Study N Agent(s) Comparator Results Comments
Strong Opioid/APAP Combinations
Raffaeli 2010 [123] 29 RA patients with chronic moderate to severe pain, not taking biologics Oxycodone/APAP started at 5/325 mg and titrated to attainment of good pain relief None 42% had good clinical response (EULAR) and 50% showed 20% improvement. Mean daily dose at end of study was 13.8 (±6.8) mg/720.4 (±291.0) mg Mild to moderate nausea and vomiting; no serious AEs. Patients were allowed antiemetic drugs and laxatives as needed.
Corsinovi 2009 [124] 154 women nursing home residents with moderate to severe OA pain Oxycodone/APAP (average dose 16/900 mg) and codeine/APAP (average dose 115/1916 mg) Conventional therapy (NSAIDs, APAP, COX-2 inhibitors) Oxycodone/APAP and codeine/APAP significantly reduced mean pain at six weeks versus conventional therapy (p<0.001 and p=0.004, respectively) AEs did not differ significantly among groups. Patients were all elderly females.
Weak Opioid/APAP Combinations
Mullican 2001 [125] 462 patients with OA or LBP Tramadol/APAP (37.5/325 mg) (average dose 131/1133 mg) Codeine/APAP (30/300 mg) (average dose 105/1054 mg) Tramadol/APAP was as effective as codeine/APAP and better tolerated Codeine patients had significantly higher rates of somnolence and constipation, while tramadol patients had higher rate of headache (NS)
Palangio 2000 [126] 469 chronic pain patients (31% had arthritis, n=145) 1 tablet of hydrocodone/ibuprofen 7.5/200 mg daily (HI-1) or 2 tablets of same (HI-2) Codeine/APAP 30/300 mg HI-2 offered significantly greater pain relief than HI-1 or comparator; no efficacy differences between HI-1 and comparator No significant difference in AEs by group (83% HI-2, 80% HI-1, and 81% Comparator) but significantly more HI-2 patients discontinued therapy due to adverse events compared to HI-1 (26% vs 15%, p=0.013)
Conaghan 2011 [127] 220 patients with hip and/or knee pain ≥60 years of age 7-day buprenorphine patches (range 5-25 µg/h) + APAP 1000 mg qid Codeine/APAP range 16 mg/1000 mg qid to 60 mg/1000 mg qid Non-inferiority of patch+APAP to codeine/APAP combination regarding analgesic efficacy Comparable incidence of AEs High withdrawal rates in both groups
Emkey 2004 [128] 306 OA patients taking a COX-2 inhibitor Tramadol/APAP (37.5/325 mg) as add-on (average dose 154/1332 mg) Placebo as add-on Tramadol/APAP patients had significantly better scores on VAS, pain relief and function; 13% of tramadol and 4% of placebo patients discontinued because of AEs  
Park 2011 [129] 97 knee OA patients in sub-study (part of larger study, n=112) Tramadol/APAP (37.5/325 mg) Mean dose 3.23 tablets/day NSAID No significant differences in analgesia or AEs  
Alwine 2000 [130] 403 patients with OA or low back pain Tramadol/APAP (37.5 mg/325 mg) 1 to 3 tablets per day 4-week active control, thereafter open label (24 m) Tramadol/APAP rated “excellent” or “very good” by 39% of patients and 40% of investigators, average daily dose was 157 mg/1363 mg. 24% of patients discontinued due to AEs
Rosenthal 2004 [131] Subset of 113 patients ≥ 65 years with painful OA flares (from larger study of 308 patients) on stable NSAID or COX-2 inhibitor therapy ≥ 3 months Tramadol/APAP (37.5/325 mg) as add on (mean daily dose 168/1.458 mg) Control continued NSAID or COX-2 inhibitor therapy Tramadol/APAP patients had significantly reduced daily pain intensity and significantly greater average daily pain relief 23% of tramadol/APAP and 9% of control patients reported treatment-related AEs. Tramadol/APAP vs control rates of constipation and somnolence were 4.3% vs 2.3% and 2.9% vs 2.3%, respectively.
Silverfield 2002 [132] 308 OA patients with flare on stable NSAID or COX-2 inhibitor therapy Tramadol/APAP (37.5/325 mg) as add on Control continued NSAID or COX-2 inhibitor therapy Tramadol/APAP patients had significantly reduced daily pain intensity and significantly greater average daily pain relief AEs occurred in 24% of tramadol/APAP and 8% of control group; 13% of tramadol/APAP and 5% of control patients discontinued for AEs
Lee 2006 [133] 277 RA patients on stable NSAID and/or DMARD therapy for ≥ 1 month Tramadol/APAP (37.5/325 mg) as add on Control continued NSAID and/or DMARD therapy Tramadol/APAP patients had significantly greater pain relief and lower daily pain intensity AEs were 57.6% in tramadol/APAP group vs 22.4% in control (p<0.001)
Choi 2007 [111] 250 patients with pain from knee OA on stable NSAID therapy Tramadol/APAP (37.5/325 mg) Mean daily dose 112.5/1.975 mg Patients were randomized to titration and non-titration groups Tramadol/APAP reduced pain in both titration and nontitration groups This was a safety study; discontinuation rate was significantly lower in titration group with nausea, vomiting and dizziness the most common AEs (all significantly more frequent in the nontitration group).
NSAID/APAP Combinations
Doherty 2011 [134] 892 patients with chronic knee pain (85% had OA) Two active arms: 1 tablet or 2 tablets daily of ibuprofen/APAP 200/500 mg Two comparative arms: Ibuprofen 400 mg or paracetamol 1000 mg At day 10, 2 combination tablets were significantly better than APAP monotherapy; at 13 weeks, significantly more patients found combination therapy (1 or 2 tablets) excellent or good versus APAP monotherapy Decreases in hemoglobin (≥ 1 g/dl) occurred in all groups but was twice as frequent in patients taking 2 combination tablets daily compared to monotherapy
Pareek 2010 [135] 220 patients with knee OA flare Etodolac 300 mg/APAP 500 mg BID Etodolac 300 mg BID Etodolac/APAP significantly reduced pain intensity (p<0.001) and improved function Results noticeable within 30 minutes of first dose; AEs similar in both groups
Pareek 2009 [136] 199 patients with OA flares Aceclofenac 100 mg/APAP 500 mg BID Aceclofenac 100 mg BID Aceclofenac/APAP was superior to monotherapy in pain intensity differences, sum of pain intensity differences, and patients/ investigators assessments Combination had more rapid onset of action; AEs similar in both groups (about 10%)

AE=adverse event, APAP=paracetamol, LBP=low back pain, NS=not significant, OA=osteoarthritis, VAS=visual analogue scale (pain measurement).