Antinociceptive synergy, additivity, and subadditivity with combinations of oral glucosamine plus nonopioid analgesics in mice

Glucosamine (2-amino-2-deoxy-D-glucose) and glucosamine-containing products have been reported to have efficacy in the treatment of various musculoskeletal disorders. Glucosamine's efficacy, including reduction of pain, is attributed to disease-modifying properties, specifically to cartilage-rebuilding associated with modulation of interleukin-1-induced activation of chondrocytes and to inhibition of proinflammatory effects of the nuclear factor-kappaB pathway. However, glucosamine has not been shown to have direct analgesic activity. We report here that commercial glucosamine (90.4% glucosamine sulfate + 9.6% excipients) administered as the sole agent ( up to 500 mg/kg p.o.) was inactive in the mouse abdominal irritant test but that certain combinations of glucosamine with nonopioid analgesics at the oral doses and ratios tested resulted in a synergistic ( ibuprofen and ketoprofen), additive ( diclofenac, indomethacin, naproxen, and piroxicam), or subadditive ( aspirin and acetaminophen) antinociceptive interaction. In the specific case of ibuprofen, the racemate ( standard ibuprofen) produced dose-related antinociception with ED50 = 26.1 +/- 3.4 mg/kg. Combinations containing racemic ibuprofen and glucosamine in greater than 1: 1 ratio ( glucosamine/ibuprofen) were synergistic in the test (e.g., ED50 = 11.0 +/- 2.1 for the 9: 1 ratio; p < 0.01, analysis of variance). Combinations containing glucosamine and ibuprofen ( 2: 1 and 9: 1) yielded plasma levels of ibuprofen that were no different from administration of ibuprofen alone. The possibility that combinations containing certain fixed ratios of glucosamine and certain nonsteroidal anti-inflammatory drugs (NSAIDs) might enhance pain relief in patients with pain or might achieve acceptable levels of pain relief with lower doses of NSAIDs ( reduced adverse effects) is presently being pursued in clinical trials.