The administration of tramadol has been widely studied in the recent past in both equine (Giorgi et al. 2007) and ruminant species (de Sousa et al. 2008; Elghazali et al. 2008). M1 concentrations are low in plasma from these species with an assumed lack of effectiveness for pain therapies. This study reports for the first time the plasma concentration of the main metabolites of tramadol (M1, M2, and M5) in the camelid species alpaca (V. pacos). To estimate the onset time and the duration of action following IM and IV injection, the clinically relevant therapeutic parameters t _e and Δt _e were calculated for an assumed MEC (Malonne et al. 2004). A target plasma concentration of tramadol of 100 ng/mL was clinically effective in the treatment of mild to moderate pain in humans (Malonne et al. 2004). The Δt _e values for IM and IV administration were similar, with small differences likely due to different initial time courses of absorption.

These data assume that the MEC as calculated for humans is relevant for alpacas and should be integrated with further pharmacodynamic studies. To determine the analgesic effect of tramadol in humans, some authors have used the plasma concentration of M1, the molecule indicated as responsible for most of the therapeutic effects (Garrido et al. 2003). In the present study, the metabolite M1 was detected at a concentration at or lower than the MEC (0.040 ± 0.030 μg/mL) reported for humans (Grond and Sablotzki 2004), and calculation of Δt _e for M1 was not possible. The low concentrations of the active metabolite are in accordance with earlier studies in goats (de Sousa et al. 2008), equines (Giorgi et al. 2007), and dogs (KuKanich and Papich 2004; Giorgi et al. 2009a, b, c), and in contrast to those reported for cats (Pypendop and Ilkiw 2008) and humans (Grond and Sablotzki 2004). The present study reports a higher plasmatic concentration of M2 than of M5 or M1. For the first time, a low plasma concentration of M5 has been reported. This could be due to the remarkable glucuronidation process in camelids (Al Katheeri et al. 2005) that leads to a high elimination rate for M1 and M5 (as glucuronides), without influencing M2.

Although the IV and IM routes of administration are almost bioequivalent (F = 81.5%) (Toutain and Bousquet-Melou 2004), the lower initial plasma concentrations of tramadol following IM administration may be therapeutically beneficial. IM administration has been suggested to have a lower incidence of side effects with a slightly longer onset of action (Lintz et al. 1999). Therefore, according to the data generated in this study, IM injection of tramadol in alpacas is a useful and better alternative to IV injection, despite the lack in the production of M1 that could limit the analgesic effect.