Table 2.

Summary of randomized clinical rrials included in this review.

First author (year)	Method	Participants number, gender, age, inclusion criteria (current disease severity and duration, mean ± SD yr)	Interventions	Time points and outcome measurements	Losses to follow-up and adverse effects
Conaghan (2013)[12]	A multicenter, double blind, randomized controlled pilot trial	463 patients. 300 women & 163 men. 1) IDEA-033 (ketoprofen 100 mg) group: 59.9 (26–83) 2) Oral celecoxib 100 mg bd) group: 62.0 (38–90). Clinical criteria (ACR). knee pain and 54 of the following: (i) age >50 yr; (ii) morning stiffness of <30 min duration; (iii) crepitus on active motion; (iv) bony tenderness; (v) bony enlargement, and (vi) no palpable warmth of the synovium	1. Topical group: IDEA-033 ketoprofen 100 mg 2. Oral group: celecoxib 100 mg bd	Baseline, 12 wk Pain, physical function (WOMAC)	There were not losses to follow-up, the adverse events were gastrointestinal disorders, skin disorders
Simon (2009)[13]	A randomized, double-blind, double-dummy, placebo-, vehicle- and active-controlled study	305 patients, 199 women & 106 men. 1) topical diclofenac solution group: 61.7 ± 9.8 2) oral diclofenac group: 62.0 ± 10.5 Clinical criteria (ACR) standard radiological criteria for OA [2] on a recent (within 3 mo) examination, (ii) pain, with regular use of a NSAID or other analgesic medication (at least 3 d a week in the previous month) and (iii) a flare of pain and minimum Likert pain score of 8	1) Topical group: topical diclofenac solution plus oral placebo tablets (topical diclofenac solution is 1.5% w/w diclofenac sodium in a vehicle solution containing 45.5% w/w DMSO) oral group: placebo solution plus oral diclofenac tablets (100 mg slow release)	Baseline,12 wk Pain, physical function stiffness and patient global assessment (PGA) (WOMAC)	Two patients from group 1, 2 from group 2, were lost to follow-up The adverse events were digestive system, skin/appendages, Headache Back pain, Arthralgia events
Rother (2007)[14]	A multicenter, randomized, double-blind, controlled trial	270 patients,157 women & 113 men 1) IDEA-033 group: 63.3 ± 10.1 2) Celecoxib group: 62.4 ± 9.6 Clinical criteria (ACR) morning stiffness of 30 min duration, crepitus on motion and age >40 yr; (ii) rating their pain in the index knee as >3 on a 5-point Likert scale; (iii) taking oral NSAIDs at least 3 d/wk for the past 3 mo or for .25 of the past 30 d	1) IDEA-033 group: 110 mg ketoprofen in 4.4 g transferable gel (IDEA-033) 2) Celecoxib group: 100 mg oral celecoxib	Baseline, 6 wk, Primary outcome measures: pain, physical function and PGA of response (WOMAC) Secondary outcome measures: stiffness (WOMAC)	One patient from group1 were lost to follow-up and Group2 were not lost to follow-up. Adverse effects were noted and recorded, such as Gastrointestinal disorders, Skin and subcutaneous tissue disorders
Tiso (2010)[15]	Prospective, randomized, unblinded pilot study	20 patients, 17 women & 3 men 1) Topical Group: 58.9 ± 10.3 2) Oral Group: 57.0 ± 7.9 Clinical criteria (ACR). Knee pain ≥3 mo and willing and able to cooperate in the assigned treatment and willing and able to complete follow-up Questionnaires	1) Topical Group: give tubes of 4% ibuprofen gel supplied by the manufacturer and instructed to apply 2 mL of gel. 2) Oral group took 800 mg ibuprofen tablets 3 times daily	Baseline, 2 wk primary outcome to measure: pain, stiffness, and physical Function, Secondary outcomes the acute SF-12v2 general health survey and a questionnaire assessing patient satisfaction with treatment	Group 1 were not losses to follow-up and one patient from group 2 were lost to follow-up adverse events were noted headache dizziness, stomachache diarrhea and acute skin rash
Tugwell (2004)[16]	A randomized, double-blind, double dummy equivalence trial	604 patients, 356 women & 248 men 1) topical group: 64 ± 10 2) oral group: 63 ± 10 included men and nonpregnant women between 40 and 85 yr old, with symptomatic primary OA of the knee and a recent (within 3 mo) radiographic examination showing “osteoarthritis”	1) Topical diclofenac solution, Pennsaid® [consisting of 1.5% (w/w) diclofenac sodium in a patented carrier including 45.5% (w/w) dimethyl sulfoxide (DMSO)] plus oral placebo capsules 2) Oral diclofenac (50 mg) capsules plus topical placebo solution [a modified carrier including 2.3% (w/w) DMSO, but no diclofenac]	Baseline, 12 wk pain and physical function (WOMAC), PGA (VAS)	Five patients from group 1 and five patients from group 2 were lost to follow-up Adverse events were noted gastrointestinal, dry skin, asthma, edema. Headache
Shinde (2017)[17]	A randomized, open-label parallel design trial	49 patients, 18 women & 31 men 1)Transdermal diclofenac patch group: 46.48 ± 12.01 2)Tablet diclofenac group: 43.04 ± 13.36 Pain duration ≥3 mo	1) Group 1 received transdermal diclofenac diethylamine patch 100 mg qd 2) Group 2 received tablet diclofenac sodium SR 100 mg qd	Baseline, 4 wk Change in baseline score (VAS)	Three patients from group 1and 4 patients from group 2 were lost to follow-up Adverse events were noted epigastric pain, burning sensation, dyspepsia, abdominal pain, rash
Sandelin (1997)[18]	Randomized, double blind, multicentre trial	212 patients,134 women & 78 men 1)Eltenac group: 61 ± 8.3 2)Diclofenac tablet group: 61 ± 7.9	1) Eltenac group: eltenac 1% gel, 3 g (= 30 mg eltenac) applied tid, combined with one placebo tablet bid 2) Diclofenac group: diclofenac tablets 50 mg bid, combined with placebo gel; 3 g applied tid	Baseline, 4 wk. Lequesne’s Index and pain (VAS)	Three patients from group 1 and 3 patients from group 2 were lost to follow-up Adverse events were noted gastrointestinal, eryt Eczema. Hema were noted Gastrointestinal, Skin or subcutaneous disorders, Infections, Rhinopharyngitis
Doi (2010)[19]	Open-labeled, randomized, controlled, multi clinic trial	73 patients, 125 women & 48 men 1) Plaster group: 66.1 ± 9.9 2) Oral group: 67.2 ± 9.4 (i) Outpatients aged 50–80 yr old with knee pain (ii) New patients at the medical institution concerned who had received no treatment for their knees within the past month (iii) Patients with the following knee symptoms in the more Symptomatic side: morning stiffness <30 min, joint crepitus, tenderness at the joint space, and palpable osteophytes (iv) Comorbid patients with hypertension, diabetes, and hyperlipidemia under medication were allowed to enter the trial (v) Patients who agreed to X-ray and laboratory tests to confirm the diagnosis. (vi) Patient who understood the aim and contents of the trial and were willing to cooperate by completing the questionnaire	1) Plaster group: flurbiprofen 40 mg in compounding agent 12 g; indometacin 70 mg in 14 g; ketoprofen 30 mg in 10 g. Bid 2) Plaster group: loxoprofen sodium 60 mg tablet; diclofenac sodium 25 mg tablet; zaltoprofen 80 mg tablet	Baseline, 4 wk Pain (JKOM and VAS)	Group 1 were not losses to follow-up and five patients from group 2 were lost to follow-up Adverse events were noted insomnia, stomach ache

ACR = American College of Rheumatology classification criteria, JKOM = Japanese knee osteoarthritis measure, NSAID = non-steroidal anti-inflammatory drugs, OA = osteoarthritis, PGA = patient global assessment, SD = standard deviation, VAS = Visual Analog Scale, WOMAC = Western Ontario and McMaster Universities Osteoarthritis Index.