Validation of the rabbit pain behaviour scale (RPBS) to assess acute postoperative pain in rabbits (Oryctolagus cuniculus).

Considering the widespread use of rabbits in research that potentially causes pain and discomfort and the limited number of pain assessment validated tools in this species, we aimed to develop and validate a scale of acute postoperative pain in rabbits (RPBS). Footage of 58 rabbits from previous studies were used, recorded at 'baseline' (before orthopaedic and soft tissue surgeries), 'pain' (after surgery), 'analgesia' (after analgesic), and '24h post' (24 hours after surgery). The videos were randomised and assessed twice by four evaluators, within one-month interval between evaluations. After content validation, RBPS was further refined using the criteria from the validation. According to the principal component analysis, RPBS was considered unidimensional. The intra- and inter-observer reliability was excellent (ICC>0.80) for all evaluators. There was a high Spearman's correlation of the RPBS with unidimensional scales (>0.80) and a moderate correlation with the Rabbit Grimace Scale (0.68), confirming criterion validity. According to the mixed linear model, the scale was responsive, shown by the increase in pain scores after surgery. Construct validity was confirmed by known-group approach and internal relationships among items. Adequate item-total correlation (>0.3) was observed for all items, except for the attention to the affected area (0.04). The internal consistency was very good (Cronbach's α coefficient = 0.78; Mcdonald's ω coefficient = 0.83). The cut-off score for rescue analgesia was ≥3, with an area under the curve >0.95, demonstrating a high discriminatory capacity of the instrument. Scores 3 and 4 were within the uncertainty diagnostic zone. Specificity was 87% and sensitivity was 90%. It was concluded that the RPBS presented content, criterion, and construct validities, responsiveness, and reliability to assess acute pain in rabbits submitted to orthopaedic and soft tissue surgeries. The cut-off for rescue analgesia serves as a basis for the administration of analgesics to rabbits submitted to painful procedures.

A possible solution to model nonlinearity in elimination and distributional clearances with α2 -adrenergic receptor agonists: Example of the intravenous detomidine and methadone combination in sedated horses.

The alpha(α)2 -agonist detomidine is used for equine sedation with opioids such as methadone. We retrieved the data from two randomized, crossover studies where detomidine and methadone were given intravenously alone or combined as boli (STUDY 1) (Gozalo-Marcilla et al., 2017, Veterinary Anaesthesia and Analgesia, 2017, 44, 1116) or as 2-hr constant rate infusions (STUDY 2) (Gozalo-Marcilla et al., 2019, Equine Veterinary Journal, 51, 530). Plasma drug concentrations were measured with a validated tandem Mass Spectrometry assay. We used nonlinear mixed effect modelling and took pharmacokinetic (PK) data from both studies to fit simultaneously both drugs and explore their nonlinear kinetics. Two significant improvements over the classical mammillary two-compartment model were identified. First, the inclusion of an effect of detomidine plasma concentration on the elimination clearances (Cls) of both drugs improved the fit of detomidine (Objective Function Value [OFV]: -160) and methadone (OFV: -132) submodels. Second, a detomidine concentration-dependent reduction of distributional Cls of each drug further improved detomidine (OFV: -60) and methadone (OFV: -52) submodel fits. Using the PK data from both studies (a) helped exploring hypotheses on the nonlinearity of the elimination and distributional Cls and (b) allowed inclusion of dynamic effects of detomidine plasma concentration in the model which are compatible with the pharmacology of detomidine (vasoconstriction and reduction in cardiac output).