Combination treatment using ibuprofen plus acetaminophen provided better relief of chronic knee pain than acetaminophen alone -- but at the cost of increased side effects, a British randomized study found.
After 10 days of use, patients taking a total daily dose of 1,200 mg of ibuprofen plus 3,000 mg of acetaminophen had a mean difference on the Western Ontario McMaster Universities osteoarthritis scale of −5.3 points (95% CI −8.5 to −2.1, P<0.01) when compared with acetaminophen monotherapy, according to Michael Doherty, MD, of Nottingham City Hospital, and colleagues.
Action Points
- Note that in this double blind study, patients with osteoarthritis of the knee had significantly better pain outcomes with a combination of acetaminophen and ibuprofen than those taking acetaminophen alone.
- Point out, however, that decreases in hemoglobin were observed in all groups but in significantly more of those taking combination tablets; reductions in hemoglobin were similar with acetaminophen and ibuprofen.
However, after 13 weeks of treatment, 6.9% of those taking the combination had a decrease in hemoglobin of 2 g/dL or more -- presumably was a result of occult GI bleeding -- compared with 0.9% of those receiving acetaminophen, Doherty and associates reported in the September issue of Annals of the Rheumatic Diseases.
Current recommendations favor acetaminophen for the treatment of osteoarthritis, mainly because it has fewer gastrointestinal adverse effects than nonsteroidal anti-inflammatory drugs (NSAIDs).
However, NSAIDs are generally thought to be more effective pain relievers.
To see if better efficacy and fewer side effects could result if the two types of medications were used together, given their presumed different mechanisms of action, Doherty's group conducted a double-blind trial that included 892 patients with knee pain.
Participants were randomized to one of four groups: acetaminophen monotherapy 1,000 mg three times a day, ibuprofen monotherapy at 400 mg three times a day, a low-dose combination tablet of 200 mg ibuprofen plus 500 mg acetaminophen three times a day, or two higher-dose combination tablets containing 400 mg of ibuprofen and 1,000 mg of acetaminophen. The latter was also taken three times a day .
Efficacy and safety were assessed after 10 days of treatment, which is the usual recommendation on duration for self-treatment, and then at three months, because many patients with chronic pain take medications for long periods.
Compared with acetaminophen monotherapy, the higher dose combination regimen led to significant improvements in stiffness at 10 days and 13 weeks (P<0.05), physical function at both time points (P<0.05), bodily pain at day 10 (P=0.02), general health at day 10 (P =0.04), and social functioning at study completion.
By the end of the study, significantly greater numbers of patients in the combination groups than in the acetaminophen group described their treatment as being good or excellent (P=0.0152 for the low dose and P=0.0002 for the high dose).
During the course of the study there were 18 serious adverse events, including a fatal ruptured aortic aneurysm, angina pectoris, and worsening of renal failure.
Overall, patients in the combination groups experienced more diarrhea, while those on acetaminophen had more liver enzyme abnormalities.
Diarrhea was reported by 9.4% and 5% of the higher and lower dose combination patients, and by 5.9% and 4% of the acetaminophen and ibuprofen monotherapy patients.
By the end of the study, 51% of patients in the higher dose combination group had experienced drug-related adverse events, compared with 42% of those on ibuprofen monotherapy (P=0.04).
During the course of the study, mean hemoglobin levels fell in all four treatment groups.
By day 10, hemoglobin had decreased by at least 1 g/dL in 10.8% and 17.5% of the lower dose and higher dose combination groups, respectively, and in 7.3% and 11.3% of the acetaminophen and ibuprofen monotherapy groups, respectively.
After 13 weeks, 38.4% of patients in the higher combination group had a decrease of 1 g/dL or more, compared with 24.1% of those in the lower combination group, 20.3% of the acetaminophen group, and 19.6% of the ibuprofen group (P<0.001).
The decreases in hemoglobin were particularly notable in older patients.
In addition to decreases in hemoglobin, platelet counts increased and red blood cell volume decreased, "suggesting that these hemoglobin decreases may relate to blood loss," the researchers observed.
They noted that the frequency of diarrhea indicated that the blood loss might be caused by irritation in the small intestine, which was unexpected in the acetaminophen group because gastrointestinal toxicity has been considered negligible with that drug.
Whether these decreases in hemoglobin are clinically significant remains unclear, the researchers cautioned.
"Nevertheless, these investigational results challenge the belief that [acetaminophen] is the treatment of choice based on an absent/lower risk of gastrointestinal complications compared with ibuprofen," they wrote.
Of particular importance will be determining the site of the occult bleeding, because if turns out to be the small bowel, proton pump inhibitors are not likely to be of use.
The authors called for further research, and concluded that if these findings of additive adverse effects with combination therapy are confirmed, it "should lead to the reconsideration of current recommendations for oral analgesic use in osteoarthritis, and in chronic pain in general."
Disclosures
The study was sponsored by Reckitt Benckiser Healthcare International.
The lead author and one co-author have served on advisory boards for Reckitt Benckliser. An additional co-author is an employee of the company, and two others formerly were employees.
Primary Source
Annals of the Rheumatic Diseases
Doherty M, et al "A randomized controlled trial of ibuprofen, paracetamol or a combination tablet of ibuprofen/paracetamol in community-derived people with knee pain" Ann Rheum Dis 2011; 70: 1534-1541.