Pharmacokinetics of tramadol and its major metabolite after intramuscular administration in piglets

Abstract

Tramadol (T) is a centrally acting atypical opioid used for treatment of dogs. Piglets might experience pain following castration, tooth clipping and tail docking and experimental procedures. The aim of this study was to assess the pharmacokinetics of T and its active metabolite M1 in male piglets after a single intramuscular injection. Six healthy male piglets were administered T (5 mg/kg) intramuscularly. Blood was sampled at scheduled time intervals and drug plasma concentrations evaluated by a validated HPLC method. T plasma concentration was quantitatively detectable from 0.083 to 8 h. M1 was quantified over a shorter time period (0.083-6 h) with a Tmax at 0.821 h. The study demonstrated that piglets produce a larger amount of M1 compared with dogs, horses and goats. The human minimum effective concentration of M1 (40 ng/mL) was exceeded for over 3 h in piglets. If it is assumed to also apply to piglets, it could be speculated that the drug efficacy might exert its action over 3 h or longer. This assumption has to be confirmed by further specific pharmacokinetic/pharmacodynamic studies.

Toxicokinetics of U-47700, tramadol, and their main metabolites in pigs following intravenous administration: is a multiple species allometric scaling approach useful for the extrapolation of toxicokinetic parameters to humans?

“…Generally, values for t 1/2 of tramadol appeared to be very species-related and, thus, indicate differences in metabolism and TK in different species as well. The t 1/2,γ of tramadol observed in this study (1.9 h) was a little bit higher than terminal t 1/2 reported for piglets (1.34 h) (Vullo et al 2014), horses (1.5 h) (Shilo et al 2008), and dogs (0.73 h) (Giorgi et al 2010), but lower than that reported in llama (2.54 h) (Cox et al 2011). Regarding the human terminal t 1/2 of tramadol published in the literature (Murthy et al 2000;Grond and Sablotzki 2004;World Health Organization 2014), values between 5 and 6 h were mostly determined.…”

“…As already shown in other animal studies, CL values of pigs were higher than those obtained for humans after i.v. administration, supporting the assumption of a faster metabolism of tramadol in pigs compared to human (Grond and Sablotzki 2004;Vullo et al 2014). On the other hand, in humans, a higher V (~ 3L/kg) was observed as compared to our study (V = ~ 1.25 L/kg) indicating a higher distribution in deep compartments (Murthy et al 2000).…”

Analgesic Efficacy of Subcutaneous–Oral Dosage of Tramadol after Surgery in C57BL/6J Mice

“…of tramadol depends on the parent compound and on its first metabolite, which is as much as 6 times more potent than tramadol itself. 25,30 Although the serum concentrations of tramadol in our mice decreased rapidly, the levels of M1 remained high for 18 h in our study, and we, therefore, expect an analgesic effect from the tested treatment.…”

“…3,27 The clinical efficacy of tramadol is highly related to its first metabolite, O-demethyltramadol hydrochloride (M1), which has 200-fold higher affinity for μ receptors and as much as 6-fold higher analgesic potency than tramadol itself. 25,30 Because of its 'double' mechanism of action, tramadol at clinical doses does not induce respiratory depression or hemodynamic changes, which are common to other opioids with high μ-receptor activity. 9,21,26 Moreover, tramadol is an affordable and non-controlled substance in many countries, thus facilitating its use.…”

Femoral head ostectomy for the treatment of acetabular fracture and coxofemoral joint luxation in a Potbelly pig

“…There is no established oral tramadol dose for miniature pigs; however, tramadol has been shown to improve anesthesia in miniature pigs when administered with tiletamine‐zolazapam and xylazine as well as when administered with ketamine‐xylazine protocols in young pigs . The pharmacokinetics of a 5 mg/kg dose of IM tramadol have been described for pigs, but more research is needed to determine the appropriate orally administered pain management for this drug in pigs.…”