These studies examined the relationship between the circulating levels of the inflammatory cytokines (IL-1β, TNF-α, IL-6, IL-1ra) and the endogenous anti-inflammatory hormones (ACTH, cortisol, EPI and NE) during and immediately following a bout of eccentric exercise-induced muscle damage (EE), as well as during a subsequent 5-d period during which the subjects received either ibuprofen (IBU, n = 12), 200 mg qid, hydrocodone bitartrate with ibuprofen (HBI, n = 12), 7.5 mg + 200 mg qid, or placebo (PLA, n = 12). Healthy college males performed 10 sets of 10 single, dominant leg eccentric knee extension repetitions at 120% of their previously tested concentric 1RM with 2 min rest between sets to induced muscle damage. Control (C) subjects (n = 12) followed the same protocol without EE. Serial blood samples were obtained via an indwelling catheter at Pre, Mid, IP, 0.25, 0.5, 1, 2, 4, 6 hours and 1, 2, 3, 4 and 5 days following EE. Significant (p \u3c 0.05) increases in EPI and NE indicate that these variables initiated their anti-inflammatory action in response to the stress of EE. A lack of a significant increase in IL-1β and TNF-α following EE lends support to a theory that eccentric exercise does not stimulate the same inflammatory cytokine cascade associated with aerobic exercise and that stimulation of IL-1β is not required to stimulate the SAM axis. An initial significant decrease (Mid and IP) followed by a subsequent significant increase in IL-6 along with the ensuing significant increase in IL-1ra, following EE, demonstrates that IL-6 exhibits dual pro- and anti-inflammatory functions. The significant (p \u3c 0.05) increases in soreness scores and CK concentrations indicate that EE induced delayed-nset muscle soreness (DOMS). Administration of IBU and HBI significantly reduced DOMS within 24-h and 48-h respectively and resulted in non-significant differences in soreness by day 4 and 5 respectively. Neither IBU nor HBI administration resulted in a significant suppression of CK, following EE. Administration of HBI stimulated an increase in TNF-α, IL-6 and IL-1ra causing the HBI group to respond similar to PLA. Neither IBU nor HBI, provided a physiological benefit over placebo administration following eccentric exercise-induced muscle damage.