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Antinociceptive synergy, additivity, and subadditivity with combinations of oral glucosamine plus nonopioid analgesics in mice.
J Pharmacol Exp Ther. 2003 Nov; 307(2):699-704.JP

Abstract

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.

Authors+Show Affiliations

Department of Pharmacology, Temple University School of Medicine, 3420 N. Broad Street, Philadelphia, PA 19140-5104, USA. ronald.tallarida@temple.eduNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

12966152

Citation

Tallarida, Ronald J., et al. "Antinociceptive Synergy, Additivity, and Subadditivity With Combinations of Oral Glucosamine Plus Nonopioid Analgesics in Mice." The Journal of Pharmacology and Experimental Therapeutics, vol. 307, no. 2, 2003, pp. 699-704.
Tallarida RJ, Cowan A, Raffa RB. Antinociceptive synergy, additivity, and subadditivity with combinations of oral glucosamine plus nonopioid analgesics in mice. J Pharmacol Exp Ther. 2003;307(2):699-704.
Tallarida, R. J., Cowan, A., & Raffa, R. B. (2003). Antinociceptive synergy, additivity, and subadditivity with combinations of oral glucosamine plus nonopioid analgesics in mice. The Journal of Pharmacology and Experimental Therapeutics, 307(2), 699-704.
Tallarida RJ, Cowan A, Raffa RB. Antinociceptive Synergy, Additivity, and Subadditivity With Combinations of Oral Glucosamine Plus Nonopioid Analgesics in Mice. J Pharmacol Exp Ther. 2003;307(2):699-704. PubMed PMID: 12966152.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Antinociceptive synergy, additivity, and subadditivity with combinations of oral glucosamine plus nonopioid analgesics in mice. AU - Tallarida,Ronald J, AU - Cowan,Alan, AU - Raffa,Robert B, Y1 - 2003/09/09/ PY - 2003/9/11/pubmed PY - 2003/12/12/medline PY - 2003/9/11/entrez SP - 699 EP - 704 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 307 IS - 2 N2 - 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. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/12966152/Antinociceptive_synergy_additivity_and_subadditivity_with_combinations_of_oral_glucosamine_plus_nonopioid_analgesics_in_mice_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&amp;pmid=12966152 DB - PRIME DP - Unbound Medicine ER -