Analgesic combo may exacerbate gastrointestinal bleeding

Combining ibuprofen and paracetamol at nonprescription doses conferred a modest improvement in pain relief in adults with knee pain/osteoarthritis. But this gain came at the expense of an increase in presumed gastrointestinal bleeding, results from a large randomized, controlled trial showed.

The trial showed that paracetamol 3 g/day may cause similar levels of blood loss as ibuprofen 1,200 mg/day, and that the combination of the two appears to be additive, or even synergistic, in terms of the number of patients with a decrease in hemoglobin greater than 2 mg/dL.

“These results need to be confirmed, along with their clinical relevance and identification of the site of gastrointestinal bleeding,” wrote the researchers, led by the Arthritis UK Pain Center at Nottingham (England) City Hospital. “If confirmed, this observation should lead to the reconsideration of current recommendations for oral analgesic use in osteoarthritis, and in chronic pain in general.”

Over a period of 13 weeks, followed 892 adults with chronic knee pain who were randomized to one of four treatment regimens, each taken three times a day: ibuprofen (400 mg), paracetamol (1 ,000 mg), one fixed-dose combination tablet (ibuprofen 200 mg/ paracetamol 500 mg), or two fixed-dose combination tablets (ibuprofen 400 mg/ paracetamol 1,000 mg).

The primary short-term efficacy end point was the difference at 10 days between groups in the WOMAC (Western Ontario McMaster Universities) osteoarthritis index pain subscale, which was normalized to a 0- to 100-mm scale.

The primary long-term efficacy endpoint was the patient global assessment of study medication after 13 weeks. This was determined by asking patients, “Taking into account both how your medicine worked for you and any side effects you think it caused you, how would you rate your medications a treatment for your painful knee?” Respondents used a five-point scale for replies (1, excellent; 2, good; 3, fair; 4, poor; 5, unacceptable).

The primary safety endpoint was the incidence of moderate and severe adverse events reported during the study period.

Inclusion criteria were age of at least 40 years; knee pain for most of the past 3 months and on 4 of 7 preceding days; discontinuation of current analgesics; Steinbrocker functional capacity class I-III; and pain affecting the index knee (after a washout period if currently taking analgesics) of 30 mm or greater and 80 mm or less on a 100-mm visual analog scale over the previous 48 hours.

The mean age of patients was 61 years, and 51% were men. More than half of participants (63%) had radiographic osteoarthritis, and 85% fulfilled American College of Rheumatology criteria for the condition.

After measuring the mean change in WOMAC pain scores from baseline, the researchers found that at day 10, two combination tablets provided significantly more pain relief than paracetamol alone (P less than .01). At 13 weeks, a greater proportion of participants taking one or two combination tablets rated their treatment as excellent/good, compared with paracetamol alone (P=.015 and .0002, respectively).

The incidence of adverse events was comparable among groups and consisted mainly of dyspepsia, diarrhea, and nausea. However, at 13 weeks a decrease in hemoglobin level by at least 1 g/dL was seen in 38% of patients taking two combination tablets, 24% of patients taking one combination tablet, 20% of those taking paracetamol monotherapy, and 20% of those on ibuprofen monotherapy.