesis efficacy. Smaller chest tubesmay 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 tubewas in place (0-to100-mmvisual 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, 23.8mmvs 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, 22.0mmvs 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.

Original languageEnglish (US)
Pages (from-to)2641-2653
Number of pages13
JournalJAMA - Journal of the American Medical Association
Volume314
Issue number24
DOIs
StatePublished - Dec 22 2015

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Pleurodesis
Malignant Pleural Effusion
Chest Tubes
Opioid Analgesics
Anti-Inflammatory Agents
Randomized Controlled Trials
Opiate Alkaloids
Pain
Pharmaceutical Preparations
Thoracoscopy
Analgesia
Phase III Clinical Trials
Group Processes
Chest Pain

ASJC Scopus subject areas

  • Medicine(all)

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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. / Rahman, Najib M.; Pepperell, Justin; Rehal, Sunita; Saba, Tarek; Tang, Augustine; Ali, Nabeel; West, Alex; Hettiarachchi, Gihan; Mukherjee, Dipak; Samuel, Johnson; Bentley, Andrew; Dowson, Lee; Miles, Jonathan; Frank Ryan, C.; Yoneda, Ken Y; Chauhan, Anoop; Corcoran, John P.; Psallidas, Ioannis; Wrightson, John M.; Hallifax, Rob; Davies, Helen E.; Gary Lee, Y. C.; Dobson, Melissa; Hedley, Emma L.; Seaton, Douglas; Russell, Nicky; Chapman, Margaret; McFadyen, Bethan M.; Shaw, Rachel A.; Davies, Robert J O; Maskell, Nick A.; Nunn, Andrew J.; Miller, Robert F.

In: JAMA - Journal of the American Medical Association, Vol. 314, No. 24, 22.12.2015, p. 2641-2653.

Research output: Contribution to journalArticle

Rahman, NM, Pepperell, J, Rehal, S, Saba, T, Tang, A, Ali, N, West, A, Hettiarachchi, G, Mukherjee, D, Samuel, J, Bentley, A, Dowson, L, Miles, J, Frank Ryan, C, Yoneda, KY, Chauhan, A, Corcoran, JP, Psallidas, I, Wrightson, JM, Hallifax, R, Davies, HE, Gary Lee, YC, Dobson, M, Hedley, EL, Seaton, D, Russell, N, Chapman, M, McFadyen, BM, Shaw, RA, Davies, RJO, Maskell, NA, Nunn, AJ & Miller, RF 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', JAMA - Journal of the American Medical Association, vol. 314, no. 24, pp. 2641-2653. https://doi.org/10.1001/jama.2015.16840
Rahman, Najib M. ; Pepperell, Justin ; Rehal, Sunita ; Saba, Tarek ; Tang, Augustine ; Ali, Nabeel ; West, Alex ; Hettiarachchi, Gihan ; Mukherjee, Dipak ; Samuel, Johnson ; Bentley, Andrew ; Dowson, Lee ; Miles, Jonathan ; Frank Ryan, C. ; Yoneda, Ken Y ; Chauhan, Anoop ; Corcoran, John P. ; Psallidas, Ioannis ; Wrightson, John M. ; Hallifax, Rob ; Davies, Helen E. ; Gary Lee, Y. C. ; Dobson, Melissa ; Hedley, Emma L. ; Seaton, Douglas ; Russell, Nicky ; Chapman, Margaret ; McFadyen, Bethan M. ; Shaw, Rachel A. ; Davies, Robert J O ; Maskell, Nick A. ; Nunn, Andrew J. ; Miller, Robert F. / 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. In: JAMA - Journal of the American Medical Association. 2015 ; Vol. 314, No. 24. pp. 2641-2653.
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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 = "Importance For treatment of malignant pleural effusion, nonsteroidal anti-inflammatory drugs (NSAIDs) are avoided because theymay reduce pleurodesis efficacy. Smaller chest tubesmay 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 tubewas in place (0-to100-mmvisual 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, 23.8mmvs 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, 22.0mmvs 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.",
author = "Rahman, {Najib M.} and Justin Pepperell and Sunita Rehal and Tarek Saba and Augustine Tang and Nabeel Ali and Alex West and Gihan Hettiarachchi and Dipak Mukherjee and Johnson Samuel and Andrew Bentley and Lee Dowson and Jonathan Miles and {Frank Ryan}, C. and Yoneda, {Ken Y} and Anoop Chauhan and Corcoran, {John P.} and Ioannis Psallidas and Wrightson, {John M.} and Rob Hallifax and Davies, {Helen E.} and {Gary Lee}, {Y. C.} and Melissa Dobson and Hedley, {Emma L.} and Douglas Seaton and Nicky Russell and Margaret Chapman and McFadyen, {Bethan M.} and Shaw, {Rachel A.} and Davies, {Robert J O} and Maskell, {Nick A.} and Nunn, {Andrew J.} and Miller, {Robert F.}",
year = "2015",
month = "12",
day = "22",
doi = "10.1001/jama.2015.16840",
language = "English (US)",
volume = "314",
pages = "2641--2653",
journal = "JAMA - Journal of the American Medical Association",
issn = "0002-9955",
publisher = "American Medical Association",
number = "24",

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TY - JOUR

T1 - Effect of opioids vs NSAIDs and larger vs smaller chest tube size on pain control and pleurodesis efficacy among patients with malignant pleural effusion

T2 - The TIME1 Randomized Clinical Trial

AU - Rahman, Najib M.

AU - Pepperell, Justin

AU - Rehal, Sunita

AU - Saba, Tarek

AU - Tang, Augustine

AU - Ali, Nabeel

AU - West, Alex

AU - Hettiarachchi, Gihan

AU - Mukherjee, Dipak

AU - Samuel, Johnson

AU - Bentley, Andrew

AU - Dowson, Lee

AU - Miles, Jonathan

AU - Frank Ryan, C.

AU - Yoneda, Ken Y

AU - Chauhan, Anoop

AU - Corcoran, John P.

AU - Psallidas, Ioannis

AU - Wrightson, John M.

AU - Hallifax, Rob

AU - Davies, Helen E.

AU - Gary Lee, Y. C.

AU - Dobson, Melissa

AU - Hedley, Emma L.

AU - Seaton, Douglas

AU - Russell, Nicky

AU - Chapman, Margaret

AU - McFadyen, Bethan M.

AU - Shaw, Rachel A.

AU - Davies, Robert J O

AU - Maskell, Nick A.

AU - Nunn, Andrew J.

AU - Miller, Robert F.

PY - 2015/12/22

Y1 - 2015/12/22

N2 - Importance For treatment of malignant pleural effusion, nonsteroidal anti-inflammatory drugs (NSAIDs) are avoided because theymay reduce pleurodesis efficacy. Smaller chest tubesmay 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 tubewas in place (0-to100-mmvisual 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, 23.8mmvs 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, 22.0mmvs 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.

AB - Importance For treatment of malignant pleural effusion, nonsteroidal anti-inflammatory drugs (NSAIDs) are avoided because theymay reduce pleurodesis efficacy. Smaller chest tubesmay 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 tubewas in place (0-to100-mmvisual 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, 23.8mmvs 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, 22.0mmvs 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.

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