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Tramadol is used frequently in the management of mild to moderate pain conditions in dogs. This use is controversial because multiple reports in treated dogs demonstrate very low plasma concentrations of O -desmethyltramadol (M1), the active metabolite. The objective of this study was to identify a drug that could be coadministered with tramadol to increase plasma M1 concentrations, thereby enhancing analgesic efficacy. In vitro studies were initially conducted to identify a compound that inhibited tramadol metabolism to N -desmethyltramadol (M2) and M1 metabolism to N , O -didesmethyltramadol (M5) without reducing tramadol metabolism to M1. A randomized crossover drug-drug interaction study was then conducted by administering this inhibitor or placebo with tramadol to 12 dogs. Blood and urine samples were collected to measure tramadol, tramadol metabolites, and inhibitor concentrations. After screening 86 compounds, fluconazole was the only drug found to inhibit M2 and M5 formation potently without reducing M1 formation. Four hours after tramadol administration to fluconazole-treated dogs, there were marked statistically significant ( P < 0.001; Wilcoxon signed-rank test) increases in plasma tramadol (31-fold higher) and M1 (39-fold higher) concentrations when compared with placebo-treated dogs. Conversely, plasma M2 and M5 concentrations were significantly lower (11-fold and 3-fold, respectively; P < 0.01) in fluconazole-treated dogs. Metabolite concentrations in urine followed a similar pattern. This is the first study to demonstrate a potentially beneficial drug-drug interaction in dogs through enhancing plasma tramadol and M1 concentrations. Future studies are needed to determine whether adding fluconazole can enhance the analgesic efficacy of tramadol in healthy dogs and clinical patients experiencing pain., (Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.)

Tramadol is widely used to manage mild to moderately painful conditions in dogs. However, this use is controversial since clinical efficacy studies in dogs showed conflicting results, while pharmacokinetic studies demonstrated relatively low circulating concentrations of O-desmethyltramadol (M1). Analgesia has been attributed to the opioid effects of M1, while tramadol and the other major metabolite (N-desmethyltramadol, M2) are considered inactive at opioid receptors. The aims of this study were to determine whether cytochrome P450 (CYP) dependent M1 formation by dog liver microsomes is slower compared with cat and human liver microsomes; and identify the CYPs responsible for M1 and M2 formation in canine liver. Since tramadol is used as a racemic mixture of (+)- and (-)-stereoisomers, both (+)-tramadol and (-)- tramadol were evaluated as substrates. M1 formation from tramadol by liver microsomes from dogs was slower than from cats (3.9-fold), but faster than humans (7-fold). However, M2 formation by liver microsomes from dogs was faster than from cats (4.8-fold) and humans (19-fold). Recombinant canine CYP activities indicated that M1 was formed by CYP2D15, while M2 was largely formed by CYP2B11 and CYP3A12. This was confirmed by dog liver microsomes studies that showed selective inhibition of M1 formation by quinidine and M2 formation by chloramphenicol and CYP2B11 antiserum, and induction of M2 formation by phenobarbital. Findings were similar for both (+)-tramadol and (-)-tramadol. In conclusion, low circulating M1 concentrations in dogs is explained in part by low M1 formation and high M2 formation, which are mediated by CYP2D15 and CYP2B11/CYP3A12, respectively., (The American Society for Pharmacology and Experimental Therapeutics.)