MultiSolfen®

…Tri-Solfen® (T-S, Medical Ethics, Melbourne, Australia), later registered and marketed in Europe as MultiSolfen® (M-S; Dechra, Northwich, UK), is a wound therapeutic for- mulation combining two local anaesthetics (lidocaine…

pplied directly to the disbudding wound, Tri-Solfen® is reported to be effective to mitigate post-operative pain [7,8]. To achieve regulatory approval for such uses, analgesic medicines must meet high standards of proof of safety, requiring detailed proscribed “margin of safety” studies examining the toxic effects of drugs at recommended dose and potential overdose levels. These trials, performed to internationally harmonized standards, are nevertheless invasive and may involve ethical constraints such as the requirement for single product use, where, in non- regulatory trials, multi-modal pain therapy may be used for optimal welfare. The need for such trials is reduced however, wherever sufficient high-quality data are publicly available. Lidocaine and bupivacaine, the local anaesthetics in Tri-Solfen® , although widely used in human and veterinary medicine for many decades, are not registered for use to mitigate pain in calves in most jurisdictions. Although their acute systemic neuro- and cardiotoxic effects are well described, unfortunately, at the time of these trials, there was insufficient information available to meet regulatory requirements for proof of safety of use in calves, including lack of information regarding potential wider biochemical, haematological or tissue toxic effects, or impacts when used via topical application to significant open wounds. We therefore have performed regulatory required margin of safety studies with Tri-Solfen® and report the outcome of these to contribute to the public record. It is hoped that these data may reduce the need for such trials for registration of lidocaine or bupivacaine containing products for calves in the future. We separately investigated and reported local anaesthetic pharmacokinetic data in calves

ming operations in Australia. This is likely to require a step-wise approach. Nevertheless, recent research and developments indicate that this can be achieved very successfully. The first major step towards achieving this goal was achieved with the development and commercial availability of Tri-Solfen® to alleviate the pain associated with mulesing. Tri-Solfen® is a farmer applied spray-on anaesthetic, haemostatic and antiseptic agent that is applied to numb the wound immediately post mulesing. It has a significant analgesic effect eliminating or significantly reducing wound pain and pain-related behaviour up to, and including, 8 hours post mulesing. It also lowers peak cortisol response, dramatically reduces bleeding and speeds up wound 1,2 contraction. Subsequent research has identified that pre-operative administration of a non-steroidal antiinflammatory agent significantly enhances the analgesic effect such that the combination not only abolishes pain-related behaviour up to and including 24 hours post mulesing, but also abolishes the cortisol response.2 In terms of pain alleviation and mitigation of stress response, this exceeds that which is achieved during equivalent surgical procedures in pets, such as ovariohysterectomy (spaying) 3,4 of cats and dogs. These recent developments have critically important welfare implications for sheep undergoing mulesing. The overwhelming weight of scientific evidence supports the fact that mulesing is the single 5 most effective preventative health measure to protect susceptible sheep against blowfly attack , yet under pressure from animal rights organisations Australian sheep farmers have committed to cease the procedure by the end of 2010. Should the procedure be stopped prematurely, (that is before genetic breeding is

ensitivity of the Tri-Solfen® formulation with no active anaesthetic or testing, before being returned to their dams and turned out to vasoconstrictor ingredients. The three spray-on gels were pasture. The remaining 239 lambs were weighed, and then each provided from the manufacturer in identical 1 L containers alternate lamb was treated with Tri-Solfen®. Mulesing wounds marked only as A, B or C. After mulesing and wound photography, were photographed prior to application of Tri-Solfen in the first lambs remained in the mulesing cradle for 3 min after which 100 of these lambs. All lambs were treated with Dicyclanil then skin and wound sensitivity scoring was performed. Lambs returned to dams on pasture. Lambs and ewes were re-yarded were then moved in their treatment groups to one of four and drafted 14 and 28 days later. Wounds initially photographed © 2008 The Authors Australian Veterinary Journal Volume 86, No 5, May 2008 161 Journal compilation © 2008 Australian Veterinary Association avj_285.fm Page 162 Thursday, April 17, 2008 5:08 PM PRODUCTION ANIMALS were re-photographed and lambs were weighed then returned to pasture. PRODUCTION ANIMALS Statistical analysis Data were analysed using SPSS version 14.0® (SPSS Inc. Chicago, Illinois). Boxplots were examined and one-way analysis of variance was used to measure the short term effects of treatment groups for which there was a reasonable amount of variation. Repeated measures analysis of variance was used to examine within-subject changes over time. Breech skin sensitivity scores before mulesing were adjusted to account for the lower number of testing sites (5) when used for comparison with post mulesing scores from the direct wound assessment sites (9). The average score per site was calculated prior to

s undertaken to address drug regulatory proof of efficacy require- ments to internationally harmonised (VICH), Good Clinical practice (GL9) guidelines [53]. Based on the data above, it was hypothesised that Tri-Solfen® application by wound in- stillation followed by a 30 s dwell time would result in a significant reduction in acute pain-induced responses during subsequent castration and in the early post-operative pe- riod as compared with untreated castrated (control) piglets. Nociceptive motor and vocal responses to castration were selected as the primary and secondary efficacy variables for assessment of pain mitigation during castration, while the primary efficacy variable for evaluation of post-operative pain-mitigation was a significant reduction in total “pain- specific” behaviour in the first 30 min following castration, as assessed via a combination of focal assessments and scan sampling. 2. Materials and Methods 2.1. Study Design The study was a multi-centred, negatively controlled, randomised and blinded study conducted between June and August 2018 to test the clinical efficacy of Tri-Solfen® (50 g/L Lignocaine hydrochloride, 5 g/L Bupivacaine hydrochloride, 0.048 g/L Adrenaline (as acid tartrate), 5 g/L Cetrimide). All study procedures were conducted under country-specific trial approvals, including ethical approval. In Germany, approval was obtained from the Schleswig-Holstein authority while approval for the Italian study was provided by the Min- istero della Salute. The study was conducted by independent contract research providers, in accordance with VICH guidelines for conduct of regulatory safety and efficacy field trials with the principles of Good Clinical Practice (GCP) as laid down in the Council Directive 2001/82/EC and guideline