Single dose oral ketoprofen or dexketoprofen for acute postoperative pain in adults

Helen Gaskell; Sheena Derry; Philip J Wiffen; R Andrew Moore

doi:10.1002/14651858.CD007355.pub3

Однократная доза кетопрофена или декскетопрофена для приема внутрь при острой послеоперационной боли у взрослых

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Referencias

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References to other published versions of this review

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otras referencias

Barden J, Derry S, McQuay HJ, Moore RA. Single dose oral ketoprofen and dexketoprofen for acute postoperative pain in adults. Cochrane Database of Systematic Reviews 2009, Issue 4. [DOI: 10.1002/14651858.CD007355.pub2]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

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Akural 2009

Methods	RCT, DB, single oral dose, 4 parallel groups. Medication administered when baseline pain was of at least moderate intensity. Pain assessed at baseline and every 15 min to 2 h, then hourly to 8 h.
Participants	Surgical removal of 1 or 2 impacted third molars. N = 82 (84 cases; 2 participants had 2 operations), 76 (78 cases) assessed (4 protocol violations, 2 inadequate pain). M 31, F 45. Mean age: 23 years.
Interventions	Ketoprofen 100 mg, n = 20. Paracetamol 1000 mg, n = 18. Ketoprofen 100 mg + paracetamol 1000 mg, n = 20. Placebo, n = 20.
Outcomes	PI: standard 4‐point scale. Use of rescue medication. Time to use of rescue medication. AEs: any, serious. Withdrawals.
Notes	Oxford Quality Score: R1, DB2, W1. Participants asked to wait ≥ 1 h before using rescue medication.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"randomly assigned", "computer‐generated allocation schedule".
Allocation concealment (selection bias)	Unclear risk	Not described.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐dummy design, "patients were given identical sealed containers of study medication".
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Double‐dummy design, "patients were given identical sealed containers of study medication".
Size	High risk	< 50 participants per treatment arm.

Arnold 1990

Methods	RCT, DB, single oral dose, 4 parallel groups. Medication administered when baseline pain was of moderate to severe intensity. Pain assessed at 0, 30 min, and 1, 2, 3, 4, 5, 6 h.
Participants	General surgery (including gynaecological and orthopaedic). N = 59. M 35, F 24. Age: 22‐70 years.
Interventions	Ketoprofen 25 mg, n = 14. Ketoprofen 100 mg, n = 16. Ibuprofen 400 mg, n = 15. Placebo, n = 14.
Outcomes	PI: standard 4‐point scale. PR: standard 5‐point scale. PGE: standard 5‐point scale. Time to use of rescue medication. Number using rescue medication. AEs: any, serious.
Notes	Oxford Quality Score: R1, DB2, W0. 4‐h analgesic and anti‐inflammatory washout before surgery.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"computer‐generated randomization chart".
Allocation concealment (selection bias)	Unclear risk	Not described.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐dummy design.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Double‐dummy design.
Size	High risk	< 50 participants per treatment arm.

Balzanelli 1996

Methods	RCT, DB, 2 parallel groups, multiple dose study. Medication administered when baseline pain was of moderate to severe intensity, then every 8 h for total of 3 days. Pain assessed at 0, 30 min, and 1, 2, 3, 4, 5 ,6, 8 h, then daily.
Participants	Surgical removal of impacted third molars. N = 60. M 37, F 23. Mean age: approximately 37 years.
Interventions	Ketoprofen lysine 80 mg, n = 30. Placebo, n = 30.
Outcomes	PI: 0‐100‐mm VAS. PGE: standard 5‐point scale. AE: any, serious. Withdrawals. Tolerability 4‐point scale at end of study.
Notes	Oxford Quality Score: R1, DB2, W1.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method not reported.
Allocation concealment (selection bias)	Unclear risk	Method not reported.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"placebo indistinguishable".
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"placebo indistinguishable".
Size	High risk	< 50 participants per treatment arm.

Cooper 1984

Methods	RCT, DB, single oral dose, 5 parallel groups. Medication administered when baseline pain was of moderate to severe intensity. Pain assessed at 0, 30 min, and 1, 2, 3, 4, 5, 6 h.
Participants	Surgical removal of impacted third molars. N = 181 (153 analysed). M 48, F 105. Mean age: 23 years.
Interventions	Ketoprofen 25 mg, n = 30. Ketoprofen 50 mg, n = 31. Ketoprofen 100 mg, n = 31. Aspirin 650 mg, n = 31. Placebo, n = 30.
Outcomes	PI: standard 4‐point scale. PR: standard 5‐point scale. PGE: standard 5‐point scale. Time to use of rescue medication. AEs: any, serious. Withdrawals.
Notes	Oxford Quality Score: R1, DB2, W1. 6‐h analgesic, anti‐inflammatory, or sedative washout before surgery.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"randomized", method not reported.
Allocation concealment (selection bias)	Low risk	"each study medication bottle was identified only by a sequential code number".
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"all capsules in each bottle appeared identical".
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"all capsules in each bottle appeared identical".
Size	High risk	< 50 participants per treatment arm.

Cooper 1988

Methods	RCT, DB, single oral dose, 4 parallel groups. Medication administered when baseline pain was of moderate to severe intensity. Pain assessed at 0, 1, 2, 3, 4, 5, 6 h.
Participants	Surgical removal of impacted third molars. N = 181 (161 analysed). M 59, F 102. Mean age: 23 years.
Interventions	Ketoprofen 25 mg, n = 42. Ketoprofen 100 mg, n = 39. Ibuprofen 400 mg, n = 37. Placebo, n = 43.
Outcomes	PI: standard 4‐point scale. PR: standard 5‐point scale. PGE: standard 5‐point scale. Numbers of participants using rescue medication. Time to use of rescue medication. Numbers with any AE Withdrawals.
Notes	Oxford Quality Score: R1, DB2, W1.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"randomly allocated", method not reported.
Allocation concealment (selection bias)	Unclear risk	Method not described.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"units of medication appeared identical".
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"units of medication appeared identical".
Size	High risk	< 50 participants per treatment arm.

Cooper 1998

Methods	RCT, DB, single oral dose, 4 parallel groups. Medication administered when baseline pain was of moderate to severe intensity. Pain assessed at 0, 15, 30, 45 min, and 1, 2, 3, 4, 5, 6 h.
Participants	Surgical removal of impacted third molars. N = 177. M 75, F 102. Mean age: 23 years.
Interventions	Dexketoprofen 25 mg, n = 50. Dexketoprofen 100 mg, n = 51. Paracetamol 1000 mg, n = 50. Placebo, n = 26.
Outcomes	PI: 100‐mm VAS and standard 4‐point scale. PR: standard 5‐point scale. Time to use of rescue medication. Number using rescue medication. AEs: any, serious. Withdrawals.
Notes	Oxford Quality Score: R1, DB2, W1. Minimum 4‐h analgesic, caffeine, and sedative washout before surgery. Rescue medication permitted after 1 h.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"treatments were randomly allocated", method not reported.
Allocation concealment (selection bias)	Unclear risk	Method not described.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"study medications all appeared identical"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"study medications all appeared identical"
Size	High risk	< 50 participants in 3 of 4 treatment arms (range 26 to 51).

Gay 1996

Methods	RCT, DB, single oral dose, 5 parallel groups. Medication administered when baseline pain was of moderate to severe intensity. Pain assessed at 0, 15, 30, 45, 60, 90 min, and 2, 3, 4, 5, 6 h.
Participants	Surgical removal of impacted third molars. N = 206 (204 analysed). M 85, F 119. Mean age: 24 years.
Interventions	Dexketoprofen tromethamine 5 mg, n = 41. Dexketoprofen tromethamine 10 mg, n = 42. Dexketoprofen tromethamine 20 mg, n = 41. Ibuprofen 400 mg, n = 41. Placebo, n = 41.
Outcomes	PI: 100‐mm VAS and standard 4‐point scale. PR: standard 5‐point scale. PGE: non‐standard 4‐point scale. Time to use of rescue medication. Number using rescue medication. AEs: any, serious. Withdrawals.
Notes	Oxford Quality Score: R1, DB2, W1. 12‐h analgesic and anti‐inflammatory washout before surgery. Rescue medication permitted after 1 h.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"randomised", method not reported.
Allocation concealment (selection bias)	Unclear risk	Method not reported.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"study medication was identical in appearance to maintain blinding".
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"study medication was identical in appearance to maintain blinding".
Size	High risk	< 50 participants per treatment arm.

Harrison 1996

Methods	RCT, DB, single oral dose, 3 parallel groups. Medication administered when baseline pain was of moderate to severe intensity. Pain assessed at 0, 10, 20, 30, 45, 60, 90 min, and 2, 3, 4, 5, 6 h.
Participants	Surgical removal of impacted third molars. N = 141 (137 in efficacy analysis). M 63, F 78. Mean age: 26 years.
Interventions	Dexketoprofen tromethamine 12.5 mg, n = 49. Dexketoprofen tromethamine 25 mg, n = 46. Placebo, n = 46.
Outcomes	PI: 100‐mm VAS and standard 4‐point scale. PR: standard 5‐point scale. PGE: non‐standard 4‐point scale. Number using rescue medication. AEs: any, serious. Withdrawals.
Notes	Oxford Quality Score: R2, DB2, W1. 12‐h analgesic and anti‐inflammatory washout before surgery. Rescue medication permitted after 1 h.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Randomization list was generated by computer program"
Allocation concealment (selection bias)	Low risk	Generation of sequence, and preparation of code envelopes and study medication performed by third party; participants assigned consecutively.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"Double‐blind conditions", "tablets of identical size, colour and weight".
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"Double‐blind conditions", "tablets of identical size, colour and weight".
Size	High risk	< 50 participants per treatment arm.

Jackson 2004

Methods	RCT, DB, single oral dose, 5 parallel groups. Medication administered when baseline pain was of moderate to severe intensity. Pain assessed at 0, 15, 30, 45 min, and 1, 2, 3, 4, 5, 6, 7, 8, 24 h.
Participants	Surgical removal of impacted third molars. N = 123 (120 analysed). M 39, F 81. Mean age: 29 years.
Interventions	Dexketoprofen trometamol 25 mg, n = 42. Rofecoxib 50 mg, n = 37. Placebo, n = 41.
Outcomes	PI: standard 4‐point scale and 100‐mm VAS PR: standard 5‐point scale and 100‐mm VAS PGE: standard 5‐point scale. Time use of rescue medication. Number using rescue medication. AEs: any, serious. Withdrawals.
Notes	Oxford Quality Score: R1, DB2, W1. Rescue medication permitted after 1 h.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"randomized", method not reported.
Allocation concealment (selection bias)	Unclear risk	Randomisation carried out by third party, but method of allocation not described.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"Double blind", "All study drugs identical [in appearance] with patient numbers only on the packaging".
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"Double blind", "All study drugs identical [in appearance] with patient numbers only on the packaging".
Size	High risk	< 50 participants per treatment arm.

McGurk 1998

Methods	RCT, DB, single oral dose, 5 parallel groups. Medication administered when baseline pain was of moderate to severe intensity. Pain assessed at 0, 10, 20, 30, 45, 60, 90 min, and 2, 3, 4, 5, 6 h.
Participants	Surgical removal of impacted third molars. N = 210 (200 in efficacy analysis). M 88, F 122. Mean age: 28 years.
Interventions	Dexketoprofen trometamol 12.5 mg, n = 44. Dexketoprofen trometamol 25 mg, n = 41. Dexketoprofen trometamol 50 mg, n = 43. Ketoprofen 50 mg (racemic), n = 43. Placebo, n = 39.
Outcomes	PI: 100‐mm VAS and standard 4‐point scale. PR: standard 5‐point scale. PGE: non‐standard 4‐point scale. Number using rescue medication. AEs: any, serious. Withdrawals.
Notes	Oxford Quality Score: R2, DB2, W1. 12‐h analgesic and anti‐inflammatory washout before surgery. Rescue medication permitted after 1 h.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"randomization list generated by a computer program in blocks of five patients".
Allocation concealment (selection bias)	Unclear risk	Method not described.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"tablets of identical appearance to ensure double‐blind conditions".
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"tablets of identical appearance to ensure double‐blind conditions".
Size	High risk	< 50 participants per treatment arm.

McQuay 2016

Methods	Multicentre, RCT, DB (double‐dummy), multiple dose, placebo‐controlled (first dose), and active comparator, 4 parallel groups. Medication administered orally every 8 h over 5‐day period. First dose administered after cessation of postoperative analgesia once participants able to take oral medication and PI ≥ 40/100. Pain assessed at 30 min, and 1, 1.5, 2, 3, 4, 6, 8 h following first dose.
Participants	Standard unilateral total hip arthroplasty due to osteoarthritis. Age 18 to 80 years; moderate to severe pain at rest on day after surgery. N = 641. M 295, F 346. Mean age: 62 years (range 29 to 80). Baseline PI: moderate in 324, severe in 315.
Interventions	Single dose phase. Dexketoprofen 25 mg, n = 161. Tramadol 100 mg, n = 160. Dexketoprofen 25 mg + tramadol 75 mg, n = 159. Placebo, n = 161.
Outcomes	PI: 100‐mm VAS. PR: standard 5‐point VRS (0 = none, 4 = complete). PGE: standard 5‐point VRS (1 = poor, 5 = excellent) at 24 h or use of rescue medication/withdrawal. Use of rescue medication. Time to use of rescue medication. AEs. Withdrawals.
Notes	Oxford Quality Score: R2, DB2, W1. Rescue medication: metamizole 500 mg.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"computer‐generated randomization sequence stratified by baseline PI‐VAS categories [moderate pain (40 to 60) and severe pain (> 60) with an imbalanced 1:3:1:3:1:3 ratio, using block size of 12]".
Allocation concealment (selection bias)	Low risk	"Interactive Voice/Web Response (IVR/IWR) system".
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"double‐dummy design".
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"double‐dummy design".
Size	Unclear risk	50‐199 participants per treatment arm (range 159 to 161).

Mehlisch 1984

Methods	RCT, DB, single oral dose, 5 parallel groups. Medication administered when baseline pain was of moderate to severe intensity. Pain assessed at 0, 30 min, and 1, 2, 3, 4, 5, 6 h.
Participants	Surgical removal of impacted third molars. N = 138 (129 analysed). M/F not given. Mean age: 26 years.
Interventions	Ketoprofen 25 mg, n = 24. Ketoprofen 50 mg, n = 27. Ketoprofen 100 mg, n = 27. Codeine 90 mg, n = 27. Placebo, n = 24.
Outcomes	PI: standard 4‐point scale. PR: standard 5‐point scale. PGE: 5‐point scale (1 to 5 and reverse order). Number using rescue medication. AEs: any.
Notes	Oxford Quality Score: R1, DB2, W0. Minimum 3‐h analgesic, anti‐inflammatory, and psychotropic washout before surgery.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"random code", method not reported.
Allocation concealment (selection bias)	Unclear risk	Method not reported.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"double blind", "identical capsules".
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"double blind", "identical capsules".
Size	High risk	< 50 participants per treatment arm.

Moore 2015c

Methods	Multicentre, RCT, DB (double‐dummy), placebo‐controlled and active comparator, 10 parallel groups. Medication administered within 4 h of surgery when PI ≥ 40/100 and 4‐point VRS ≥ 2. Pain assessed at 0, 15, 30, 45 min, and 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24 h.
Participants	Outpatient surgical removal, under local anaesthesia, of ≥ 1 third molar (≥ fully or partially impacted in mandibular bone). N = 606 for efficacy, 611 for safety. M 247, F 359. Mean age: 27 years (range 18 to 64). Baseline PI: 64% moderate, 35% severe (3 mild, 2 missing data).
Interventions	Dexketoprofen 12.5 mg, n = 60. Dexketoprofen 25 mg, n = 60. Tramadol 37.5 mg, n = 59. Tramadol 75 mg, n = 59. Dexketoprofen 12.5 mg + tramadol 37.5 mg, n = 60. Dexketoprofen 12.5 mg + tramadol 75 mg, n = 62. Dexketoprofen 25 mg + tramadol 37.5 mg, n = 63. Dexketoprofen 25 mg + tramadol 75 mg, n = 61. Ibuprofen 400 mg, n = 60. Placebo, n = 62.
Outcomes	PI: standard 4‐point VRS (0 = none, 3 = severe). PR: standard 5‐point VRS (0 = none, 4 = complete). PGE: standard 5‐point VRS (1 = poor, 5 = excellent) at 24 h or use of rescue medication/withdrawal. Use of rescue medication. Time to use of rescue medication.
Notes	Oxford Quality Score: R2, DB2, W1. Rescue medication: paracetamol 1000 mg (maximum 4 doses in 24 h) after ≥ 1 h.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"computer‐generated" "blocked randomisation procedure, with block size of 10".
Allocation concealment (selection bias)	Low risk	"Interactive Voice/Web Response (IVR/IWR) system".
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"double‐dummy design".
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"double‐dummy design".
Size	Unclear risk	50‐199 participants per treatment arm (range 59 to 63).

Moore 2016

Methods	Multicentre, RCT, DB, placebo‐controlled and active control, 4 parallel groups. Single and multiple dose phases. Medication administered orally every 8 h over 3‐day period. First dose administered after cessation of postoperative analgesia once participants able to take oral medication and PI ≥ 40/100. Pain assessed at 30 min, and 1, 1.5, 2, 3, 4, 6, 8 h.
Participants	Abdominal hysterectomy for benign conditions. N = 606. All F. Mean age: 48 years (range 25 to 73). Baseline PI: moderate 38%, severe 62%.
Interventions	Dexketoprofen 25 mg, n = 151. Tramadol 100 mg, n = 150. Dexketoprofen 25 mg + tramadol 75 mg, n = 152. Placebo, n = 153.
Outcomes	PI: 100‐mm VAS. PR: standard 5‐point VRS (0 = none, 4 = complete). PGE: standard 5‐point VRS (1 = poor, 5 = excellent) at 8 h or use of rescue medication/withdrawal. Use of rescue medication. Time to use of rescue medication. AEs. Withdrawals.
Notes	Oxford Quality Score: R2, DB2, W1. Rescue medication: metamizole 500 mg.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"computer‐generated randomization sequence stratified by baseline PI‐VAS categories [moderate pain (40 to 60) and severe pain (> 60)] with an imbalanced 3:3:3:1:1:1 ratio, using block size of 12]".
Allocation concealment (selection bias)	Low risk	"Interactive Voice/Web Response (IVR/IWR) system".
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"double‐dummy design".
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"double‐dummy design".
Size	Unclear risk	50‐199 participants per treatment arm (range 150 to 153).

Olson 1999

Methods	RCT, DB, single dose oral liquid formulation of ketoprofen, 4 parallel groups. Medication administered when baseline pain was of severe intensity. Pain assessed at 0, 15, 30, 60, 90 min, and 2, 3, 4, 5, 6 h.
Participants	Episiotomy. N = 108 (terminated early, recruitment target N = 276). All F. Mean age: 24 years.
Interventions	Ketoprofen 25 mg liquid formulation, n = 28. Ketoprofen 50 mg liquid formulation, n = 26. Dipyrone 500 mg liquid formulation, n = 27. Placebo, n = 27.
Outcomes	PI: standard 4‐point scale. PR: standard 5‐point scale. PGE: non‐standard 4‐point scale. Time to use of rescue medication. Number using rescue medication. AEs; any, severe. Withdrawals.
Notes	Oxford Quality Score: R1, DB1, W1. 2 women entered with 2nd degree vaginal tears. Minimum 6‐h washout before surgery for any medication that could confound results.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"randomly assigned", method not described.
Allocation concealment (selection bias)	Unclear risk	Method not reported, medication assignment in sealed envelopes.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Study medications not identical in appearance. Nurse preparing study medication also administered it. A second nurse, blinded to the medication given, observed the woman.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Study medications not identical in appearance. Nurse preparing study medication also administered it. A second nurse, blinded to the medication given, observed the woman.
Size	High risk	< 50 participants per treatment arm.

Olson 2001

Methods	RCT, DB, triple dummy, single oral dose, 4 parallel groups. Medication administered when baseline pain was of moderate to severe intensity. Pain assessed at 0, 10, 20, 30, 45, 60, 90 min, and 2, 3, 4, 5, 6 h.
Participants	Surgical removal of impacted third molars. N = 239. M 76, F 163. Mean age: 23 years.
Interventions	Ketoprofen 25 mg, n = 67. Ibuprofen liquigel 400 mg, n = 67. Paracetamol 1000 mg, n = 66. Placebo, n = 39.
Outcomes	PI: 100‐mm VAS and standard 4‐point scale. PR: standard 5‐point scale. PGE: non‐standard 4‐point scale. Time to use of rescue medication. Number using rescue medication. AEs: any, serious. Withdrawals.
Notes	Oxford Quality Score: R1, DB2, W1. Analgesic and anti‐inflammatory washout before surgery (5 × half‐life).
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"randomization schedule generated by the sponsor", method not described.
Allocation concealment (selection bias)	Low risk	"Numbers were assigned to subjects in sequential order within the appropriate strata".
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Placebo capsules and caplets matched the active treatments; "all unit doses were identical in appearance".
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Placebo capsules and caplets matched the active treatments; "all unit doses were identical in appearance".
Size	High risk	< 50 participants in 1 of 4 treatment arms (range 39 to 67).

Schreiber 1996

Methods	RCT, DB, single and multiple oral dose phases, 4 parallel groups. Medication administered when baseline pain was of moderate to severe intensity. Pain assessed at 0, 30 min, and 1, 2, 4 h after the 1st dose.
Participants	Knee (meniscus or ligament reconstruction) or ankle surgery. N = 230. M 110, F 103. Mean age: 40 years.
Interventions	Dexketoprofen tromethamine 12.5 mg, n = 52. Dexketoprofen tromethamine 25 mg, n = 52. Ketoprofen 50 mg, n = 54. Placebo, n = 55.
Outcomes	PI: 100‐mm VAS and standard 4‐point scale. PR: standard 5‐point scale. PGE: non‐standard 4‐point scale. Number using rescue medication. Withdrawals.
Notes	Oxford Quality Score: R2, DB2, W1. 12‐h analgesic and anti‐inflammatory washout before surgery.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"randomisation list", in blocks of 8. Judged low risk as computer randomisation described in related studies carried out by same sponsor.
Allocation concealment (selection bias)	Low risk	Generation of sequence and preparation of code envelopes and study medication performed by third party; participants assigned consecutively.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"tablets of identical size, colour and weight", packaging indistinguishable except for randomisation number.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"tablets of identical size, colour and weight", packaging indistinguishable except for randomisation number.
Size	Unclear risk	50 to 199 participants per treatment arm (range 52 to 55)

Seymour 1996

Methods	R, DB, double dummy, single oral dose, 5 parallel groups. Medication administered when baseline pain was of moderate to severe intensity. Pain assessed at 0, 15, 30, 45, 60, 90 min, and 2, 3, 4, 5, 6 h.
Participants	Surgical removal of impacted third molars. N = 206. M 66, F 140. Mean age: 25 years.
Interventions	Ketoprofen 12.5 mg, n = 42. Ketoprofen 25 mg, n = 41. Paracetamol 500 mg, n = 41. Paracetamol 1000 mg, n = 41. Placebo, n = 41.
Outcomes	PGE: non‐standard 4‐point scale. Time to use of rescue medication. Number using rescue medication. AEs: any, serious. Withdrawals.
Notes	Oxford Quality Score: R1, DB2, W1. 12‐h analgesic washout before surgery.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"randomized trial", method not described.
Allocation concealment (selection bias)	Unclear risk	Method not described.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"double‐dummy technique", "ketoprofen dosages identical in appearance and standard paracetamol tablets were used. Matched placebos were prepared for both medications".
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"double‐dummy technique", "ketoprofen dosages identical in appearance and standard paracetamol tablets were used. Matched placebos were prepared for both medications".
Size	High risk	< 50 participants per treatment arm.

Seymour 2000

Methods	RCT, DB, single oral dose, 3 parallel groups Medication administered when baseline pain was of moderate to severe intensity. Pain assessed at 0, 15, 30, 45, 60, 90 min, and 2, 3, 4, 5, 6 h.
Participants	Surgical removal of impacted third molars. N = 180. M 58, F 122. Mean age: 27 years.
Interventions	Buffered ketoprofen 12.5 mg, n = 61. Ibuprofen 200 mg, n = 59. Placebo, n = 60.
Outcomes	PI: standard 4‐point scale. PR: 100‐mm VAS and standard 5‐point scale. PGE: non‐standard 4‐point scale. Time to use of rescue medication. Number using rescue medication. AEs: any, serious. Withdrawals.
Notes	Oxford Quality Score: R1, DB2, W1. 12‐h analgesic washout before surgery.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"randomized", method not described.
Allocation concealment (selection bias)	Unclear risk	Method not described.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"double‐dummy technique", "both tablets and dragees were of identical appearance, irrespective of their contents".
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"double‐dummy technique", "both tablets and dragees were of identical appearance, irrespective of their contents".
Size	Unclear risk	50‐199 participants per treatment arm.

Sunshine 1988

Methods	RCT, DB, single dose, parallel groups. Medication administered when baseline pain was of at least moderate intensity. Pain assessed at 0, 30, 60 min then hourly to 6 h.
Participants	Study 3. 'General surgery' procedures (details not reported). N = 123. All M (Veterans Administration hospital). Age: not reported.
Interventions	Ketoprofen 50 mg, n = 32. Ketoprofen 150 mg, n = 31. Paracetamol 650 mg + codeine 60 mg, n = 28. Placebo, n = 32.
Outcomes	PI: 4‐point VRS. PR: 5‐point VRS. PGE: 4‐point medication rating (0 = no help, 3 = excellent) and 7‐point VRS overall rating (1 = very much worse, 7 = very much better).
Notes	Oxford Quality Score: R1, DB1, W1.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomisation not specifically mentioned, but used the same methods as other studies described as randomised. Method of sequence generation not described. "The same general methods were used in all of the studies under discussion. All studies met current standards of well‐controlled trials"
Allocation concealment (selection bias)	Unclear risk	Not reported.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	"double‐blind", method not reported.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	"double‐blind", method not reported.
Size	High risk	< 50 participants per treatment arm.

Sunshine 1993

Methods	RCT, DB, single and multiple oral dose, parallel groups. Medication administered when baseline pain was of severe intensity. Pain assessed at 0, 30, 60 min then hourly to 8 h.
Participants	Caesarean section. N = 250. All F. Mean age: 26 years.
Interventions	Ketoprofen 50 mg, n = 48. Ketoprofen 100 mg, n = 48. Paracetamol 650 mg, n = 48. Paracetamol 650 mg + oxycodone 10 mg, n = 48. Placebo, n = 48.
Outcomes	PI: standard 4‐point scale. PR: 100‐mm VAS and standard 5‐point scale. PGE: non‐standard 4‐point scale. Time to use of rescue medication. Number using rescue medication. Withdrawals.
Notes	Oxford Quality Score: R1, DB2, W1.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"randomly assigned", method not described.
Allocation concealment (selection bias)	Unclear risk	Method not described.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"All study medication was identical in appearance".
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"All study medication was identical in appearance".
Size	High risk	< 50 participants per treatment arm.

Sunshine 1998

Methods	RCT, DB, single oral dose, 5 parallel groups. Medication administered when baseline pain was of severe intensity. Pain assessed at 0, 15, 30 min, and 1, 1.5, 2, 3, 3.5, 4, 5, 6 h.
Participants	Surgical removal of ≥ 1 impacted third molars. N = 179 (175 analysed for efficacy). M 58, F 117. Mean age: 22 years.
Interventions	Ketoprofen 6.25 mg, n = 35. Ketoprofen 12.5 mg, n = 35. Ketoprofen 25 mg, n = 35. Ibuprofen 200 mg, n = 35. Placebo, n = 35.
Outcomes	PI: standard 4‐point scale. PR: 100‐mm VAS and standard 5‐point scale. AEs: any, serious. Withdrawals.
Notes	Oxford Quality Score: R1, DB2, W1. 24‐h analgesic washout before surgery.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"randomly assigned", randomisation method not reported.
Allocation concealment (selection bias)	Unclear risk	Not reported.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"all study medication identical in appearance".
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"all study medication identical in appearance".
Size	Unclear risk	< 50 participants per treatment arm.

Turek 1988

Methods	RCT, DB, single oral dose, 3 parallel groups. Medication administered when baseline pain was of severe intensity. Pain assessed at 0, 30 min, and 1, 2, 3, 4, 5, 6 h
Participants	Elective surgery (113 orthopaedic, 23 abdominal, 11 gynaecology, 8 urology, and 6 miscellaneous procedures). N = 161 (160 analysed). M 81, F 81. Mean age: 47 years.
Interventions	Ketoprofen 50 mg, n = 41. Ketoprofen 150 mg, n = 39. Paracetamol 650 mg + codeine 60 mg, n = 39. Placebo, n = 42.
Outcomes	PI: standard 4‐point scale. PR: standard 5‐point scale. PGE: non‐standard 4‐point scale. Time to use of rescue medication. Number using rescue medication. AEs: any, serious. Withdrawals.
Notes	Oxford Quality Score: R1, DB2, W1. 3‐h analgesic and anti‐inflammatory washout before surgery. Rescue medication permitted after 1 h.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"randomized", method not described.
Allocation concealment (selection bias)	Unclear risk	Method not described.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	"double‐blind", method not described.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	"double‐blind", method not described.
Size	High risk	< 50 participants per treatment arm.

Vidal 1999

Methods	RCT, DB, single and multiple oral dose phases, 4 parallel groups. Medication administered when baseline pain was of severe intensity. Pain assessed at 0, 15, 30, 45 min, and 1, 2, 3, 4, 5, 6 h for single dose phase.
Participants	Hallux vagus (bunion) surgery. N = 188 (172 analysed). M 25, F 163. Mean age: 54 years.
Interventions	Dexketoprofen trometamol 12.5 mg, n = 47. Dexketoprofen trometamol 25 mg, n = 47. Ketoprofen 50 mg, n = 47. Placebo, n = 47.
Outcomes	PI: 100‐mm VAS and standard 4‐point scale. PR: standard 5‐point scale. PGE: non‐standard 4‐point scale. Time to use of rescue medication. Number using rescue medication. Withdrawals.
Notes	Oxford Quality Score: R2, DB2, W1. Rescue medication via PCA morphine.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation "by computer program" for each centre.
Allocation concealment (selection bias)	Low risk	Generation of sequence, and preparation of code envelopes and study medication performed by third party; allocation "in chronological order of inclusion in each centre".
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"All the treatments .... were tablets of identical size, colour and weight".
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"All the treatments .... were tablets of identical size, colour and weight".
Size	High risk	< 50 participants per treatment arm.

AE: adverse event; DB: double blind; F: female; h: hour; M: male; min: minute; N: number of participants in study; n: number of participants in treatment arm; PCA: patient‐controlled analgesia; PGE: Patient Global Evaluation of efficacy; PI: pain intensity; PR: pain relief; R: randomised (Oxford Quality Score); RCT: randomised controlled trial; VAS: visual analogue scale (see 'Glossary'; Appendix 4); VRS: verbal rating scale; W: withdrawal (Oxford Quality Score).

Characteristics of excluded studies [ordered by study ID]

Ir a:

estudios incluidos
estudios a la espera de clasificación

Study	Reason for exclusion
Avila 1991	No placebo, no baseline pain.
Bagan 1998	No placebo.
Berti 2000	No placebo, preoperative administration.
Esparza‐Villalpando 2016	No relevant control for postoperative administration, intervention given irrespective of baseline pain intensity.
Gallardo 1982	3‐hour study period, no 4‐hour data.
Giudice 1987	No placebo.
Jimenez‐Martinez 2004	No placebo.
Kantor 1984	Included women with uterine cramps.
Letarget 1998	No placebo.
Lobo 1983	3‐hour study period, no 4‐hour data.
Olmedo 2001	No 4‐ to 6‐hour data reported.
Perez 2002	No placebo.
Schreiber 1998	No placebo.
Sunshine 1986	Included women with uterine cramps.
Tufano 1981	Study not randomised or double blind. Intravenous route.
Zapata 2000	No placebo.

Characteristics of studies awaiting assessment [ordered by study ID]

Ir a:

estudios incluidos
estudios excluidos

Yatomi 1979

Methods
Participants
Interventions
Outcomes
Notes	Japanese ‐ unable to obtain copy.

Data and analyses

Open in table viewer

Comparison 1. Ketoprofen 12.5 mg versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Participants with ≥ 50% pain relief over 6 hours Show forest plot	3	274	Risk Ratio (M‐H, Fixed, 95% CI)	4.21 [2.68, 6.63]
Open in figure viewer Analysis 1.1 Comparison 1 Ketoprofen 12.5 mg versus placebo, Outcome 1 Participants with ≥ 50% pain relief over 6 hours.
2 Participants using rescue medication over 6 hours Show forest plot	2	198	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.74, 0.90]
Open in figure viewer Analysis 1.2 Comparison 1 Ketoprofen 12.5 mg versus placebo, Outcome 2 Participants using rescue medication over 6 hours.
3 Participants with any adverse event Show forest plot	3	274	Risk Ratio (M‐H, Fixed, 95% CI)	1.33 [0.48, 3.64]
Open in figure viewer Analysis 1.3 Comparison 1 Ketoprofen 12.5 mg versus placebo, Outcome 3 Participants with any adverse event.

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Comparison 2. Ketoprofen 25 mg versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Participants with ≥ 50% pain relief over 6 hours Show forest plot	8	535	Risk Ratio (M‐H, Fixed, 95% CI)	4.88 [3.48, 6.85]
Open in figure viewer Analysis 2.1 Comparison 2 Ketoprofen 25 mg versus placebo, Outcome 1 Participants with ≥ 50% pain relief over 6 hours.
1.1 Dental surgery	6	452	Risk Ratio (M‐H, Fixed, 95% CI)	5.07 [3.50, 7.36]
1.2 Other surgery	2	83	Risk Ratio (M‐H, Fixed, 95% CI)	3.96 [1.77, 8.86]
2 Participants using rescue medication over 6 hours Show forest plot	6	402	Risk Ratio (M‐H, Fixed, 95% CI)	0.60 [0.52, 0.69]
Open in figure viewer Analysis 2.2 Comparison 2 Ketoprofen 25 mg versus placebo, Outcome 2 Participants using rescue medication over 6 hours.
3 Participants with any adverse event Show forest plot	7	490	Risk Ratio (M‐H, Fixed, 95% CI)	1.15 [0.68, 1.96]
Open in figure viewer Analysis 2.3 Comparison 2 Ketoprofen 25 mg versus placebo, Outcome 3 Participants with any adverse event.

Open in table viewer

Comparison 3. Ketoprofen 50 mg versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Participants with ≥ 50% pain relief over 4‐6 hours Show forest plot	8	594	Risk Ratio (M‐H, Fixed, 95% CI)	2.49 [1.97, 3.14]
Open in figure viewer Analysis 3.1 Comparison 3 Ketoprofen 50 mg versus placebo, Outcome 1 Participants with ≥ 50% pain relief over 4‐6 hours.
1.1 Dental surgery	3	190	Risk Ratio (M‐H, Fixed, 95% CI)	9.04 [4.23, 19.30]
1.2 Other surgery	5	404	Risk Ratio (M‐H, Fixed, 95% CI)	1.79 [1.40, 2.28]
2 Participants using rescue medication over 6‐8 hours Show forest plot	6	468	Risk Ratio (M‐H, Fixed, 95% CI)	0.56 [0.47, 0.66]
Open in figure viewer Analysis 3.2 Comparison 3 Ketoprofen 50 mg versus placebo, Outcome 2 Participants using rescue medication over 6‐8 hours.
2.1 6 hours	4	263	Risk Ratio (M‐H, Fixed, 95% CI)	0.42 [0.33, 0.54]
2.2 8 hours	2	205	Risk Ratio (M‐H, Fixed, 95% CI)	0.77 [0.61, 0.98]
3 Participants with any adverse event Show forest plot	5	342	Risk Ratio (M‐H, Fixed, 95% CI)	1.64 [0.98, 2.75]
Open in figure viewer Analysis 3.3 Comparison 3 Ketoprofen 50 mg versus placebo, Outcome 3 Participants with any adverse event.

Open in table viewer

Comparison 4. Ketoprofen 80 mg or 100 mg versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Participants with ≥ 50% pain relief Show forest plot	6	381	Risk Ratio (M‐H, Fixed, 95% CI)	4.29 [3.02, 6.08]
Open in figure viewer Analysis 4.1 Comparison 4 Ketoprofen 80 mg or 100 mg versus placebo, Outcome 1 Participants with ≥ 50% pain relief.
1.1 Dental surgery	4	255	Risk Ratio (M‐H, Fixed, 95% CI)	8.33 [4.67, 14.86]
1.2 Other surgery	2	126	Risk Ratio (M‐H, Fixed, 95% CI)	1.94 [1.26, 3.00]
2 Participants using rescue medication over 6‐8 hours Show forest plot	4	259	Risk Ratio (M‐H, Fixed, 95% CI)	0.54 [0.44, 0.67]
Open in figure viewer Analysis 4.2 Comparison 4 Ketoprofen 80 mg or 100 mg versus placebo, Outcome 2 Participants using rescue medication over 6‐8 hours.
2.1 6 hours	3	163	Risk Ratio (M‐H, Fixed, 95% CI)	0.49 [0.38, 0.65]
2.2 8 hours	1	96	Risk Ratio (M‐H, Fixed, 95% CI)	0.63 [0.44, 0.89]
3 Participants with any adverse event Show forest plot	3	175	Risk Ratio (M‐H, Fixed, 95% CI)	1.19 [0.65, 2.16]
Open in figure viewer Analysis 4.3 Comparison 4 Ketoprofen 80 mg or 100 mg versus placebo, Outcome 3 Participants with any adverse event.

Open in table viewer

Comparison 5. Dexketoprofen 10 mg or 12.5 mg versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Participants with ≥ 50% pain relief over 4‐6 hours Show forest plot	5	480	Risk Ratio (M‐H, Fixed, 95% CI)	2.43 [1.79, 3.28]
Open in figure viewer Analysis 5.1 Comparison 5 Dexketoprofen 10 mg or 12.5 mg versus placebo, Outcome 1 Participants with ≥ 50% pain relief over 4‐6 hours.
1.1 Dental surgery	4	373	Risk Ratio (M‐H, Fixed, 95% CI)	3.16 [2.08, 4.80]
1.2 Other surgery	1	107	Risk Ratio (M‐H, Fixed, 95% CI)	1.53 [1.00, 2.35]
2 Participants using rescue medication over 6‐8 hours Show forest plot	5	480	Risk Ratio (M‐H, Fixed, 95% CI)	0.68 [0.58, 0.81]
Open in figure viewer Analysis 5.2 Comparison 5 Dexketoprofen 10 mg or 12.5 mg versus placebo, Outcome 2 Participants using rescue medication over 6‐8 hours.
2.1 6 hours	4	373	Risk Ratio (M‐H, Fixed, 95% CI)	0.73 [0.61, 0.86]
2.2 8 hours	1	107	Risk Ratio (M‐H, Fixed, 95% CI)	0.49 [0.30, 0.82]
3 Participants with any adverse event Show forest plot	4	380	Risk Ratio (M‐H, Fixed, 95% CI)	0.70 [0.36, 1.35]
Open in figure viewer Analysis 5.3 Comparison 5 Dexketoprofen 10 mg or 12.5 mg versus placebo, Outcome 3 Participants with any adverse event.

Open in table viewer

Comparison 6. Dexketoprofen 20 mg or 25 mg versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Participants with ≥ 50% pain relief over 4‐6 hours Show forest plot	8	1177	Risk Ratio (M‐H, Fixed, 95% CI)	1.96 [1.68, 2.28]
Open in figure viewer Analysis 6.1 Comparison 6 Dexketoprofen 20 mg or 25 mg versus placebo, Outcome 1 Participants with ≥ 50% pain relief over 4‐6 hours.
1.1 Dental surgery	5	444	Risk Ratio (M‐H, Fixed, 95% CI)	4.66 [3.12, 6.95]
1.2 Other surgery	3	733	Risk Ratio (M‐H, Fixed, 95% CI)	1.48 [1.26, 1.74]
2 Participants using rescue medication over 6‐8 hours Show forest plot	7	635	Risk Ratio (M‐H, Fixed, 95% CI)	0.68 [0.59, 0.77]
Open in figure viewer Analysis 6.2 Comparison 6 Dexketoprofen 20 mg or 25 mg versus placebo, Outcome 2 Participants using rescue medication over 6‐8 hours.
2.1 6 hours	5	445	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.56, 0.78]
2.2 8 hours	2	190	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.57, 0.89]
3 Participants with any adverse event Show forest plot	6	536	Risk Ratio (M‐H, Fixed, 95% CI)	1.41 [0.89, 2.23]
Open in figure viewer Analysis 6.3 Comparison 6 Dexketoprofen 20 mg or 25 mg versus placebo, Outcome 3 Participants with any adverse event.

Figure 1

Study flow diagram.

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Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Figure 3

Forest plot of comparison: 3 Ketoprofen 50 mg versus placebo, outcome: 3.1 Participants with at least 50% pain relief over four to six hours.

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Figure 4

Ketoprofen 50 mg: percent of participants with at least 50% pain relief over four to six hours. Size of circle is proportional to size of study (inset scale). Dental studies: yellow; bunionectomy study: dark blue; other non‐dental studies: light blue.

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Figure 5

Forest plot of comparison: 6 Dexketoprofen 20 mg or 25 mg versus placebo, outcome: 6.1 Participants with at least 50% pain relief over four to six hours.

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Figure 6

Dexketoprofen 20/25 mg: percent of participants with at least 50% pain relief over four to six hours. Size of circle is proportional to size of study (inset scale). Dental studies: yellow; bunionectomy study: dark blue; other non‐dental studies: light blue.

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Analysis 1.1

Comparison 1 Ketoprofen 12.5 mg versus placebo, Outcome 1 Participants with ≥ 50% pain relief over 6 hours.

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Analysis 1.2

Comparison 1 Ketoprofen 12.5 mg versus placebo, Outcome 2 Participants using rescue medication over 6 hours.

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Analysis 1.3

Comparison 1 Ketoprofen 12.5 mg versus placebo, Outcome 3 Participants with any adverse event.

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Analysis 2.1

Comparison 2 Ketoprofen 25 mg versus placebo, Outcome 1 Participants with ≥ 50% pain relief over 6 hours.

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Analysis 2.2

Comparison 2 Ketoprofen 25 mg versus placebo, Outcome 2 Participants using rescue medication over 6 hours.

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Analysis 2.3

Comparison 2 Ketoprofen 25 mg versus placebo, Outcome 3 Participants with any adverse event.

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Analysis 3.1

Comparison 3 Ketoprofen 50 mg versus placebo, Outcome 1 Participants with ≥ 50% pain relief over 4‐6 hours.

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Analysis 3.2

Comparison 3 Ketoprofen 50 mg versus placebo, Outcome 2 Participants using rescue medication over 6‐8 hours.

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Analysis 3.3

Comparison 3 Ketoprofen 50 mg versus placebo, Outcome 3 Participants with any adverse event.

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Analysis 4.1

Comparison 4 Ketoprofen 80 mg or 100 mg versus placebo, Outcome 1 Participants with ≥ 50% pain relief.

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Analysis 4.2

Comparison 4 Ketoprofen 80 mg or 100 mg versus placebo, Outcome 2 Participants using rescue medication over 6‐8 hours.

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Analysis 4.3

Comparison 4 Ketoprofen 80 mg or 100 mg versus placebo, Outcome 3 Participants with any adverse event.

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Analysis 5.1

Comparison 5 Dexketoprofen 10 mg or 12.5 mg versus placebo, Outcome 1 Participants with ≥ 50% pain relief over 4‐6 hours.

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Analysis 5.2

Comparison 5 Dexketoprofen 10 mg or 12.5 mg versus placebo, Outcome 2 Participants using rescue medication over 6‐8 hours.

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Analysis 5.3

Comparison 5 Dexketoprofen 10 mg or 12.5 mg versus placebo, Outcome 3 Participants with any adverse event.

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Analysis 6.1

Comparison 6 Dexketoprofen 20 mg or 25 mg versus placebo, Outcome 1 Participants with ≥ 50% pain relief over 4‐6 hours.

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Analysis 6.2

Comparison 6 Dexketoprofen 20 mg or 25 mg versus placebo, Outcome 2 Participants using rescue medication over 6‐8 hours.

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Analysis 6.3

Comparison 6 Dexketoprofen 20 mg or 25 mg versus placebo, Outcome 3 Participants with any adverse event.

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Summary of findings for the main comparison. Ketoprofen 25 mg compared with placebo for acute postoperative pain

Ketoprofen 25 mg compared with placebo for acute postoperative pain
Patient or population: adults with moderate or severe acute postoperative pain Settings: clinic or hospital Intervention: ketoprofen 25 mg Comparison: placebo
Outcomes	Probable outcome with intervention	Probable outcome with placebo	RR, NNT, NNTp, or NNH (95% CI)	Number of studies, participants, or events	Quality of the evidence (GRADE)	Comments
Participants with ≥ 50% pain relief over 6 hours	620 in 1000	120 in 1000	RR 4.9 (3.5 to 6.9) NNT 2.0 (1.8 to 2.3)	8 studies 535 participants	High quality	Good quality studies, important outcome available, robust numbers.
Median (mean) time to use of rescue medication	5.3 hours (4.6 hours)	1.6 hours (2.5 hours)	Not estimated	2 studies 188 participants (5 studies 277 participants)	Very low quality	Small numbers of participants.
Participants using rescue medication over 6 hours	460 in 1000	79 in 1000	RR 0.60 (0.52 to 0.69) NNTp 3.0 (2.4 to 4.1)	6 studies 402 participants	Moderate	Modest numbers of participants and events.
Participants with ≥ 1 adverse event following a single dose	100 in 1000	91 in 1000	RR 1.2 (0.68 to 2.0) NNH not calculated	7 studies 490 participants	High quality	Good quality studies, important outcome available, robust numbers.
Participants with a serious adverse event following a single dose	No serious adverse events reported		Not estimated	8 studies 535 participants	Very low quality	No events in single dose studies not designed to evaluate serious but rare adverse events.
CI: confidence interval; NNH: number needed to treat for an additional harmful outcome; NNT: number needed to treat for an additional beneficial outcome; NNTp: number needed to treat to prevent an additional outcome: RR: risk ratio.
We used the following descriptors for levels of evidence (EPOC 2015). High: this research provides a very good indication of the likely effect. The likelihood that the effect will be substantially different^a is low. Moderate: this research provides a good indication of the likely effect. The likelihood that the effect will be substantially different^a is moderate. Low: this research provides some indication of the likely effect. However, the likelihood that it will be substantially different^a is high. Very low: this research does not provide a reliable indication of the likely effect. The likelihood that the effect will be substantially different^a is very high. ^a Substantially different: a large enough difference that it might affect a decision.

Summary of findings for the main comparison. Ketoprofen 25 mg compared with placebo for acute postoperative pain

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Summary of findings 2. Ketoprofen 50 mg compared with placebo for acute postoperative pain

Ketoprofen 50 mg compared with placebo for acute postoperative pain
Patient or population: adults with moderate or severe acute postoperative pain Settings: clinic or hospital Intervention: ketoprofen 50 mg Comparison: placebo
Outcomes	Probable outcome with intervention	Probable outcome with placebo	RR, NNT, NNTp, or NNH (95% CI)	Number of studies, participants, or events	Quality of the evidence (GRADE)	Comments
Participants with ≥ 50% pain relief over 4‐6 hours	570 in 1000	230 in 1000	RR 2.5 (2.0 to 3.1) NNT 2.9 (2.4 to 3.7)	8 studies 594 participants	High quality	Good quality studies, important outcome available, robust numbers.
Median (mean) time to use of rescue medication	Approximately 5 hours (3.4 hours)	Approximately 3 hours (2.5 hours)	Not estimated	1 study 77 participants (5 studies, 342 participants)	Very low quality	Small numbers of participants.
Participants using rescue medication over 6 hours	320 in 1000	750 in 1000	RR 0.42 (0.33 to 0.52) NNTp 2.3 (1.8 to 3.1)	4 studies 263 participants	High quality	Reasonable numbers of participants and high event rate.
Participants with ≥ 1 adverse event following a single dose	180 in 1000	110 in 1000	RR 1.6 (0.98 to 2.8) NNH not calculated	5 studies 342 participants	High quality	Good quality studies, important outcome available, robust numbers.
Participants with a serious adverse event following a single dose	No serious adverse events reported		Not estimated	9 studies 688 participants	Very low quality	No events in single dose studies not designed to evaluate serious but rare adverse events
CI: confidence interval; NNH: number needed to treat for an additional harmful outcome; NNT: number needed to treat for an additional beneficial outcome; NNTp: number needed to treat to prevent an additional outcome: RR: risk ratio.
We used the following descriptors for levels of evidence (EPOC 2015). High: this research provides a very good indication of the likely effect. The likelihood that the effect will be substantially different^a is low. Moderate: this research provides a good indication of the likely effect. The likelihood that the effect will be substantially different^a is moderate. Low: this research provides some indication of the likely effect. However, the likelihood that it will be substantially different^a is high. Very low: this research does not provide a reliable indication of the likely effect. The likelihood that the effect will be substantially different^a is very high. ^a Substantially different: a large enough difference that it might affect a decision.

Summary of findings 2. Ketoprofen 50 mg compared with placebo for acute postoperative pain

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Summary of findings 3. Dexketoprofen 10 mg‐12.5 mg compared with placebo for acute postoperative pain

Dexketoprofen 10 mg‐12.5 mg compared with placebo for acute postoperative pain
Patient or population: adults with moderate or severe acute postoperative pain Settings: clinic or hospital Intervention: dexketoprofen 10 mg‐12.5 mg Comparison: placebo
Outcomes	Probable outcome with intervention	Probable outcome with placebo	RR, NNT, NNTp, or NNH (95% CI)	Number of studies, participants, or events	Quality of the evidence (GRADE)	Comments
Participants with ≥ 50% pain relief over 4‐6 hours	440 in 1000	180 in 1000	RR 2.4 (1.8 to 3.3) NNT 3.9 (3.0 to 5.7)	5 studies 480 participants	High quality	Good quality studies, important outcome available, robust numbers.
Median (mean) time to use of rescue medication	3.6 hours (4.9 hours)	1.4 hours (3.6 hours)	Not estimated	1 study 122 participants (3 studies 253 participants)	Very low quality	Small numbers of participants.
Participants using rescue medication over 6 hours	490 in 1000	680 in 1000	RR 0.73 (0.61 to 0.86) NNTp 5.3 (3.5 to 11)	4 studies 373 participants	High quality	Reasonable numbers of participants and high event rate.
Participants with ≥ 1 adverse event following a single dose	68 in 1000	96 in 1000	RR 0.70 (0.36 to 1.4) NNH not calculated	4 studies 380 participants	High quality	Good quality studies, important outcome available, robust numbers.
Participants with a serious adverse event following a single dose	No serious adverse events reported		Not estimated	6 studies 574 participants	Very low quality	No events in single dose studies not designed to evaluate serious but rare adverse events.
CI: confidence interval; NNH: number needed to treat for an additional harmful outcome; NNT: number needed for an additional beneficial outcome; NNTp: number needed to treat to prevent an additional outcome: RR: risk ratio.
We used the following descriptors for levels of evidence (EPOC 2015). High: this research provides a very good indication of the likely effect. The likelihood that the effect will be substantially different^a is low. Moderate: this research provides a good indication of the likely effect. The likelihood that the effect will be substantially different^a is moderate. Low: this research provides some indication of the likely effect. However, the likelihood that it will be substantially different^a is high. Very low: this research does not provide a reliable indication of the likely effect. The likelihood that the effect will be substantially different^a is very high. ^a Substantially different: a large enough difference that it might affect a decision.

Summary of findings 3. Dexketoprofen 10 mg‐12.5 mg compared with placebo for acute postoperative pain

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Summary of findings 4. Dexketoprofen 20 mg or 25 mg compared with placebo for acute postoperative pain

Dexketoprofen 20 mg or 25 mg compared with placebo for acute postoperative pain
Patient or population: adults with moderate or severe acute postoperative pain Settings: clinic or hospital Intervention: dexketoprofen 20 mg or 25 mg Comparison: placebo
Outcomes	Probable outcome with intervention	Probable outcome with placebo	RR, NNT, NNTp, or NNH (95% CI)	Number of studies, participants, or events	Quality of the evidence (GRADE)	Comments
Participants with ≥ 50% pain relief over 4‐6 hours	520 in 1000	270 in 1000	RR 2.0 (1.6 to 2.2) NNT 4.1 (3.3 to 5.2)	8 studies 1177 participants	High quality	Good quality studies, important outcome available, robust numbers
Median (mean) time to use of rescue medication	4.7 hours (5.2 hours)	1.8 hours (3.6 hours)	Not estimated	3 studies 281 participants (3 studies, 251 participants)	Very low quality	Small numbers of participants.
Participants using rescue medication over 6 hours	470 in 1000	690 in 1000	RR 0.66 (0.56 to 0.78) NNTp 4.7 (3.3 to 8.0)	5 studies 445 participants	High quality	Reasonable numbers of participants and high event rate.
Participants with ≥ 1 adverse event following a single dose	160 in 1000	100 in 1000	RR 1.4 (0.89 to 2.2) NNH not calculated	6 studies 536 participants	High quality	Good quality studies, important outcome available, robust numbers.
Participants with a serious adverse event following a single dose	No serious adverse events reported		Not estimated	9 studies 1271 participants	Very low quality	No events in single dose studies not designed to evaluate serious but rare adverse events.
CI: confidence interval; NNH: number needed to treat for an additional harmful outcome; NNT: number needed for one additional beneficial outcome; NNTp: number needed to treat to prevent an additional outcome: RR: risk ratio.
We used the following descriptors for levels of evidence (EPOC 2015). High: this research provides a very good indication of the likely effect. The likelihood that the effect will be substantially different^a is low. Moderate: this research provides a good indication of the likely effect. The likelihood that the effect will be substantially different^a is moderate. Low: this research provides some indication of the likely effect. However, the likelihood that it will be substantially different^a is high. Very low: this research does not provide a reliable indication of the likely effect. The likelihood that the effect will be substantially different^a is very high. ^a Substantially different: a large enough difference that it might affect a decision.

Summary of findings 4. Dexketoprofen 20 mg or 25 mg compared with placebo for acute postoperative pain

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Comparison 1. Ketoprofen 12.5 mg versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Participants with ≥ 50% pain relief over 6 hours Show forest plot	3	274	Risk Ratio (M‐H, Fixed, 95% CI)	4.21 [2.68, 6.63]

2 Participants using rescue medication over 6 hours Show forest plot	2	198	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.74, 0.90]

3 Participants with any adverse event Show forest plot	3	274	Risk Ratio (M‐H, Fixed, 95% CI)	1.33 [0.48, 3.64]

Comparison 1. Ketoprofen 12.5 mg versus placebo

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Comparison 2. Ketoprofen 25 mg versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Participants with ≥ 50% pain relief over 6 hours Show forest plot	8	535	Risk Ratio (M‐H, Fixed, 95% CI)	4.88 [3.48, 6.85]

1.1 Dental surgery	6	452	Risk Ratio (M‐H, Fixed, 95% CI)	5.07 [3.50, 7.36]
1.2 Other surgery	2	83	Risk Ratio (M‐H, Fixed, 95% CI)	3.96 [1.77, 8.86]
2 Participants using rescue medication over 6 hours Show forest plot	6	402	Risk Ratio (M‐H, Fixed, 95% CI)	0.60 [0.52, 0.69]

3 Participants with any adverse event Show forest plot	7	490	Risk Ratio (M‐H, Fixed, 95% CI)	1.15 [0.68, 1.96]

Comparison 2. Ketoprofen 25 mg versus placebo

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Comparison 3. Ketoprofen 50 mg versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Participants with ≥ 50% pain relief over 4‐6 hours Show forest plot	8	594	Risk Ratio (M‐H, Fixed, 95% CI)	2.49 [1.97, 3.14]

1.1 Dental surgery	3	190	Risk Ratio (M‐H, Fixed, 95% CI)	9.04 [4.23, 19.30]
1.2 Other surgery	5	404	Risk Ratio (M‐H, Fixed, 95% CI)	1.79 [1.40, 2.28]
2 Participants using rescue medication over 6‐8 hours Show forest plot	6	468	Risk Ratio (M‐H, Fixed, 95% CI)	0.56 [0.47, 0.66]

2.1 6 hours	4	263	Risk Ratio (M‐H, Fixed, 95% CI)	0.42 [0.33, 0.54]
2.2 8 hours	2	205	Risk Ratio (M‐H, Fixed, 95% CI)	0.77 [0.61, 0.98]
3 Participants with any adverse event Show forest plot	5	342	Risk Ratio (M‐H, Fixed, 95% CI)	1.64 [0.98, 2.75]

Comparison 3. Ketoprofen 50 mg versus placebo

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Comparison 4. Ketoprofen 80 mg or 100 mg versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Participants with ≥ 50% pain relief Show forest plot	6	381	Risk Ratio (M‐H, Fixed, 95% CI)	4.29 [3.02, 6.08]

1.1 Dental surgery	4	255	Risk Ratio (M‐H, Fixed, 95% CI)	8.33 [4.67, 14.86]
1.2 Other surgery	2	126	Risk Ratio (M‐H, Fixed, 95% CI)	1.94 [1.26, 3.00]
2 Participants using rescue medication over 6‐8 hours Show forest plot	4	259	Risk Ratio (M‐H, Fixed, 95% CI)	0.54 [0.44, 0.67]

2.1 6 hours	3	163	Risk Ratio (M‐H, Fixed, 95% CI)	0.49 [0.38, 0.65]
2.2 8 hours	1	96	Risk Ratio (M‐H, Fixed, 95% CI)	0.63 [0.44, 0.89]
3 Participants with any adverse event Show forest plot	3	175	Risk Ratio (M‐H, Fixed, 95% CI)	1.19 [0.65, 2.16]

Comparison 4. Ketoprofen 80 mg or 100 mg versus placebo

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Comparison 5. Dexketoprofen 10 mg or 12.5 mg versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Participants with ≥ 50% pain relief over 4‐6 hours Show forest plot	5	480	Risk Ratio (M‐H, Fixed, 95% CI)	2.43 [1.79, 3.28]

1.1 Dental surgery	4	373	Risk Ratio (M‐H, Fixed, 95% CI)	3.16 [2.08, 4.80]
1.2 Other surgery	1	107	Risk Ratio (M‐H, Fixed, 95% CI)	1.53 [1.00, 2.35]
2 Participants using rescue medication over 6‐8 hours Show forest plot	5	480	Risk Ratio (M‐H, Fixed, 95% CI)	0.68 [0.58, 0.81]

2.1 6 hours	4	373	Risk Ratio (M‐H, Fixed, 95% CI)	0.73 [0.61, 0.86]
2.2 8 hours	1	107	Risk Ratio (M‐H, Fixed, 95% CI)	0.49 [0.30, 0.82]
3 Participants with any adverse event Show forest plot	4	380	Risk Ratio (M‐H, Fixed, 95% CI)	0.70 [0.36, 1.35]

Comparison 5. Dexketoprofen 10 mg or 12.5 mg versus placebo

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Comparison 6. Dexketoprofen 20 mg or 25 mg versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Participants with ≥ 50% pain relief over 4‐6 hours Show forest plot	8	1177	Risk Ratio (M‐H, Fixed, 95% CI)	1.96 [1.68, 2.28]

1.1 Dental surgery	5	444	Risk Ratio (M‐H, Fixed, 95% CI)	4.66 [3.12, 6.95]
1.2 Other surgery	3	733	Risk Ratio (M‐H, Fixed, 95% CI)	1.48 [1.26, 1.74]
2 Participants using rescue medication over 6‐8 hours Show forest plot	7	635	Risk Ratio (M‐H, Fixed, 95% CI)	0.68 [0.59, 0.77]

2.1 6 hours	5	445	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.56, 0.78]
2.2 8 hours	2	190	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.57, 0.89]
3 Participants with any adverse event Show forest plot	6	536	Risk Ratio (M‐H, Fixed, 95% CI)	1.41 [0.89, 2.23]

Comparison 6. Dexketoprofen 20 mg or 25 mg versus placebo

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Referencias

References to studies included in this review

Akural 2009 {published data only}

Arnold 1990 {published data only}

Balzanelli 1996 {published data only}

Cooper 1984 {published data only}

Cooper 1988 {published data only}

Cooper 1998 {published data only}

Gay 1996 {published data only}

Harrison 1996 {unpublished data only}

Jackson 2004 {published data only}

McGurk 1998 {published data only}

McQuay 2016 {published data only}

Mehlisch 1984 {published data only}

Moore 2015c {published data only}

Moore 2016 {published data only}

Olson 1999 {published data only}

Olson 2001 {published data only}

Schreiber 1996 {unpublished data only}

Seymour 1996 {published data only}

Seymour 2000 {published data only}

Sunshine 1988 {published data only}

Sunshine 1993 {published data only}

Sunshine 1998 {published data only}

Turek 1988 {published data only}

Vidal 1999 {unpublished data only}

References to studies excluded from this review

Avila 1991 {published data only}

Bagan 1998 {published data only}

Berti 2000 {published data only}

Esparza‐Villalpando 2016 {published data only}

Gallardo 1982 {published data only}

Giudice 1987 {published data only}

Jimenez‐Martinez 2004 {published data only}

Kantor 1984 {published data only}

Letarget 1998 {unpublished data only}

Lobo 1983 {published data only}

Olmedo 2001 {published data only}

Perez 2002 {unpublished data only}

Schreiber 1998 {unpublished data only}

Sunshine 1986 {published data only}

Tufano 1981 {published data only}

Zapata 2000 {unpublished data only}

References to studies awaiting assessment

Yatomi 1979 {published data only}

Additional references

Aldington 2011

Barbanoj 2001

Barden 2004

BNF 2016

Bulley 2009

Clarke 2014

Collins 1997

Collins 2001

Cook 1995

Cooper 1991

Dechartes 2013

Dechartres 2014

Derry 2009a

Derry 2009b

Derry 2015

Derry 2016

EPOC 2015

FitzGerald 2001

Grahame‐Smith 2002

Gregory 2016

Guyatt 2011

Guyatt 2013a

Guyatt 2013b

Hawkey 1999

Hernández‐Diaz 2000

Herrero 2003

Higgins 2011

Jadad 1996a

Jadad 1996b

L'Abbé 1987

Laporte 2004

McQuay 1982