The purpose of the present study was to evaluate the nature of the antinociceptive interaction among dexketoprofen (DEX), a mixed inhibitor of the cyclo-oxygenases, and tramadol (TRAM), a weak opioid with monoaminergic activity that inhibits norepinephrine and serotonin re-uptake. We assessed antinociception in the acetic acid writhing test, the tail flick and the formalin (FT) tests, and gastrointestinal transit (GIT) after the administration of a charcoal meal. The analysis of the interaction was carried out using isobolograms and interaction indexes or the fixed-dose method GIT. The administration of DEX or TRAM individually induced dose-dependent antinociception in all the algesiometric tests. In the three tests, TRAM was between 5.2 (FT, phase I) and 35 times (FT, Phase II) more potent than DEX. When testing combinations at different potency ratios (1 : 1, 1 : 3, 3 : 1), we could demonstrate synergy in all algesiometric tests, only when drugs were combined in a 1 : 1 proportion. Interestingly, the proportion of the drugs in the combination could change the type of interaction from synergy to antagonism. On the inhibition of GIT, a dose-related inhibition was established for TRAM, but not for DEX. Using a fixed-dose protocol, we could demonstrate antagonism between DEX and TRAM on the inhibition of GIT. The results of the present study suggest that a combination of DEX and TRAM in a 1 : 1 proportion could be adequate to use in future clinical trials in humans.

Preclinical studies have demonstrated antinociceptive synergism between dexketoprofen (DEX) and tramadol (TRM) in acute animal models of nociception. The aim of the present study was to investigate the type of interaction between DEX and TRM in a chronic musculoskeletal pain model in mice, which fairly replicates the characteristics of chronic osteoarticular pain in humans. Inflammation was induced by a subplantar injection of complete Freund's adjuvant (CFA) in male CF1 mice. Nociceptive thresholds were evaluated using the hot plate, the nocifensive spontaneous behavior and the acetone tests, while plasma extravasation (PE) was assessed with Evan's blue. We used the following experimental groups: control (no inflammation), acute (1 day after CFA injection), and chronic inflammation (7 days after CFA). Dose-response curves for DEX and TRM, individually and combined in a 1 : 1 proportion based on their potency were obtained, and the doses that produced a 50% inhibition calculated. The isobolographic analysis revealed that in all groups of study (no inflammation, acute, and chronic inflammation), the combination of DEX : TRM was synergistic, for both the inhibition of nociception and the PE. The results suggest that the DEX : TRM (1 : 1) combination could be useful in the management of acute and chronic inflammatory musculoskeletal pains in humans; in addition, the synergistic interaction between the drugs observed both during acute and chronic inflammation suggests that less doses would be required of each drug to obtain effective analgesia.

The construction of near-infrared spectral libraries as an alternative to qualitative analysis methods for identifying pharmaceutical raw materials is proposed. Various conceptual and practical aspects of library construction are assessed and discussed. The procedure is demonstrated by constructing a library including NIR spectra for 125 different raw materials using the correlation coefficient as the discriminating criterion. Compounds with very similar spectra can be identified by constructing sub-cascading libraries branching off the main one that are developed by using chemometric procedures with higher discriminating ability. The construction of sub-libraries and their performance and discriminating power in three different situations are illustrated. The proposed methodology affords the expeditious unequivocal identification of all the compounds included in a library.

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