Lomax Sheil Windosr_2008_AVJ

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PRODUCTION ANIMALS © 2008 The Authors Australian Veterinary Journal Volume 86, No 5, May 2008Journal compilation © 2008 Australian Veterinary Association 159 PRODUCTION ANIMALS Blackwell Publishing Asia Impact of topical anaesthesia on pain alleviation and wound healing in lambs after mulesing S LOMAX, a M SHEIL b and P A WINDSOR a,c Objective To investigate the impact of using the topicalanaesthetic preparation Tri-Solfen® on pain alleviation and wound healing in lambs undergoing mulesing. Design Three separate trials, placebo controlled and/orrandomised, were carried out over a 5 month period on threemobs of between 60 and 263 merino lambs undergoing routine mulesing. Procedure Wound pain was assessed using 10 and 75 gcalibrated Von-Frey monofilaments to determine sensitivity to light touch and pain stimulation over a 4 to 8 h period. Pain-related behaviour was documented by trained, blindedobservers using a numerical rating scale. Wound healing rates were determined using scaled digital photography and imageanalysis software to calculate contraction in wound surface area 2 and 4 weeks after mulesing. Results There was rapid (3 min) and prolonged (up to 8 h)wound analgesia as shown by pain response scores (P ≤ 0.01),with absent or significantly diminished primary and secondary hyperalgesia (P ≤ 0.01) and significant reduction in pain-relatedbehaviour (P < 0.001) in treated versus untreated lambs. Inaddition there was improved wound healing in the treated lambs (P ≤ 0.05). Conclusion Tri-Solfen® effects rapid and prolonged woundanalgesia, reduction in pain-related behaviour and improved wound healing in lambs undergoing routine mulesing, providingeffective alleviation of pain associated with routine mulesing in sheep. Key words: lambs, mulesing, analgesia,

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undergoing routine mulesing, providingeffective alleviation of pain associated with routine mulesing in sheep. Key words: lambs, mulesing, analgesia, welfare Aust Vet J 2008;86:159–168doi: 10.1111/j.1751-0813.2008.00285.x LTLight touch sensationPPain sensation WSAWound surface area A nimal husbandry procedures such as mulesing, taildocking and castration are currently performed on between 15 to 20 million merino lambs annually inAustralia. These procedures cause acute pain and stress, 1,2 resulting in significant disruption to normal behaviour. 2,3 Despite this, they are currently performed routinely withoutpain management. Whilst the procedures may be justified foranimal preventative health or production management reasons, there is growing opposition to them, particularly from animal advocacy organisations. Increasingly, the infliction of pain is considered to breech acceptable standards of humane animal care. Mulesing, the practice of cutting loose folds of skin from the breech area of sheep, is the most important recent example. Concern for the welfare of lambs undergoing this procedure is resulting in international retail boycotts of Australian wool.The ideal long term solution is to develop painless alternatives tosuch procedures. In the interim, the development of effective pain management must be given high priority to decrease animal suffering. At present however, there is lack of commercially available pain-alleviating options that meet the practical and economical constraints of production animal husbandry.Topical local anaesthesia may be well suited to productionanimal farming because of its low cost, practicality and ease of application. Local anaesthetic agents generally have poor skin penetrability, which limits their use for pre-procedural skin

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practicality and ease of application. Local anaesthetic agents generally have poor skin penetrability, which limits their use for pre-procedural skin anaesthesia. However, they are well known to be rapidly and highly effective when applied to open wounds or mucosal tissues 4–9 and may therefore provide an effective means ofproviding analgesia in the immediate and intermediate post-procedural period, which is arguably the time of maximal pain and stress. 1,2,10–12 Recently, Tri-Solfen® (Bayer Animal Health, Gordon, NSW) aspray-on topical anaesthetic and antiseptic gel became commercially available for use on farms in Australia. The product was specifically designed for pain management in sheep undergoing surgical procedures such as mulesing. It contains lignocaine (as the hydrochloride) 40.6 g/L and bupivacaine (as the hydrochloride) 4.5 g/L, adrenaline (as tartrate) 24.8 mg/L and cetrimide 5.0 g/L. It is sprayed directly on the wound immediately after the procedure.In this paper we report results from a series of trials investigatingthe impact of using Tri-Solfen® topical anaesthesia on pain alleviation and wound healing rates, as well as weight gain and mortality in lambs undergoing routine mulesing. Methods Three separate studies were performed on lambs of mixed sexfrom commercial flocks aged 6 to 12 weeks undergoing routine mulesing (study 1) or mulesing and marking (including surgical castration, tail docking and ear notching, plus ear tagging and vaccination) (studies 2 and 3). Lambs were born in both autumn a Faculty of Veterinary Science, University of Sydney, PMB 3, Camden, New South Wales, 2570 b Animal Ethics Pty Ltd, PO Box 363, Yarra Glen, Victoria 3775 c author for correspondence: pwindsor@camden.usyd.edu.au avj_285.fm Page 159 Thursday, April 17,

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Ethics Pty Ltd, PO Box 363, Yarra Glen, Victoria 3775 c author for correspondence: pwindsor@camden.usyd.edu.au avj_285.fm Page 159 Thursday, April 17, 2008 5:08 PM

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PRODUCTION ANIMALS PRODUCTION ANIMALS Australian Veterinary Journal Volume 86, No 5, May 2008© 2008 The AuthorsJournal compilation © 2008 Australian Veterinary Association 160 and spring of 2006 and were pastured with their dams on twoproperties, in the southern highlands and central tablelands of NSW respectively. General management and mulesing On the day of each trial, lambs from each flock were yarded anddrafted into a holding yard. They were then selected at random, weighed, ear-tagged and placed in mulesing cradles. Pre-operativeskin sensitivity scoring was performed as required (see below).Lambs were then mulesed by accredited mulesing contractor using standard ‘V’ modified mulesing technique. In Trials 2 and 3, lambs were also surgically tail docked and ram lambs were surgically castrated immediately prior to mulesing. After this, lambs were managed according to one of three trial protocols in which outcomes were measured at different time points and varying conditions, as outlined below. Outcomes measuredincluded skin and wound sensitivity, pain-related behaviour, wound healing, weight change and mortality. Assessment of skin and wound sensitivity Von-Frey monofilaments are used to quantitate sensation. Theyare calibrated to bend at predetermined pressures to provide repeatable light touch (LT) or pain (P) stimulation. Thesewere used to test skin and wound sensitivity to LT (10Nmonofilament) and P (75N monofilament) stimulation before mulesing and up to 8 h after mulesing at five predetermined sites on the skin of the breech and nine sites on the mulesing wound (Figure 1A and B). Evidence of local anaesthesia, allodynia (pain from stimuli suchas light touch that is not usually painful), and/or primary and secondary hyperalgesia (exaggerated response

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sthesia, allodynia (pain from stimuli suchas light touch that is not usually painful), and/or primary and secondary hyperalgesia (exaggerated response to a painful stimulus directly in the damaged tissues or in surrounding undamaged tissues respectively), was assessed at each site. Typical LT and P induced involuntary reflexes and motor responses in the rump and head were graded by vigour. Rump response scores were graded as follows: 0 = no response; 1 = minor involuntary motorresponse such as local skin twitch, subcutaneous muscle twitchor anal contraction; 2 = partial rump withdrawal reflex such asmultiple subcutaneous muscle group contraction and/or lifting of the tail; 3 = full rump withdrawal reflex with lifting of therump off the cradle. Facial response scores were graded asfollows: 0 = no response; 1 = minor facial ‘awareness’ such as eyewidening, blinking or nasal flaring; 2 = partial startle reflex of thehead such as slight lifting of the snout or partial head rotation; 3 = full startle reflex of the head, resulting in a major movementsuch as lifting head off the cradle, full head jerk or full head rotation. Scores for each site were added to achieve a total scorefor each lamb. Total scores were calculated out of 30 for skin sensitivity around the mulesed area, and out of 54 for direct wound sensitivity. Pain-related behaviour Pain-related behaviour was assessed using a numerical ratingscale at various different time points after mulesing. The scale was developed based on a combination of previous fieldobservations and reports of behavioural changes in response tomulesing and/or castration. 1,2 A trained observer (veterinarian orexperience sheep handler, ‘blind’ to the treatment) was asked to observe each lamb for a period of time sufficient to

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trained observer (veterinarian orexperience sheep handler, ‘blind’ to the treatment) was asked to observe each lamb for a period of time sufficient to determine posture, gait and evoked behaviour, then grade each lamb on a scale from 0 to 3 where: 0 = no evidence of pain relatedbehaviour; 1 = mildly abnormal posture, gait or behaviours suchas mild arching of the back without wide rear leg stance orextension of back legs, ventral lying with legs partially extended, mild stiffening of gait without overt limping or leg dragging; 2 = moderate abnormalities of posture, gait and behaviours such as;statue standing head down with prominent arching of the back, prominent extension and/or abduction of hind legs, marked agitation with leg stamping, ventral lying with hind legs fully Figure 1.Diagram of sites of light touch and pain stimulation sensorytesting. A. On skin of the breech; B. Directly on the mulesing wound sites. avj_285.fm Page 160 Thursday, April 17, 2008 5:08 PM

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PRODUCTION ANIMALS © 2008 The Authors Australian Veterinary Journal Volume 86, No 5, May 2008Journal compilation © 2008 Australian Veterinary Association 161 PRODUCTION ANIMALS extended, limping or markedly abnormal gait with hind legabduction and/or dragging, anorexia and lack of interest in feeding; 3 = extreme abnormalities of posture, gait and/or behavioursuch as; rear leg collapse, dog sitting, lateral lying or lying with head flat, prominent tremors and shaking, inability to stand and/ or marked and unusual leaning. Wound healing Wound healing was assessed by mapping wound surface area(WSA) using digital photography and Scion Image PC® digitalimage analysis software (National Institute Health, USA). Digital photographs were taken with a linear scale held against the wool immediately above the wound. Using the image analysis software, pixels per cm 2 were calculated, then the wound outlinewas mapped and surface area was calculated in cm 2 . Tworecordings were made for each image by two separate assessorsand the results were averaged to provide the final surface area measurement. Wounds were photographed at the time of mulesing (before application of any treatment) and 14 and 28 days later. Images were identified by lamb tag number and assessors were blind to treatment protocol at the time of performing assessments. Weights Weights were recorded at time 0, and day 14 and 28 in Trial 3using digital scales (Rudweigh®) which were calibrated and zeroed prior to each measurement and accurate to 0.1 kg. Trial protocolsTrial 1 A placebo controlled trial (n = 60) was initiated toexamine skin and wound sensitivity to LT and P sensation 3 min and 4 h after mulesing in lambs that were undergoing mulesing only. Tail docking and castration of wether lambs had been

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y to LT and P sensation 3 min and 4 h after mulesing in lambs that were undergoing mulesing only. Tail docking and castration of wether lambs had been previously performed and wounds were fully healed. Pain-related behaviour was measured 1, 2 and 4 hours aftermulesing and wound healing was documented as outlined above. Lambs were managed in 4 sequential groups (15 in each group): Group 1 = mulesing ‘control’ group (no post mulesingtreatment applied); Groups 2 to 4 were treatment groups. Each treatment group received one of three post-mulesing treatments (A, B or C) which were spray-on gels applied by metered dose immediately after mulesing. Treatments A and Cconsisted of Tri-Solfen® and B was placebo gel. They wereapplied directly to the wound using the commercially supplied Tri-Solfen® metered dose applicator, in doses of 6 to 12 mLsbased on lamb weight, according to manufacturer recommenda- tions for Tri-Solfen®. The placebo was visually indistinguishable from Tri-Solfen® and consisted of the blue spray-on gel base of the Tri-Solfen® formulation with no active anaesthetic or vasoconstrictor ingredients. The three spray-on gels wereprovided from the manufacturer in identical 1 L containers marked only as A, B or C. After mulesing and wound photography, lambs remained in the mulesing cradle for 3 min after which skin and wound sensitivity scoring was performed. Lambs were then moved in their treatment groups to one of four20 m 2 pasture covered yards at a minimum of 40 m from thehandling yards, for quiet observation and pain-related behaviour scoring. Lambs were then re-yarded and placed in the mulesing cradle for 4-hour wound sensitivity assessment, before being returned to their dams and turned out to pasture. Lambs werere-yarded 2 and 4 weeks later when

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e for 4-hour wound sensitivity assessment, before being returned to their dams and turned out to pasture. Lambs werere-yarded 2 and 4 weeks later when wounds were examined andre-photographed. Trial 2 This trial examined wound sensitivity to P stimulationand pain-related behaviour in 80 lambs undergoing both mulesing and marking. The first 24 lambs were allocated to wound sensitivity testing. General management with mulesing was as above. Alternate lambs were treated with Tri-Solfen® or remained untreated. Spinosyn (Extinosad®, Elanco AnimalHealth, Macquarie Park, NSW) with blue food dye added toachieve blinding was applied according to recommendations as a flystrike preventative treatment. Lambs remained in the cradle for 3 min after which skin and wound sensitivity was performed. They were then housed in a mixed treatment group in an indoor pen and returned to the mulesing cradle at one and 4 h after mulesing for repeat skin and wound sensitivity testing, before being returned to their dams and turned out to pasture. The remaining 56 lambs were identified by a coloured number, andused to assess pain-related behaviour. After mulesing lambs were randomly allocated to receive Tri-Solfen® or remain untreated (28 lambs in each group) and Spinosyn was applied, as above. Lambs were then moved to 3 × 4 m indoor pens for quietobservation and pain-related behaviour scoring. An additional eight lambs served as unmulesed controls. These were placed in the cradle but remained unmulesed and unmarked. Each pen thus contained seven lambs, including six mulesed lambs (mixed treated and untreated) and one handled but unmulesed control lamb. Behaviour scoring was performed 5 min after return to the pen, and at 1 and 4 h. Lambs were then returned to their dams and turned out to

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ontrol lamb. Behaviour scoring was performed 5 min after return to the pen, and at 1 and 4 h. Lambs were then returned to their dams and turned out to pasture. Trial 3 This trial examined wound sensitivity, wound healingand weight change in a mob of 263 lambs undergoing mulesing and marking. Wound and skin sensitivity to LT and P sensation was assessed in the first 24 lambs with an extra assessment 8 hours after mulesing. General management with mulesing occurred as above. Alternate lambs were then either treated with Tri-Solfen® or remained untreated. Dicyclanil (Clik®, NovartisAnimal Health Australasia Pty Ltd, North Ryde, NSW) was used to prevent flystrike (8 mL applied to wool around the wound). Lambs remained in the cradle for 3 min after which skin and wound sensitivity was assessed. They were then kept in a pasture covered holding yard and returned to the mulesing cradle at 4 and 8 h after mulesing for repeat skin and wound sensitivity testing, before being returned to their dams and turned out to pasture. The remaining 239 lambs were weighed, and then each alternate lamb was treated with Tri-Solfen®. Mulesing wounds were photographed prior to application of Tri-Solfen in the first100 of these lambs. All lambs were treated with Dicyclanil then returned to dams on pasture. Lambs and ewes were re-yardedand drafted 14 and 28 days later. Wounds initially photographed avj_285.fm Page 161 Thursday, April 17, 2008 5:08 PM

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PRODUCTION ANIMALS PRODUCTION ANIMALS Australian Veterinary Journal Volume 86, No 5, May 2008© 2008 The AuthorsJournal compilation © 2008 Australian Veterinary Association 162 were re-photographed and lambs were weighed then returnedto pasture. 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 toexamine 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 mulesing and multiplied by 9. Where there were significant differences in baseline measurements ANCOVA/ regression was used to adjust for these differences. Post-hocpair-wise comparisons are reported for analyses in which the between group comparison was significant at P < 0.05. Multiplelinear regression was used to examine relationships between contiguous variables. Results Weather conditions In Trial 1, weather was cool to cold and dry at 5 to17 ° C with nofly activity. In Trial 2, weather was warm and wet, with heavy rain within 24 h with moderate fly activity. In Trial 3, weather was hot and dry at 27 to 33 ° C with extremely high fly activity,resulting in seven lambs found with fly-strike prior to mulesing,and these were excluded from the trial. Lamb weights Mean initial body weight in Trial 1 was 13.1 ± 2.5 kg, Trial 2 was16.8 kg ± 4 kg and Trial 3 was 14.2 ± 2.6 kg. In Trial 3, weightswere recorded

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ights Mean initial body weight in Trial 1 was 13.1 ± 2.5 kg, Trial 2 was16.8 kg ± 4 kg and Trial 3 was 14.2 ± 2.6 kg. In Trial 3, weightswere recorded Day 0, 14 and 28 on the mob of 263 lambs. Sevenflyblown lambs on day 0 were excluded from further recordings, and 14 of the remaining 256 lambs either died or were missing for one or more follow up recordings. Weight data was therefore available for 242 lambs, 121 untreated and 121 Tri-Solfen® treated. There was a mean weight gain of 600 g after 2 weeks (both groups), and 1.3 and 1.4 kg after 4 weeks in untreated and Tri-Solfen® treated lambs respectively. Morbidity and mortality There were no clinical signs consistent with lignocaine-inducedneuro or cardiotoxicity in any lambs treated with Tri-Solfen®. There was zero mortality in Trial 1. In Trial 2, lambs faced an unexpected major Haemonchus contortus burden post mulesingwith anaemia and anorexia. Weight and mortality data were therefore not pursued. In Trial 3, 10 of 263 lambs wereconfirmed to have died during the 4 week trial period (mortality 3.8%). Of these two had been flyblown on day 0, two were Tri- Solfen® treated, two were untreated and four were unable to beidentified due to loss of ear tags. In addition seven lambs were missing (three treated, three untreated, one flyblown day 0),presumed to have either died or escaped and mixed into a mobin large adjoining paddock. Response to LT and P stimulation of the wound and surrounding skin Pre mulesing There was very little response to LT or P stimulationof intact skin of the breech prior to mulesing. Mean response scores from the five testing sites (maximum possible score of 30) were ≤ 0.1 ± 0.4 for LT and ≤ 1.9 ± 3.4 for P, across all threetrials (Figures 2, 3 and 4). There were no significant

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es (maximum possible score of 30) were ≤ 0.1 ± 0.4 for LT and ≤ 1.9 ± 3.4 for P, across all threetrials (Figures 2, 3 and 4). There were no significant differences between groups within each trial. Post mulesingMulesed, untreated sheep. These demonstratedincreasing allodynia and primary hyperalgesia with a significant Figure 2.Graphs showing mean total response score ( ±±±± SE) to light touchof the wound with a 10N Von Frey filament at various time points before and after mulesing. A. Trial 1, with results to 4 h post mulesing; B. Trial 3 with results to 8 h post mulesing. avj_285.fm Page 162 Thursday, April 17, 2008 5:08 PM

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PRODUCTION ANIMALS © 2008 The Authors Australian Veterinary Journal Volume 86, No 5, May 2008Journal compilation © 2008 Australian Veterinary Association 163 PRODUCTION ANIMALS increase in response over time to LT (P ≤ 0.001 in Trials 1 and 3,Figure 2) and P stimulation (P < 0.001, Trials 1 and 3, and P = 0.01 Trial 2, Figure 3). Untreated sheep also demonstratedincreasing secondary hyperalgesia, with an increase in response to P stimulation of intact skin around the mulesed area over time(P ≤ 0.003, Figure 4). Maximal hyperalgesic responses to Pstimulation were elicited from the tail and/or the right and left cut skin edges proximal to the tail in all three trials. The central body of the wound distal to the tail was relatively insensitive with maximum mean P response scores on the right and left ≤ 0.7 atall time points in all three trials. Figure 5 show mean response scores to P stimulation at each testing site, at each of the different time points in Trial 3. Tri-Solfen® treated sheep Primary allodynia, and primary andsecondary hyperalgesia were either absent (Trials 2 and 3) or significantly reduced (Trial 1) in Tri-Solfen® treated lambs over the 4 to 8 hour monitored periods. In Trials 2 and 3 there was no significant change in response to LT and P stimulation over time. In Trial 1, LT and P response scores were significantly belowthose of untreated (P < 0.001 for LT, and P ≤ 0.01 for P) orplacebo treated (P < 0.001 and P = 0.002, respectively) lambs(Figures 2 to 4, Table 1). Placebo gel treated sheep (Trial 1) The LT responses were similarto untreated sheep and significantly greater than Tri-Solfen® treated sheep (P < 0.001) (Figures 2 to 4, Table 1).Response scores to P stimulation were lower than in untreatedsheep (P = 0.014) however were

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olfen® treated sheep (P < 0.001) (Figures 2 to 4, Table 1).Response scores to P stimulation were lower than in untreatedsheep (P = 0.014) however were significantly higher than inTri-Solfen® treated sheep (P < 0.001). Hyperalgesia to P stimu-lation in the skin around the mulesed area was similar to untreated sheep and significantly higher than Tri-Solfen® treated sheep (P = 0.002). Pain-related behaviour Results are summarised in Figure 6 and Table 2. There was asignificant increase in pain-related behaviour scores between 1 Figure 3.Graphs showing mean total response score ( ±±±± SE) to pain stimu-lation of the wound with a 75N Von Frey filament at various time points before and after mulesing. A. Trial 1; B. Trial 2 with results to 4 h post mulesing; C. Trial 3 up to 8 h post mulesing. Figure 4. Graph showing mean total response score (±±±± SE) to pain stimula-tion of the skin around the mulesed area with a 75N Von Frey filament before mulesing and 4 h and 8 h after mulesing. avj_285.fm Page 163 Thursday, April 17, 2008 5:08 PM

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PRODUCTION ANIMALS PRODUCTION ANIMALS Australian Veterinary Journal Volume 86, No 5, May 2008© 2008 The AuthorsJournal compilation © 2008 Australian Veterinary Association 164 and 2 4 hours after mulesing (Trial 1), and between 5 minutesand 1 hour after mulesing and marking (Trial 2) with a significant group effect (P < 0.001 and P = 0.055 Trials 1 and 2respectively). Tri-Solfen® treated sheep demonstrated significantlylower pain–related behaviour scores compared with placebo gel treated (P = 0.03, Trial 1), and untreated mulesed lambs (P < 0.001 Trial 1, P = 0.05, Trial 2) and were not significantlydifferent from unmulesed controls (Trial 2). Placebo gel treated sheep also had lower pain-related behaviour scores thanuntreated sheep (P = 0.01, Trial 1), although this was lessprominent than in Tri-Solfen® treated sheep. Wound healingTrial 1 Despite equivalent body weights, mean initial WSA wassignificantly smaller in untreated than in placebo (P = 0.002)and Tri-Solfen® treated (P = 0.03) lambs (Figure 7). At day 14mean WSA was not significantly different between the groups. Using repeated measures analysis there was a significant group Figure 5.Colour coded representation of the mean motor response score at each testing site to pain stimulation with a 75N Von Frey monofilament, beforeand at times up to 8 hours after mulesing in Trial 3 lambs, comparing untreated lambs with those treated with Tri-Solfen®. Table 1.Between subject effects and pairwise comparisons of response to light touch (LT) and pain (P) stimulation of wound and surrounding skin follow - ing mulesing comparing untreated lambs with those treated with Tri-Solfen (Trials 1–3) and placebo gel (Trial 1)Group 1Group 2LT response score woundP response score woundP response score Peri-mules

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e treated with Tri-Solfen (Trials 1–3) and placebo gel (Trial 1)Group 1Group 2LT response score woundP response score woundP response score Peri-mules skinMean Diff (1-2)SEp groupMean Diff (1-2)SEp groupMean Diff (1-2)SEp groupTrial 1mulesTri-Solfen1.580.28< 0.0018.100.81<0.0011.380.37< 0.001mulesplacebo0.540.320.102.360.930.0140.20.430.64placeboTri-Solfen1.040.28< 0.0015.830.81<0.0011.180.370.002Trial 2mulesTri-Solfen8.032.590.005Trial 3mulesTri-Solfen1.720.22< 0.0017.731.010.013.80.780.012 avj_285.fm Page 164 Thursday, April 17, 2008 5:08 PM

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PRODUCTION ANIMALS © 2008 The Authors Australian Veterinary Journal Volume 86, No 5, May 2008Journal compilation © 2008 Australian Veterinary Association 165 PRODUCTION ANIMALS effect, with placebo-gel and Tri-Solfen® treated groupsdemonstrating faster wound contraction than untreated lambs over the first 14 days after mulesing (P = 0.05). By day 28, allthree groups had ≥ 90% of wounds fully healed (mean WSA < 0.7 cm 2 in all groups). Mean bare area 28 days after mulesingwas 20 ± 5 cm 2 , and was not statistically different between thegroups. There was no significant correlation between lamb weight or initial wound size and bare area size at 28 days. Therewas no clinical evidence of wound infection or flystrike in any of the wounds during the observed period. Trial 3 Mean initial WSA was not significantly differentbetween untreated and Tri-Solfen® treated lambs. There was a significant effect of treatment group on WSA measurements over time (P = 0.005). At day 14 and day 28 Tri-Solfen® treatedsheep had a significantly smaller average WSA than untreated sheep (P = 0.007 and P = 0.02 respectively, Figure 7). There waspositive correlation between lamb weight and WSA on day 0 (R = 0.46, P = 0.001) indicating larger initial wound size in largerlambs. Mean bare area at day 28 was 13.1 ± 5.5 cm 2 , and was Figure 6.Mean numerical rating scale pain-related behaviour scores attime points up to 4 h following mulesing in lambs comparing untreated lambs with: A. lambs treated with Tri-Solfen® or placebo gel (Trial 1); B. lambs treated with Tri-Solfen® and unmulesed controls (Trial 2). Table 2.Between subject effects and pairwise comparisons of pain-relatedbehaviour (mean numerical rating scale scores) following mulesing, comparing untreated mulesed lambs, with:

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ts and pairwise comparisons of pain-relatedbehaviour (mean numerical rating scale scores) following mulesing, comparing untreated mulesed lambs, with: mulesed lambs treated with Tri-Solfen (Trials 1 and 2); placebo gel (Trial 1); or unmulesed controls (Trial 2 ) Group 1Group 2Numerical rating scale scoreMean Difference (1-2)Std Errorp valueTrial 1mulesplacebo gel0.50.190.01mulesTri-Solfen0.950.19< 0.001placebo gelTri-Solfen0.450.190.03Trial 2mulescontrol0.870.20.001mulesTri-Solfen0.780.2< 0.001controlTri-Solfen−0.090.20.7 Figure 7.Mean ( ±±±± SE) mulesing wound surface area (cm 2 ) in Tri-Solfen®and placebo treated, and untreated lambs immediately after mulesing and 14 and 28 days later. avj_285.fm Page 165 Thursday, April 17, 2008 5:08 PM

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PRODUCTION ANIMALS PRODUCTION ANIMALS Australian Veterinary Journal Volume 86, No 5, May 2008© 2008 The AuthorsJournal compilation © 2008 Australian Veterinary Association166not significantly different between Tri-Solfen® treated anduntreated lambs. Wound contraction was significantly slower in Trial 3 than in Trial 1 lambs.DiscussionResults from our trials indicate that highly significant alleviationof pain and improved wound healing can be achieved in lambs after mulesing, with and without tail docking, using a commercially available topical anaesthetic and antiseptic spray-on gel preparation. This has a major potential welfare benefit for lambs having this the procedure.The safety and efficacy profiles of local anaesthetic agents arewell described in sheep.13–16 Lignocaine is highly effective as alocal anaesthetic agent when administered using infiltrativetechniques in lambs undergoing castration and tail docking,17,18however, there is little information regarding the use of topicalanaesthesia in lambs. Tri-Solfen® contains lignocaine, bupi- vacaine and adrenalin in doses equivalent to formulations thathave been used to provide effective topical wound anaesthesia and haemostasis in humans.4,5 The combination of lignocaineand bupivacaine is designed to provide rapid onset local anaesthesiaof prolonged duration. The addition of adrenalin is designed to achieve haemostasis and to intensify and prolong the local effect of the anaesthetic actives by reducing systemic absorption. Recently, Paull et al reported a reduction in peak cortisolresponse and in pain-related behaviour post-mulesing, in lambstreated with Tri-Solfen®,20 providing the first documentedevidence that topical anaesthesia may provide an effective pain-alleviation strategy for lambs

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reated with Tri-Solfen®,20 providing the first documentedevidence that topical anaesthesia may provide an effective pain-alleviation strategy for lambs undergoing mulesing. These results are supported and enhanced by our own findings.Documenting the efficacy of pain relief in animals can be difficult,especially in lambs where behavioural responses to pain can be subtle and conflicting. We elected to combine behavioural observations with direct wound sensory testing, rather thanmeasurement of biochemical or physiological responses, as these provide an indirect assessment of pain and are readily confounded by non-pain related variables such as handling, stress and wounding. Cortisol levels, for example, rise during surgical procedures even when pain is completely abolished by general anaesthesia.21,22 This is because cortisol plays animportant role in maintaining blood volume, mediating the inflammatory response and facilitating wound healing so that levels may rise even if pain is absent.23 This may explain thefindings of Paull et al,20 who reported that treatment of lambswith non-steroidal inflammatory drugs resulted in a significant reduction in post-mulesing pain-related behaviour, but not in acorresponding reduction in cortisol response.Similar issues limit the reliability of parameters such as heartrate, blood pressure or endorphin release, for estimating pain alleviation in this setting. In addition Tri-Solfen® contains adrenalin, which can have important and confounding effects on such physiological parameters.Quantitative sensory testing is a validated technique that iswidely used in scientific literature. Observation of reflex responsesto an acute painful stimulus is an objective, repeatable and readilymeasurable form of assessing pain and allows

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rature. Observation of reflex responsesto an acute painful stimulus is an objective, repeatable and readilymeasurable form of assessing pain and allows the assessor to distinguish between various analgesic interventions.24 Ourfindings provide new and important information, particularly regarding the onset, evolution and distribution of pain frommulesing wounds.Our results indicate that mild hypersensitivity to LT and Pstimulation is evident within the wound within in the first few minutes after mulesing. This is followed by increasing allodynia, and primary and secondary hyperalgesia which escalates in the ensuing 8 hours. These findings are consistent with published studies on pain from skin incisions and open wounds.28–31Local anaesthetic agents act directly on nerve tissue to reversibly block conduction of signals responsible for the sensation of pain. By blocking the initial nerve fibre signals local anaesthetics notonly effect wound anaesthesia, but can also prevent or reduce the subsequent pain escalation response. This occurs even when local anaesthetics are administered after the incision,27,29,32 a findingsupported by our results.There appeared to be a moderate pain alleviating effect of theplacebo gel. This consisted of the gel base of the Tri-Solfen® formulation without anaesthetics or adrenalin. It is possible that the gel base had an independent intrinsic analgesic effect by forming a barrier over the surface of the wound. Barrier gels and creams have been shown to provide an analgesic effect whenapplied to open wounds, by coating denuded nerve endings and providing a barrier against on-going environmental exposure and touch stimulation.33,34Another important finding was that the cut skin edge was more sensitive than the body of the wound,

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g environmental exposure and touch stimulation.33,34Another important finding was that the cut skin edge was more sensitive than the body of the wound, particularly in close proximity to the tail. This suggests that the highest nerve fibre density exists in this area and highlights the importance of ensuringadequate cover of the area with the anaesthetic agent. We examined pain-related behaviour in lambs using a numericalrating scale. These are subjective and can lack sensitivity, but are commonly used for grading pain behaviour35–37 and have beenused in many pain trials.38–41 We attempted to limit subjectivityand reduce potential bias by using a single observer blinded to treatment protocol and having a clearly defined scale based on abnormal postures and behaviours that have previously been defined in lambs after mulesing.1,2,11,20 In addition we examinedlambs grouped according to treatment (Trial 1) and in mixed treatment groups (Trial 2), and included placebo gel and unmulesed control groups. Our results, indicating that Tri-Solfen® treatment significantly reduced or abolished wound pain and pain related behaviour in the first 4 h after mulesing concurs with and supports the recent findings of Paull et al.20 Our findingsof absent or significantly reduced wound pain in treated lambs 8 hours after mulesing are also consistent with the findings of Paull et al20 who reported a significant reduction in pain relatedbehaviour (specifically less stiff walking and less standing with hunched posture compared with untreated lambs, and normal feeding) at a similar time point (4 to 8 h post mulesing). avj_285.fm Page 166 Thursday, April 17, 2008 5:08 PM

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PRODUCTION ANIMALS © 2008 The AuthorsAustralian Veterinary Journal Volume 86, No 5, May 2008Journal compilation © 2008 Australian Veterinary Association167 PRODUCTION ANIMALSIn our trials, pain-related behaviour was greater, and earlier inonset, in Trial 2 than Trial 1 lambs. Observation conditions may have played a role in this finding, as pain-related behaviours may be heightened where animals are held in relatively confined indoor pens as occurred in Trial 2, rather than open paddocks removed from visual and auditory stressors as occurred in Trial 1.However, the finding is most likely to reflect that Trial 2 lambswere also undergoing tail docking and castration. Castration iscommonly performed at the time of mulesing and generates significant pain unrelated to the mulesing wound. This pain was not addressed in our trial, and may explain the increased variability in post-mulesing pain-related behaviour scores in Trial 2. To minimise the suffering associated with mulesing and marking it will be necessary to develop strategies to deal with castration-related pain in wether lambs. Studies investigating the efficacy oftopical anaesthesia for alleviation of castration-related pain have begun.Wound healing is a critical outcome of the mulesing procedure.Wound contraction results in reduction of wrinkle and enlargementof the bare area of the breech, which are believed to be the principle factors that reduce susceptibility to fly-strike. Despite this, there is currently very little information documenting wound healing patterns after mulesing and our findings contribute important new information.Initial wound surface area had an important impact on woundhealing rates with larger wounds taking significantly longer to heal within each trial group. Interestingly, and

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e area had an important impact on woundhealing rates with larger wounds taking significantly longer to heal within each trial group. Interestingly, and contrary to expectations, initial wound size did not appear to correlate with resulting bare area size in untreated lambs. Together these findings suggest that limiting initial mulesing wound size may result in production and welfare benefits without necessarily having a negative effect on bare area enlargement. This may be an important area for future study.Studies suggest that local anaesthetic infiltration can have delete-rious effects on wound healing after surgical incisions,42 butimpaired wound healing has generally not been apparent in clinical trials.43 We have documented a significant improvementin wound contraction rates in lambs treated with Tri-Solfen®. In Trial 1, there was an unanticipated and inadvertent discrepancyin initial wound size between groups. Nevertheless improved wound healing with Tri-Solfen® was suggested by finding a sig- nificant group effect over the first 14 day evaluation period. This was confirmed in the second larger trial in which initial wound size bias was eliminated. These results support the conclusions of Eroglu et al,44 that topical anaesthesia does not impair, and mayimprove wound healing. However, it is probable that actives other than the local anaesthetic agents in Tri-Solfen®, such as the antiseptic and the gel base may be responsible for this effect, as improved healing was also documented in placebo (gel base with antiseptic) treated lambs in Trial 1.The between-trial wound healing results are interesting in thatthey appear to conflict with results from a previous study which reported improved wound healing in younger unweaned lambsbeing mulesed and

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ting in thatthey appear to conflict with results from a previous study which reported improved wound healing in younger unweaned lambsbeing mulesed and tail-docked, than in older weaned lambsbeing mulesed only.45 Our findings appear to be the reverse. Inour trials, lambs being mulesed only (Trial 1) had markedly faster wound healing rates than those undergoing tail docking and mulesing (Trial 3), despite larger initial wound size. We suspect that seasonal conditions, particularly high fly activity, may be an important factor in this discrepancy. The flocks that exhibited the most delayed wound healing, both in our trial and that of Dun and Donnelly,45 were mulesed during hot conditionswith high fly activity compared with their counterparts. Of note, slower healing was associated with higher mortality in Trial 3. These observations suggest that production and welfare benefits may be achieved by controlling the seasonal conditions under which mulesing is performed, and suggest the need for further study of this important observation.Acute weight loss of up to 10% body weight has been reportedin lambs in the first week after mulesing.1,11 This weight losswas prevented in a group of 21 weaned lambs treated with Tri-Solfen® (unreported data Thompson, Sheil 2005), but notin unweaned lambs treated with Tri-Solfen® in the trial by Paull et al21 We showed a mean weight gain 2 and 4 weeks aftermulesing, with no significant difference between treated and untreated lambs, but no weights were recorded in the first 13 days after mulesing due to the need to minimise wound trauma.Our finding of absence of clinical cardio and neurotoxicityconcurs with other trials reporting the safety of relatively high dose topical lignocaine application to peripheral wound sites,

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rdio and neurotoxicityconcurs with other trials reporting the safety of relatively high dose topical lignocaine application to peripheral wound sites, particularly when administered in combination with adrenalin.6–9,46,47This is further supported by unpublished data (Thompson, Sheil 2005) that peak plasma lignocaine levels in Tri-Solfen® treated lambs occurred 30 to 60 minutes after mulesing and remained 100 times below toxic thresholds despite application of up to twice the recommended therapeutic dose (n = 12).In conclusion, the topical anaesthetic and antiseptic formula-tion Tri-Solfen®, is effective at alleviating pain and enhancing wound healing in lambs post-mulesing. These results suggestthat if widely adopted, the use of topical anaesthesia has the capacity to dramatically reduce the burden of acute animal husbandry related pain and suffering in young lambs through-out Australia.AcknowledgementsThis research program was approved by the Animal EthicsCommittee of the University of Sydney and conforms to the provisions of the Declaration of Helsinki (2000). The support of Mr Steven Burgun and staff at Arthursleigh and Mr Geoff Moore and staff at Yerilla, the statistical support of AssociateProfessor Jennifer Peat PhD and funds for handling equipmentfrom the McGarvie Smith Institute is gratefully acknowledged. References1. Fell LR, Shutt DA. Behavioural and hormonal responses to acute surgicalstress in sheep. Appl Anim Behav Sci 1989;22:283–294.2. Grant C. Behavioural responses of lambs to common painful husbandryprocedures. Appl Anim Behav Sci 2004;87:255–273. avj_285.fm Page 167 Thursday, April 17, 2008 5:08 PM

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PRODUCTION ANIMALS PRODUCTION ANIMALS Australian Veterinary Journal Volume 86, No 5, May 2008© 2008 The AuthorsJournal compilation © 2008 Australian Veterinary Association1683. Lee C, Fisher AD. The Welfare Consequences of Mulesing Sheep. Aust Vet J2007;85:89–93. 4. Bush S. Is cocaine needed in topical anaesthesia? J Emerg Med2002;19:418–422. 5. Smith GA, Strausbaugh SD, Harbeck-Weber C, et al. Comparison of topical anesthetics without cocaine to tetracaine-adrenaline-cocaine and lidocaine infil- tration during repair of lacerations: bupivacaine-norepinephrine is an effectivenew topical anesthetic agent. Pediatrics 1996;97:301–307.6. Argov S, Levandovsky O. Local anaesthesia in anal surgery: a simple, safe procedure. Am J Surg 2006;191:111–113.7. Brofeldt B, Cornwell P, Doherty D, Batra K, Gunther R. Topical lidocaine in the treatment of partial-thickness burns. J Burn Care Rehabil 1989;10:63–68.8. Jellish WS, Gamelli RL, Furry PA, McGill VL, Fluder EM. Effect of topical local anesthetic application to skin harvest sites for pain management in burn patients undergoing skin-grafting procedures. Ann Surg 1999;229:115–120.9. Johnstone RE, Wax MK, Bishop DJ, Chafin JB. Large doses of topicallidocaine during microvascular surgery are not associated with toxic bloodconcentrations. Anesthesiology 1995;82:593–596.10. Shutt DA, Fell LR, Connell R, et al. Stress-induced changes in plasmaconcentrations of immunoreactive beta-endorphin and cortisol in response to routine surgical procedures in lambs. Aust J Biol Sci 1987;40:97–103.11. Chapman RE, Fell LR, Shutt DA. A comparison of stress in surgically and non-surgically mulesed sheep. Aust Vet J 1994;71:243–247.12. Jongman EC, Morris JP, Barnett JL, Hemsworth PH. EEG changes in 4-week-old lambs in response to

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rgically mulesed sheep. Aust Vet J 1994;71:243–247.12. Jongman EC, Morris JP, Barnett JL, Hemsworth PH. EEG changes in 4-week-old lambs in response to castration, tail docking and mulesing. Aust Vet J2000;78:339–343. 13. Morishima HO, Pedersen H, Finster M, et al. Toxicity of lidocaine in adult, newborn, and fetal sheep. Anesthesiology 1981;55:57–61.14. Rutten AJ, Nancarrow C, Mather LE, et al. Hemodynamic and centralnervous system effects of intravenous bolus doses of lidocaine, bupivacaine, and ropivacaine in sheep. Anesth Analg 1989;69:291–299.15. Feldman HS, Dvoskin S, Halldin MH, Ask AL, Doucette AM. Comparative local anesthetic efficacy and pharmacokinetics of epidurally administered ropivacaine and bupivacaine in the sheep. Region Anesth 1997;22:451–460.16. Huang YF, Pryor ME, Mather LE, Veering BT. Cardiovascular and central nervous system effects of intravenous levobupivacaine and bupivacaine in sheep. Anesth Analg 86(4):797–804, 1998 Apr 1998;86:797–804.17. Wood GN, Molony V, Fleetwood-Walker SM, Hodgson JC, Mellor DJ. Effects of local anesthesia and intravenous naloxone on the changes in behaviour and plasma concentrations of cortisol produced by castration and tail docking with tight rubber rings in young lambs. Res Vet Sci 1991;51:193–199.18. Dinniss AS, Mellor DJ, Stafford KJ, Bruce RA, Ward RN. Acute cortisol responses of lambs to castration using a rubber ring and/or a castration clamp with or without local anaesthetic. NZ Vet J 1997;45:114–121.19. Mellor DJ, Stafford KJ. Acute castration and/or tailing distress and its allevia- tion in lambs. NZ Vet J 2000;48:33–43.20. Paull DR, Lee C, Colditz IG, Atkinson SJ, Fisher AD. The effect of a topical anaesthetic formulation, systemic flunixin and carprofen, singly or in combination, on

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e C, Colditz IG, Atkinson SJ, Fisher AD. The effect of a topical anaesthetic formulation, systemic flunixin and carprofen, singly or in combination, on cortisol and behavioural responses of Merino lambs to mulesing. Aust Vet J2007;85:98–106. 21. Hughan SC, Loose JM, Caddy DJ, et al. Combined xylazine and ketamine as an analgesic regimen in sheep. Aust Vet J 2001;79:207–211.22. Fox SM, Mellor DJ, Firth EC, Hodge H, Lawoko CR. Changes in plasmacortisol concentrations before, during and after analgesia, anaesthesia and anaesthesia plus ovariohysterectomy in bitches. Res Vet Sci 1994;57:110–118. 23. Grose R, Werner S, Kessler D, et al. A role for endogenous glucocorticoids in wound repair. EMBO Rep 2002;3:575–582.24. Duarte A, Pospisilova E, Reilly E, et al. Reduction of postincisional allodyniaby subcutaneous bupivacaine: findings with a new model in the hairy skin of therat. Anesthesiology 2005;103:113–125.25. Fu KY, Light AR, Maixer W. Relationship between nociceptor activity,peripheral edema, spinal microglial activation and long-term hyperalgesia induced by formalin. Neuroscience 2000;101:1127–1135.26. Brennan TJ, Umali EF, Zahn PK. Comparison of pre-versus post-incisionadministration of intrathecal bupivacaine and intrathecal morphine in a rat modelof postoperative pain. Anesthesiology 1997;87:1517–1528.27. Dahl JB, Brennum J, Arendt-Nielsen L, Jensen TS, Kehlet H. The effect ofpre-verses post-injury infiltration with lidocaine on thermal and mechanical hyperalgaesia after heat injury to the skin. Pain 1993;53:43–51.28. Hardie EM. Recognition of pain behaviour in animals. In: Hellebrekers L,editor. Animal Pain. Van der wees, Utrecht, Netherlands, 2000:51–69.29. Pogatzki EM, Vandermeulen EP, Brennan TJ. Effect of plantar local anes- thetic

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editor. Animal Pain. Van der wees, Utrecht, Netherlands, 2000:51–69.29. Pogatzki EM, Vandermeulen EP, Brennan TJ. Effect of plantar local anes- thetic injection on dorsal horn neuron activity and pain behaviours caused by incision. Pain 2002;97:151–161.30. Meyer RA, Ringkamp M, Campbell JN, Raja SN. Neural mechanisms of hyperalgesia after tissue injury. J Hopkins Apl Tech D 2005;26:56–66.31. Wall PD. The painful consequence of peripheral injury. J Hand Surg1984;9:37–39. 32. Lam KW, Pun TC, Ng EH, Wong KS. Efficacy of preemptive analgesia for wound pain after laproscopic operations in infertile women: a randomised,double blind and placebo control study. BJOG 2004;111:340–344.33. Emflorgo CA. The assessment and treatment of wound pain. J Wound Care1999;8:384–385. 34. Bose B. Burn wound dressing with human amniotic membrane. Ann Roy CollSurg 1979;61:444–447.35. Mathews K. Pain Assessment and General Approach to Management. VetClin N Am–Small Anim Pract 2000;30:734–755.36. Anil S, Anil L, Deen J. Challenges of pain assessment in domestic animals. JAm Vet Med Assoc 2002;220:313–318.37. Hartrick C, Kovan J, Shapiro S. The numeric rating scale for clinical pain measurement: A ratio measure? Pain Pract 2003;3:310–316.38. Kent JE, Meikle L, Molony V, McKendrick IJ. Qualitative versus quantitative assessment of an acute pain in lambs. Proc of Meetings: Sheep Vet Soc2001;25:65–66. 39. Kent JE, Thrusfield MV, Molony V, Hosie BD, Sheppard BW. A randomised, controlled field trial of two new techniques for castration and tail docking of lambs less than two days of age. Vet Rec 2004;154:193–200.40. Carpenter R, Wilson D, Evans A. Evaluation of intraperitoneal and incisional lidocaine or bupivacaine for analgesia following ovariohysterectomy in the dog.

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ter R, Wilson D, Evans A. Evaluation of intraperitoneal and incisional lidocaine or bupivacaine for analgesia following ovariohysterectomy in the dog. Vet Anaesth Analg 2004;31:46–52.41. Thornton PD, Waterman-Pearson AE. Quantification of the pain and distress response to castration in young lambs. Res Vet Sci 1999;66:107–118.42. Brower MC, Johnson ME. Adverse effects of local anesthetic infilitration on wound healing. Region Anesth Pain M 2003;28:233–240.43. Dahl JB, SM, Kehlet H. Wound infiltration with local anesthetics for postoper- ative pain relief (review). Acta Anaesthesiol Scand 1994;38:7–14.44. Eroglu E, Eroglu F, Agalar F, et al. The effect of lidocaine/prilocaine cream on an experimental wound healing model. Eur J Emerg Med 2001;8:199–201.45. Dun RB, Donnelly FB. Effectiveness of the Mules operation at lamb marking. Aust J Exp Agric Anim Husb 1965;5:6–10.46. Karatassas A, Morris G, Slavotinek AH. The relationship between regional blood flow and absorption of lignocaine. Aust NZ J Surg 1993;63:766–771.47. Palve H, Kirvela O, Olin H, Syvalahti E, Kanto J. Maximum recommended doses of lignocaine are not toxic. Br J Anaesth 1995;74:704–705.(Accepted for publication 11 March 2008) avj_285.fm Page 168 Thursday, April 17, 2008 5:08 PM