AU2021221418A1

AU2021221418A1 - Medicated supplement for animals

Info

Publication number: AU2021221418A1
Application number: AU2021221418A
Authority: AU
Inventors: Allan Giffard; Nigel McKanna; Charles Robert Olsson
Original assignee: Medical Ethics Pty Ltd
Current assignee: Medical Ethics Pty Ltd
Priority date: 2021-08-23
Filing date: 2021-08-23
Publication date: 2023-03-09
Also published as: WO2023023702A1

Abstract

A method of providing pre-emptive and ongoing pain relief to an animal following a surgical or animal husbandry procedure, said method comprising the step of providing the animal access to a medicated supplement comprising at least one type of pain relieving agent, whereby the animal is able to self-medicate prior to undergoing the surgical or animal husbandry procedure and continue to self-medicate following the procedure.

Description

MEDICATED SUPPLEMENT FOR ANIMALS

[0001] TECHNICAL FIELD

[0002] This invention generally relates to a medicated supplement containing a pain relieving agent and to a method of providing pre-emptive and ongoing pain relief to an animal following a surgical or animal husbandry procedure, whereby the animal self-medicates prior to undergoing the surgical or animal husbandry procedure and continues to self-medicate following the procedure, preferably without human interference. In preferred embodiments, the medicated supplement is a molasses lick block containing meloxicam.

[0003] BACKGROUND ART

[0004] Castration of male animals is a practice commonly conducted in livestock production systems for the improvement of safety, management, growth, and performance [1]. Although there are long-term benefits to castration, the procedure is highly invasive, causing pain, inflammation, and infection [2,3]. Pain relief for livestock undergoing surgical husbandry procedures, including castration, is recommended for animal welfare, and in some cases has been shown to improve production [4-6].

[0005] In Australia, cattle are mostly castrated by producers, therefore limiting the use of veterinary prescription drugs such as local anaesthetics and sedatives due to technicalities of administration and safety considerations. Topical anaesthetic (TA) Tri-Solfen@ (Animal Ethics Pty Ltd) is a commonly used pain relief product, sprayed directly into the scrotum post operatively and has been shown to reduce post-operative pain in sheep and cattle for up to 24 hours [7,8].

[0006] The non-steroidal anti-inflammatory drug (NSAID) meloxicam is becoming more widely adopted by producers, available by veterinary prescription as a subcutaneous (SC) or intramuscular (IM) injection (Metacam@ Boehringer Ingelheim) or via oral trans mucosal (OTM) application (Ilium®Buccalgesic; Troy Laboratories, Australia) [9,10]. Meloxicam is an anti inflammatory, analgesic and anti-pyretic shown to successfully reduce inflammation and pain associated behaviours in castrated cattle for up to 72 hours [3,11]. Meloxicam is preferred over other NSAIDs for its long half-life of 27 hours (oral; PO) and specificity to cyclooxygenase (COX)-2 [11,12]. Specificity to COX-2 is important for targeted, local pain relief as COX-2 is mostly expressed in damaged tissue [13]. Meloxicam inhibits COX-2, reducing synthesis of the proinflammatory mediator, prostaglandin, which intensifies pain sensation and augments inflammation [13-16].

[0007] The duration of action of meloxicam (up to 72 hours) is one of the longest of available NSAIDs [17]. However, the duration of pain and inflammation resulting from surgical castration has been shown to exceed 35 days, with healing occurring between 4 to 9 weeks post castration

[3,18-21]. Currently available pain relief products and their application methods are impractical for addressing the long-term pain and inflammation of castration, necessitating an alternative delivery system. Current methods of meloxicam delivery, including SC or IM injection, OTM or oral solution (PO), are invasive, and require restraint of the animal, making them impractical for administering pre-emptive analgesia or subsequent doses, especially in extensive farming systems.

[0008] Therefore, a novel, independent mode of drug delivery to enable pre-emptive analgesia and multiple doses is warranted to achieve an improved pain mitigation protocol for surgical castration of calves. As described herein, the administration of NSAIDs via feed/supplements is a viable alternative to these invasive methods, allowing the drug to be consumed prior to surgical procedures and continued after.

[0009] The delivery of the NSAID flunixin meglumine via medicated pellets has successfully enabled therapeutic concentrations to be established within 6 hours of consumption

[22]. Comparative pharmacokinetic studies of PO versus IM delivery of meloxicam show that the bioavailability is often reduced when orally administrated, necessitating a greater dosage from 0.5mg/kg SC to 1.0mg/kg PO [18,22-24]. The elimination half-life of PO meloxicam (28.5h) is significantly longer than SC meloxicam (12.5h), at a dose rate of 0.5mg/kg and 1.0mg/kg respectively [24]. Oral administration of meloxicam is advantageous due to the longer elimination half-life and slower absorption, consequentially extending the duration of action of the drug

[15,22].

[0010] DETAILED DESCRIPTION OF THE INVENTION

[0011] The present inventors have developed a medicated supplement/medicated feed supplement containing a pain relieving agent and a method of providing pre-emptive and ongoing pain relief to an animal following a surgical or animal husbandry procedure, whereby the animal self-medicates (premedicates) prior to undergoing the surgical or animal husbandry procedure and continues to self-medicate following the procedure, preferably without human interference.

[0012] According to a first aspect of the present invention, there is provided a method of providing pre-emptive and ongoing pain relief to an animal following a surgical or animal husbandry procedure, said method comprising the step of providing the animal access to a medicated supplement comprising at least one type of pain relieving agent, whereby the animal is able to self-medicate prior to undergoing the surgical or animal husbandry procedure and continue to self-medicate following the procedure.

[0013] According to a second aspect of the present invention, there is provided use of a medicated supplement comprising at least one type of pain relieving agent in the manufacture of a medicament for providing pre-emptive and ongoing pain relief treatment to an animal following a surgical or animal husbandry procedure, wherein said treatment comprises providing the animal access to the medicament such that the animal is able to self-medicate prior to undergoing the surgical or animal husbandry procedure and continue to self-medicate following the procedure.

[0014] According to a third aspect of the present invention, there is provided a medicated supplement comprising at least one type of pain relieving agent for use in providing pre-emptive and ongoing pain relief to an animal following a surgical or animal husbandry procedure, said use comprising the step of providing the animal access to the medicated supplement such that the animal is able to self-medicate prior to undergoing the surgical or animal husbandry procedure and continue to self-medicate following the procedure.

[0015] According to a fourth aspect of the present invention, there is provided a medicated supplement for an animal comprising at least one type of pain relieving agent, capable of providing pre-emptive and post-surgical or animal husbandry procedure pain relief to the animal when the animal self-medicates prior to undergoing the surgical or animal husbandry procedure and following the procedure.

[0016] According to a fifth aspect of the present invention, there is provided a method of manufacturing a medicated supplement for an animal comprising at least one type of pain relieving agent, capable of providing pre-emptive and post-surgical or animal husbandry procedure pain relief to the animal when the animal self-medicates, said method comprising the step of combining ingredients, including supplement ingredients and at least one type of pain relieving agent, to form the medicated supplement.

[0017] The medicated supplement can be in the form of a block, such as a lick block or dry lick. Likewise, the supplement component of the medicated supplement can be, for example, a block, such as a lick block or dry lick. Preferably, the block is in the form of a molasses lick block or dry lick.

[0018] The medicated supplement's ingredient content/supplement content can be tailored for the particular animal type for which it is provided, or even for the geographic location of the animal. For example, grain versus grass fed animals many require different ingredient contents, such as a different mineral content. The medicated supplement can also be tailored for the palate of the animal (e.g. molasses and salt content).

[0019] The at least one pain relieving agent can be used to prevent, minimise or obviate any relevant type of pain, such as inflammatory pain, experienced by the animal as a result of the surgical or animal husbandry procedure - such as a laceration, a surgical incision, a major abrasion or a major bum. For example, pain may be caused by an animal husbandry procedure such as mulesing, shearing, castration, spaying, tail docking, ear tagging, ear notching, de homing, crush dehorning, scoop dehorning, hot iron disbudding, branding, hot iron branding or marking.

[0020] In some embodiments, the pain relieving agent can be an analgesic agent or combination of different types of analgesic agents. For example, the pain relieving agent can be any suitable type of anti-inflammatory agent or combination of different types of anti inflammatory agents. In some embodiments the pain relieving agent can be at least one analgesic agent in combination with at least one anti-inflammatory agent.

[0021] Potentially suitable pain relieving agents include one or more of the following: acetaminophen, aspirin, salicylic acid, methyl salicylate, choline salicylate, glycol salicylate, 1 menthol, camphor, mefenamic acid, fluphenamic acid, indomethacin, diclofenac, alclofenac, ibuprofen, ketoprofen, pranoprofen, fenoprofen, sulindac, fenbufen, clidanac, flurbiprofen, indoprofen, protizidic acid, fentiazac, tolmetin, tiaprofenic acid, bendazac, bufexemacpiroxicam, phenylbutazone, oxyphenbutazone, clofezone, pentazocine, mepirizole, hydrocortisone, cortisone, dexamethasone, fluocinolone, triamcinolone, medrysone, prednisolone, flurandrenolide, prednisone, halcinonide, methylprednisolone, fludrocortisone, corticosterone, paramethasone, betamethasone, naproxen, suprofen, piroxicam, diflunisal, meclofenamate sodium, carprofen, flunixin, tolfenamic acid and meloxicam.

[0022] In some embodiments, the pain relieving agent can be a non-steroidal anti inflammatory drug (NSAIDs). The NSAID can be a salicylate (e.g. aspirin (acetylsalicylic acid), diflunisal (dolobid), salicylic acid and other salicylates, salsalate (disalcid)), propionic acid derivative (e.g. ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen), acetic acid derivative (e.g. indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, aceclofenac, nabumetone), enolic acid (oxicam) derivative (e.g. piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, isoxicam, phenylbutazone), anthranilic acid derivative (fenamate) (e.g. mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid), selective COX-2 inhibitor (e.g. celecoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib, etoricoxib, firocoxib), sulfonanilide (e.g. nimesulide), or other (e.g. clonixin, licofelone, H-harpagide in Figwort or Devil's Claw).

[0023] In addition to containing at least one type of pain relieving agent, the medicated supplement can for example comprise one or more of the following types of ingredients: a nitrogen source; a protein source; a carbohydrate source; a fat source; minerals; vitamins; salt; an energy source; a fibre source; a solidifying, binding or gelling agent; a pH adjuster; a filler; a flavouring agent (to increase palatability); a biological active; and general types of excipients. One or more of these ingredients can be provided by the supplement component itself or using further additives.

[0024] Any suitable source or sources of nitrogen can be used. The nitrogen can derive from a source of protein or not. In an example, the source of nitrogen is urea (non-protein source) or sulfate of ammonia. Any suitable quantity of nitrogen or nitrogen source can be used. For example, the nitrogen or nitrogen source content can be about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20% weight/weight.

[0025] Any suitable source or sources of protein can be used. Suitable sources of protein include cottonseed meal, fish meal, soybean meal, oilseed meal (e.g., soybean, canola, cottonseed, flax, peanut, sunflower), corn gluten meal, luceme (alfalfa), clovers, beans, grass and urea. High-protein grains include lupins and peas. High-protein seeds include white ('fuzzy') cottonseed and lupins. Any suitable quantity of protein or protein source can be used. For example, the protein or protein source content can be about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20% weight/weight.

[0026] Any suitable source or sources of carbohydrate can be used. Suitable sources of carbohydrate include maize, sorghum, wheat, oats, rice, grass and molasses. Any suitable quantity of carbohydrate or carbohydrate source can be used. For example, the carbohydrate or carbohydrate source content can be about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20% weight/weight.

[0027] Any suitable source or sources of fat can be used. Suitable sources of fat include tallow, specialty bypass fats, oils and grease, cotton seed, sunflower seeds, grass and groundnuts. For example, the fat or fat source content can be about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, , 16, 17, 18, 19 or 20% weight/weight.

[0028] Any suitable type or types of mineral can be used. Examples of suitable minerals include sodium, phosphorus, sulphur, calcium, sodium, iron, copper, manganese, zinc, iodine, selenium and cobalt. Any suitable mineral quantity can be used. For example, the mineral content can be about 0.5, 1.0, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 and 5% weight/weight.

[0029] Any suitable type or types of vitamin can be used. Examples of suitable vitamins include vitamin A, B, C, D and E. Any suitable vitamin quantity can be used. For example, the vitamin content can be about 0.5, 1.0, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 and 5% weight/weight.

[0030] Any suitable type or types of flavouring agent can be used. Examples of suitable flavouring agents include molasses and salt. For example, the flavouring agent can be about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20% weight/weight.

[0031] Any suitable type or types of salt can be used. Examples of suitable salts include sea salt and sodium chloride. Any suitable quantity of salt can be used. For example, the salt content can be about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19 or 20% weight/weight.

[0032] Any suitable type or types of energy source can be used. Examples of suitable energy sources include grains (e.g. corn, oats, barley), corn hominy, corn screenings, confectionery products, bakery wastes, cull fruits and vegetables, and molasses. For example, the energy source content can be about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20% weight/weight.

[0033] Any suitable type or types of fibre source can be used. Examples of suitable fibre sources include oilseed hulls (e.g., soybean, cottonseed), fruit and vegetable pulps (e.g., citrus, beet), and grain hulls (e.g., oats, barley). For example, the fibre source content can be about 0.5,

1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20% weight/weight.

[0034] Any suitable type or types of biological actives (apart from the pain relieving agent) can be used. Examples of suitable biological actives include antibiotics, antimicrobials, rumen stimulants (to encourage the growth of rumen microbes), methane-reducing agents (e.g. 3 nitrooxypropanol) and ionophores (compounds that alter rumen fermentation patterns, to increase feed efficiency and body weight gain). Any suitable quantity of biological active/s can be used. For example, the biological active/s content can be about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7 .5%, 8%, 8.5%, 9%, 9.5% or 10% weight/weight.

[0035] Suitable general excipients include antioxidants, colourants, emulsifiers, preservatives, solvents, solubilisers, viscosity increasing agents, diluents, carriers and so forth. Any suitable quantity of water can be used. For example, the water content can be about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20% weight/weight.

[0036] Molasses can provide the following: improves palatability (flavouring agent); provides minerals/trace elements such as sulphur; provides carbohydrates/fermentable sugars; and, functions as a binding agent. Any suitable source and quantity of molasses can be used. For example, the molasses content can be about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,50,51,52, 53, 54, 55, 56, 57, 58, 59 and 60% weight/weight. In other embodiments, molasses can be used to balance the ingredient content to 100%. The molasses can be produced from sugarcane, for example.

[0037] Solidifying, binding or gelling agents help solidify the supplement/make the medicated supplement a coherent mass. Suitable examples include calcium oxide, magnesium oxide, calcium hydroxide, di-ammonium phosphate, cement, bentonite and hydrated lime (quick lime). Any suitable solidifying, binding and/or gelling agent/s quantity can be used. For example, the solidifying, binding and/or gelling agent/s content can be about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37, 38, 39 or 40% weight/weight.

[0038] pH adjusters help adjust the final pH of the medicated supplement. Examples of suitable pH adjusters include organic acids such as citric, tartaric, boric and phosphoric acid. Any suitable pH adjuster quantity can be used. For example, the pH adjuster content can be about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10% weight/weight.

[0039] Fillers help bulk up the medicated supplement, to get it to the correct volume. The filler can be digestible or not. Examples of suitable fillers include bran (digestible) and earth (not digestible). Any suitable filler/s quantity can be used. For example, the filler/s content can be about 1,2,3,4,5,6,7,8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20,21,22,23,24,25,26,27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40% weight/weight.

[0040] In some embodiments the supplement can comprise: forages and fibrous coproducts; roughage; straws, residues and fibrous coproducts; weeds; roots, tubers and associated coproducts; grains, grain coproducts and screenings; oilseeds and oilseed coproducts; or liquid coproducts.

[0041] In some embodiments the supplement can comprise grasses, legumes, cereals, cereal grains and seed, silages, straws, oil cakes and meals, fishmeal, or by products.

[0042] In some embodiments, the at least one pain relieving agent is substantially uniformly dispersed throughout the medicated supplement.

[0043] The medicated supplement can be fed to any suitable type of animal. Suitable animals include farm animals, livestock and ruminants, preferably ruminants. Suitable animals include sheep, cattle, horses, buffalo, goats, pigs and yak, including juveniles thereof - eg. piglets, calves, lambs etc.

[0044] Sheep, cattle, lambs, calves and other animals could be fed this medicated supplement prior to and after routine surgeries or procedures for a period of time to avoid, minimise, reduce or relieve pain and potentially improve healing via reduced inflammation and well known properties of NSAIDs or other analgesics.

[0045] The method comprises the animal self-medicating. Preferably, animals would help themselves ad lib to such a medicated supplement. Preferably, the animal can self-medicate prior to the procedure (ie. premedicate) as often as it likes, as well as post-procedure so as to provide ongoing pain relief. That is, the animal consumes as much of the medicated supplement as it desires, as often as it desires, provided that the pain relieving agent in not consumed in a harmful dose. In some embodiments, the animal continues to self-medicate throughout some, most or an entire inflammatory period following the procedure, preferably without human interference.

[0046] Any suitable type or types and quantity or quantities of pain relieving agent can be used. For example, the pain relieving agent content can be about 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.095, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1%, 1.5%, 2%, 2.5%, 3% , 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5% or 10% weight/weight.

[0047] In some embodiments, the pain relieving agent could comprise between about 0.5 kg per (metric) ton up to about 20 kg per (metric) ton of total medicated supplement formula (eg. 0.5 to 20 kg and all 0.01 kg increments there between). In some embodiments, the medicated supplement comprises about 1000 mg to about 2000 mg of pain relieving agent per about 1kg of medicated supplement, being about 1-2 kilos/per tonne of supplement.

[0048] In some embodiments, the medicated supplement provides a dose to the animal in the order of about 10, 15, 20, 25, 30, 35, 40, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 and 100mg pain relieving agent/animal/day (depending on the size of the animal).

[0049] In some embodiments, the medicated supplement provides a dose to the animal in the order of about 0.9mg to about 1.0mg pain relieving agent per kg of animal per day.

[0050] In some embodiments, ruminants (such as cattle and sheep) consume approximately 100 g to 300 g of block per day, including all 0.1 g increments inbetween. For example, cows may consume approximately 200 g to 300 g per day. For example, lambs may consume approximately 50 g per day. For example, calves may consume approximately 100 to 300 g per day.

[0051] The animal may premedicate (self-medicate) for any suitable period of time, including for about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days or more. The animal may self-medicate for any suitable period of time after the surgical or animal husbandry procedure, including for about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 0.5 weeks, 1 week, 1.5 weeks, 2 weeks, 2.5 weeks, 3 weeks, 3.5 weeks, 4 weeks, 4.5 weeks, 5 weeks, 5.5 weeks, 6 weeks or more. In some embodiments, the medicated supplement may be fed to the animal (self-medicate) for a period of about 7-10 days prior to the surgical or animal husbandry procedure and about 1 to 3 weeks after the surgical or animal husbandry procedure. In some embodiments, the medicated supplement is fed to the animal for a total period of about 2 to 5 weeks. In some embodiments, the animal continues to self-medicate preferably throughout the entire inflammatory period following the procedure, without human interference.

[0052] The method may comprise a step of feeding to the animal a first medicated supplement containing a first type of pain relieving agent for a first period of time, then a second medicated supplement containing a second type of pain relieving agent for a second period of time. The first and second periods of time could, for example, each be 1 to 2 week periods. If required, the method may comprise a step of feeding to the animal a third (or fourth) medicated supplement containing a third (or fourth) type of pain relieving agent for a third (or fourth) period of time.

[0053] As mentioned, the medicated supplement can be a medicated lick block such as a molasses lick block that can be used to deliver at least one type of pain relieving agent to one or more animals in a controlled manner.

[0054] According to a sixth aspect of the present invention, there is provided a method of manufacturing a medicated molasses lick block, said method comprising the steps of:

[0055] combining ingredients, including molasses and at least one type of pain relieving agent, to form a block mixture;

[0056] pouring the block mixture into a mould; and

[0057] allowing the block mixture to set to form a medicated molasses lick block comprising the at least one type of pain relieving agent substantially uniformly dispersed throughout the medicated molasses lick block.

[0058] The block can be manufactured using a hot process (requiring heating of one or more ingredients) or cold process. Preferably, the block is manufactured using a cold process. More preferably, the block is manufactured using a cold moulding process.

[0059] A body of the block can be of any suitable size and shape. The block body can comprise a top surface, a bottom surface and at least one side surface. Potential shapes for the block body include a rectangular, hexagonal or octagonal prism or cylinder/disc, for example.

[0060] The block body can be of any suitable weight but preferably has a weight of between about 5 and 1000 kg, and more preferably about 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150,200,250,300,350,400,450,500,550,600,650,700,750,800,850,900,950and1000kg.

[0061] Particularly preferred embodiments of a medicated molasses lick block are described below.

[0062] Preferably, the medicated molasses lick block comprises about 40-55% weight/weight molasses, more preferably about or at least about 50% weight/weight molasses.

[0063] Preferably the medicated molasses lick block comprises about 2 to 10% weight/weight salt, more preferably about 5% weight/weight salt.

[0064] Preferably, the medicated molasses lick block comprises at least one type of phosphate. Any suitable type or types and quantity of phosphate can be used. For example, the phosphate content can be about 5-10% weight/weight, more preferably about 5% weight/weight phosphate. For example, di-calcium phosphate can be used, preferably about 5-10% weight/weight, more preferably about 5% weight/weight.

[0065] Preferably, the medicated molasses lick block comprises at least one type of hydrated lime. Any suitable type and quantity of hydrated lime can be used. For example, the hydrated lime content can be about 0-5% weight/weight, preferably 5% weight/weight.

[0066] Preferably, the medicated molasses lick block comprises magnesium oxide. Any suitable quantity of magnesium oxide can be used. For example, the magnesium oxide content can be about 5-20% weight/weight, preferably about 5-10% weight/weight, more preferably about 5% weight/weight.

[0067] Preferably, the medicated molasses lick block comprises minerals such as copper, cobalt, zinc and selenium. Any suitable mineral quantity can be used. For example, the mineral content can be up to about 2% weight/weight, preferably about 1-2% weight/weight, more preferably about 2% weight/weight.

[0068] Preferably, the medicated molasses lick block comprises up to about 10% weight/weight water, more preferably about 5-10% water, and even more preferably about 10% water.

[0069] Preferably, the medicated molasses lick block comprises up to about 10% weight/weight of phosphoric acid, more preferably about 5-10% weight/weight of phosphoric acid, and even more preferably about 5% weight/weight phosphoric acid. Typically, an 85% starting stock solution of phosphoric acid can be used to prepare the block.

[0070] Preferably, the medicated molasses lick block comprises about 2-4% weight/weight of oil such as vegetable oil, more preferably about 2% weight/weight of oil.

[0071] Optionally, the medicated molasses lick block comprises at least one type of protein source/meal. Any suitable type or types and quantity or quantities of meal can be used. For example, the meal content can be up to about 2% weight/weight. Suitable meal is, for example, cottonseed meal, fish meal, soybean meal and oilseed meal.

[0072] Preferably, the medicated molasses lick block comprises about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06. 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5 or 10% weight/weight of each type of pain relieving agent (including all 0.01 increments between 0.01 and 10%). A preferred type of pain relieving agent is an anti-inflammatory agent.

[0073] The pain relieving agent may typically comprise between about 0.5 kg per ton up to about 10 kg per ton of total block formula (eg. 0.5 to 10 kg and all 0.01 kg increments there between).

[0074] Preferably the medicated lick block comprises about 1000 mg to 2000 mg of pain relieving agent per about 1kg of block.

[0075] Preferably, the medicated lick block provides a dose to the animal in the order of about 10, 15, 20, 25, 30, 35, 40, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 and 100mg pain relieving agent/animal/day (depending on the size of the animal).

[0076] Preferably, the medicated lick block provides a dose to the animal in the order of about 0.9mg to about 1.0mg pain relieving agent per kg of animal per day.

[0077] A particularly preferred medicated molasses lick block comprises the following ingredients (all weight/weight):

[0078] about 40-55% (or to balance) molasses, preferably about 50%;

[0079] up to about 5% hydrated lime, preferably about 5%;

[0080] about 5-20% magnesium oxide, preferably about 5-10%, more preferably about 5%;

[0081] about 5-10% water, preferably about 10%;

[0082] up to about 5% phosphoric acid, preferably about 5%; and

[0083] each type of pain relieving agent (e.g. NSAID, such as carprofen or meloxicam) quantity to suit so as to provide a pain relieving effect, preferably about 0.1-0.2%.

[0084] Another particularly preferred medicated molasses lick block comprises the following ingredients (all weight/weight):

[0085] about 24% vegetable oil, preferably about 2%;

[0086] about 40-55% (or to balance) molasses, preferably about 50%;

[0087] about 2 to 10% salt, preferably about 5%;

[0088] about 5 to 10% phosphate (e.g. di-calcium phosphate), preferably about 5%;

[0089] up to about 5% hydrated lime, preferably about 5%;

[0090] about 5 to 20% magnesium oxide, preferably about 5-10%, more preferably about %;

[0091] up to about 2% minerals, preferably about 1-2%, more preferably about 2%;

[0092] up to about 10% water, preferably about 5-10%, more preferably about 10%;

[0093] up to about 5% phosphoric acid, preferably about 5%; and

[0094] each type of pain relieving agent (e.g. NSAID, such as carprofen or meloxicam) quantity to suit so as to provide a pain relieving effect, preferably about 0.1-0.2%.

[0095] Another particularly preferred medicated molasses lick block comprises the following ingredients (all weight/weight):

[0096] about 2% vegetable oil;

[0097] about 50% molasses;

[0098] about 5% salt;

[0099] about 5 % di-calcium phosphate;

[00100] about 5% hydrated lime;

[00101] about 5% magnesium oxide;

[00102] about 2% minerals;

[00103] about 10% water;

[00104] about 5% phosphoric acid; and

[00105] the at least one type of pain relieving agent, quantity to suit, preferably about 0.1%.

[00106] Such medicated molasses lick blocks can be suitable for providing pain relief to animals such as farm animals, livestock or ruminants.

[00107] The method can further comprise the step of administering to the animal an anaesthetic or analgesic composition. For example, the method can comprise the step of topically administering to the animal an anaesthetic or analgesic composition as part of the surgical or animal husbandry procedure, prior to the procedure, and/or following the procedure. The topical anaesthetic or analgesic composition can be, for example, Tri-Solfen® (Animal Ethics, Pty Ltd), as described in Australian Patent Number 2007221941 or Australian Patent Number 2006202528 - the entire contents of which are incorporated herein by way of reference.

[00108] The topical anaesthetic or analgesic composition can have, for example, one of the following formulations:

[00109] 1. A topical anaesthetic or analgesic composition comprising:

[00110] at least one local anaesthetic agent;

[00111] a carrier comprising a hydrophilic or hydroalcoholic gelling agent for forming a long lasting barrier over the open wound;

[00112] an antiseptic agent; and

[00113] a vasoconstrictor.

[00114] The composition can comprise one or more ingredients such as an antioxidant, a detectable marker for indicating the presence of the composition on the animal, a local anaesthetic agent having a rapid onset of action, and/or a local anaesthetic agent having a long duration of action. It is to be understood that the local anaesthetic having a rapid onset of action and having a long duration of action can be one and the same, e.g. bupivacaine.

[00115] 2. A topical anaesthetic or analgesic composition comprising:

[00116] about 100 mg/mL non-crystallising liquid sorbitol (70%);

[00117] about 50.0 mg/mL lignocaine HCl (or other anaesthetic agent having a rapid onset of action);

[00118] about 5.0 mg/mL bupivacaine HCl (or other anaesthetic agent having a long duration of action);

[00119] about 1.5 mg/mL sodium metabisulfite;

[00120] about 5.0 mg/mL cetrimide

[00121] about 45.0 g/mL adrenaline tartrate;

[00122] about 5.0 mg/mL hydroxy cellulose; and

[00123] (optionally) dye.

[00124] 3. A topical anaesthetic or analgesic composition comprising:

[00125] about 100 mg/mL non-crystallising liquid sorbitol (70%);

[00126] about 40.0 mg/mL lignocaine HCl (or other anaesthetic agent);

[00127] about 1.5 mg/mL sodium metabisulfite;

[00128] about 5.0 mg/mL cetrimide;

[00129] about 36.0 g/mL adrenaline tartrate;

[00130] about 5.0 mg/mL hydroxy cellulose; and

[00131] (optionally) dye.

[00132] Preferred embodiments of the invention are defined in the paragraphs below:

[00133] 1. A method of providing pre-emptive and ongoing pain relief to an animal following a surgical or animal husbandry procedure, said method comprising the step of providing the animal access to a medicated supplement comprising at least one type of pain relieving agent, whereby the animal is able to self-medicate prior to undergoing the surgical or animal husbandry procedure and continue to self-medicate following the procedure.

[00134] 2. Use of a medicated supplement comprising at least one type of pain relieving agent in the manufacture of a medicament for providing pre-emptive and ongoing pain relief treatment to an animal following a surgical or animal husbandry procedure, wherein said treatment comprises providing the animal access to the medicament such that the animal is able to self medicate prior to undergoing the surgical or animal husbandry procedure and continue to self medicate following the procedure.

[00135] 3. A medicated supplement comprising at least one type of pain relieving agent for use in providing pre-emptive and ongoing pain relief to an animal following a surgical or animal husbandry procedure, said use comprising the step of providing the animal access to the medicated supplement such that the animal is able to self-medicate prior to undergoing the surgical or animal husbandry procedure and continue to self-medicate following the procedure.

[00136] 4. A medicated supplement for an animal comprising at least one type of pain relieving agent, capable of providing pre-emptive and post-surgical or animal husbandry procedure pain relief to the animal when the animal self-medicates prior to undergoing the surgical or animal husbandry procedure and following the procedure.

[00137] 5. A method of manufacturing a medicated supplement for an animal comprising at least one type of pain relieving agent, capable of providing pre-emptive and post-surgical or animal husbandry procedure pain relief to the animal when the animal self-medicates, said method comprising the step of combining ingredients, including supplement ingredients and at least one type of pain relieving agent, to form the medicated supplement.

[00138] 6. The method of paragraph 1, the use of paragraph 2, the medicated supplement of paragraph 3 or 4, or the method of paragraph 5, wherein the at least one type of pain relieving agent is an analgesic agent and/or an anti-inflammatory agent.

[00139] 7. The method, use or medicated supplement of paragraph 6, wherein the at least one type of pain relieving agent is acetaminophen, aspirin, salicylic acid, methyl salicylate, choline salicylate, glycol salicylate, 1-menthol, camphor, mefenamic acid, fluphenamic acid, indomethacin, diclofenac, alclofenac, ibuprofen, ketoprofen, pranoprofen, fenoprofen, sulindac, fenbufen, clidanac, flurbiprofen, indoprofen, protizidic acid, fentiazac, tolmetin, tiaprofenic acid, bendazac, bufexemacpiroxicam, phenylbutazone, oxyphenbutazone, clofezone, pentazocine, mepirizole, hydrocortisone, cortisone, dexamethasone, fluocinolone, triamcinolone, medrysone, prednisolone, flurandrenolide, prednisone, halcinonide, methylprednisolone, fludrocortisone, corticosterone, paramethasone, betamethasone, naproxen, suprofen, piroxicam, diflunisal, meclofenamate sodium, carprofen, flunixin, tolfenamic acid, meloxicam, salicylate, diflunisal, salsalate, propionic acid derivative, acetic acid derivative, enolic acid derivative, anthranilic acid derivative, selective COX-2 inhibitor, sulfonanilide, clonixin, licofelone, or H-harpagide in Figwort or Devil's Claw.

[00140] 8. The method, use or medicated supplement of paragraph 7, wherein the at least one type of pain relieving agent is meloxicam.

[00141] 9. The method of any one of paragraphs 1, 5, 6, 7 and 8, the use of any one of paragraphs 2, 6, 7 and 8, or the medicated supplement of any one of paragraphs 3, 4, 6, 7 and 8, wherein the medicated supplement comprises about 1000 mg to 2000 mg of pain relieving agent per about 1 kg of medicated supplement.

[00142] 10. The method of any one of paragraphs 1, 5, 6, 7, 8 and 9, the use of any one of paragraphs 2, 6, 7, 8 and 9, or the medicated supplement of any one of paragraphs 3, 4, 6, 7, 8 and 9, wherein the medicated supplement or supplement component thereof is in the form of a lick block or dry lick.

[00143] 11. The method, use or medicated supplement of paragraph 10, wherein the lick block or dry lick is a molasses lick block.

[00144] 12. The method, use or medicated supplement of paragraph 11, wherein the molasses lick block comprises the following ingredients (all weight/weight):

[00145] about 40-55% (or to balance) molasses, preferably about 50%;

[00146] up to about 5% hydrated lime, preferably about 5%;

[00147] about 5-20% magnesium oxide, preferably about 5-10%, more preferably about 5%;

[00148] about 5-10% water, preferably about 10%;

[00149] up to about 5% phosphoric acid, preferably about 5%; and

[00150] each type of pain relieving agent (e.g. NSAID, such as carprofen or meloxicam) quantity to suit so as to provide a pain relieving effect, preferably about 0.1-0.2%.

[00151] 13. The method, use or medicated supplement of paragraph 11, wherein the molasses lick block comprises the following ingredients (all weight/weight):

[00152] about 24% vegetable oil, preferably about 2%;

[00153] about 40-55% (or to balance) molasses, preferably about 50%;

[00154] about 2 to 10% salt, preferably about 5%;

[00155] about 5 to 10% phosphate (e.g. di-calcium phosphate), preferably about 5%;

[00156] up to about 5% hydrated lime, preferably about 5%;

[00157] about 5 to 20% magnesium oxide, preferably about 5-10%, more preferably about %;

[00158] up to about 2% minerals (including for example copper, cobalt, zinc and selenium), preferably about 1-2%, more preferably about 2%;

[00159] up to about 10% water, preferably about 5-10%, more preferably about 10%;

[00160] up to about 5% phosphoric acid, preferably about 5%; and

[00161] each type of pain relieving agent (e.g. NSAID, such as carprofen or meloxicam) quantity to suit so as to provide a pain relieving effect, preferably about 0.1-0.2%.

[00162] 14. The method, use or medicated supplement of paragraph 11, wherein the molasses lick block comprises the following ingredients (all weight/weight):

[00163] about 2% vegetable oil;

[00164] about 50% molasses;

[00165] about 5% salt;

[00166] about 5 % di-calcium phosphate;

[00167] about 5% hydrated lime;

[00168] about 5% magnesium oxide;

[00169] about 2% minerals;

[00170] about 10% water;

[00171] about 5% phosphoric acid; and

[00172] the at least one type of pain relieving agent, quantity to suit, preferably about 0.1.

[00173] 15. The method of any one of paragraphs 1 and 5 to 14, the use of any one of paragraphs 2 and 6 to 14, or the medicated supplement of any one of paragraphs 3, 4 and 6 to 14, wherein the surgical or animal husbandry procedure is selected from a surgical incision, a major abrasion, a major bum, mulesing, shearing, castration, spaying, tail docking, ear tagging, ear notching, de-horning, crush dehoming, scoop dehorning, hot iron disbudding, branding, hot iron branding or marking.

[00174] 16. The method, use or the medicated supplement of paragraph 15, wherein the surgical or animal husbandry procedure is castration.

[00175] 17. The method of any one of paragraphs 1 and 5 to 16, the use of any one of paragraphs 2 and 6 to 16, or the medicated supplement of any one of paragraphs 3, 4 and 6 to 16, wherein the animal is a farm animal, livestock or ruminant, preferably a sheep, a head of cattle, pig, horse, buffalo, goat or yak.

[00176] 18. The method of paragraph 1, the use of paragraph 2, or medicated supplement of paragraph 3, further comprising a step of topically administering to the animal an anaesthetic or analgesic composition prior to, as part of, or following the surgical or animal husbandry procedure.

[00177] 19. The method of any one of paragraphs 1 and 5 to 18, the use of any one of paragraphs 2 and 6 to 18, or the medicated supplement of any one of paragraphs 3, 4 and 6 to 18, wherein the animal self-premedicates for a period of about 7-10 days prior to the surgical or animal husbandry procedure, and self-medicates for a period of about 1 to 3 weeks after the surgical or animal husbandry procedure.

[00178] 20. The method of any one of paragraphs 1 and 5 to 19, the use of any one of paragraphs 2 and 6 to 19, or the medicated supplement of any one of paragraphs 3, 4 and 6 to 19, wherein:

[00179] the medicated supplement establishes pre-emptive analgesia and maintains long-term analgesia;

[00180] the medicated supplement reduces inflammation and ameliorates pain responses; and/or

[00181] the animal continues to self-medicate throughout some, most or an entire inflammatory period following the procedure, without human interference.

[00182] 21. The method of any one of paragraphs 1 and 5 to 19, the use of any one of paragraphs 2 and 6 to 19, or the medicated supplement of any one of paragraphs 3, 4 and 6 to 19, having one or more features as described elsewhere in this specification.

[00183] Any of the features described herein can be combined in any combination with any one or more of the other features described within the scope of the invention.

[00184] The reference to any prior art in this specification is not, and should not be taken as an acknowledgement or any form of suggestion that the prior art forms part of the common general knowledge.

[00185] Preferred features, embodiments and variations of the invention may be discerned from the following Preferred Embodiments of the Invention section which provides sufficient information for those skilled in the art to perform the invention. The Preferred Embodiments of the Invention section is not to be regarded as limiting the scope of the preceding Detailed Description of the Invention in any way.

[00186] BRIEF DESCRIPTION OF THE FIGURES

[00187] Figure 1. Table 1: Wound scoring scale.

[00188] PREFERRED EMBODIMENTS OF THE INVENTION

[00189] Example 1 - Manufacture of a medicated molasses lick block

[00190] This example describes the manufacture of a medicated molasses lick block (also referred to herein as "medicated feed", "medicated lick block", "medicated feed block" or "medicated supplement block") containing a pain relieving agent, manufactured using a cold

moulding process.

[00191] Molasses and hydrated lime were mixed together in water using a high-speed mixer. Other ingredients, including salt, di-calcium phosphate, magnesium oxide, phosphoric acid, minerals, oil and pain relieving agent were added in turn, and the mixture was poured into a mould and allowed to set for about 48 hours.

[00192] The block consisted of the following ingredients (all weight/weight):

[00193] 2% vegetable oil

[00194] 40-50% molasses

[00195] 5% salt

[00196] 5% di-calcium phosphate

[00197] 5% hydrated lime

[00198] 5% magnesium oxide

[00199] 2% minerals (including copper, cobalt, zinc, selenium)

[00200] 10% water

[00201] 5% phosphoric acid (prepared from an 85% stock solution)

[00202] 01.% meloxicam (1000 mg of pain relieving agent meloxicam per 1kg of block)

[00203] When set, the block had a toffee-like consistency.

[00204] The block had a weight of 20 kg. The pain relieving agent was substantially uniformly dispersed throughout the block. The consistency of the block was like toffee.

[00205] Some of the advantages of the block as described in this Example are stated below:

[00206] 1. It is rain-resistant in that it will not readily dissolve in rain.

[00207] 2. It is stable within the following temperature range: -20 to 50°C. Therefore, the block is suitable for use in Australia as well as countries having similar climates/environmental conditions such as South-East Asia, including New Zealand, Indonesia, Laos, Vietnam, Malaysia, Cambodia, China, India and Myanmar.

[00208] 3. It is highly palatable, particularly to ruminants such as sheep and cattle.

[00209] 4. The pain relieving agent (and other biological actives) can be substantially uniformly dispersed throughout the block and are stabilised upon formation of the block.

[00210] 5. The block releases the pain relieving agent in a uniform and controlled manner.

[00211] 6. The block enables controlled consumption - low daily dose of pain relieving agent, thereby minimising the risk of overdosing.

[00212] 7. The rate of cold production of the block is high, being about 50 tonnes of block per day.

[00213] 8. The block need not require urea as an ingredient.

[00214] 9. Animals can self regulate consumption to control pain and at the same time intake essential nutrients to increase productivity.

[00215] 10. The block saves farmers having to muster and handle animals, as well as delivering pain relieving injectables.

[00216] Example 2 - Delivery of meloxicam via a medicated molasses lick block to surgically castrated calves

[00217] 1.0 Summary

[00218] Livestock husbandry procedures such as surgical castration inflict long-term pain and inflammation, highlighting animal welfare and production concerns. Pain relief products available to producers including topical anaesthetics (TA) and non-steroidal anti-inflammatory drugs (NSAIDs) are limited to peri or post-operative administration, failing to address procedural pain, and lasting only 24-72 hours. The administration of NSAID meloxicam orally via a medicated lick block is a novel concept that would enable pre-emptive and long-term analgesia to be established and maintained. The effect of oral meloxicam delivered via a medicated lick block (as described in Example 1) was evaluated against conventional subcutaneous meloxicam in surgically castrated calves. Molasses lick blocks were medicated with meloxicam (as described in Example 1). Plasma meloxicam concentration (PMC), inflammation, percentage of change in weight (PWC) and behaviour were compared between surgically castrated Bos taurus male calves. Calves were randomly allocated to treatment groups: medicated meloxicam lick block (ML), subcutaneous meloxicam injection (M), no meloxicam (NC) or sham castration (PC). Prior to castration/sham castration, all calves received a sub-sedative dose of xylazine. Castrates received pre-operative lignocaine injected in the scrotum and spermatic cord, then 3ml topical anaesthetic (TA) in the scrotum post-operative. On all days except the first day post-castration, PMC was greatest in ML calves (P<0.001). The PCW was minimised in ML calves compared to M and NC calves (P=0.044). Eating increased in ML calves immediately after castration and was reduced when the medicated block was removed (P<0.001). Locomotion was greatest in ML calves (P=0.018). There was a trend for scrotal diameter to be less in ML calves compared to M (P=0.069). These findings show that meloxicam was successfully administered via the medicated lick block and that pre-emptive and daily cumulation of meloxicam improved welfare in surgically castrated calves. Results showed that the combination of oral meloxicam and topical anaesthetic reduced weight loss and increased locomotion and eating. Ultimately, the administration of meloxicam via a medicated lick block enabled pre-emptive and long-term analgesia to be established, improving animal welfare in surgical castration by reducing inflammation and ameliorating pain responses. The application of this technology will enable pre-emptive and long-term analgesia for surgical or husbandry procedures in various species, incuding mulesing, shearing, castration, spaying, tail docking, ear tagging, ear notching, de homing, crush dehorning, scoop dehorning, hot iron disbudding, branding, hot iron branding and marking.

[00219] 2.0 Materialsand Methods

[00220] An experiment was conducted at the University of Sydney's research farm "JB Pye Farm", near Camden, NSW. Forty weaned Bos taurus male calves, 30 bulls and 10 steers, approximately 4 to 6 months of age were enrolled in this study. The calves had been weaned approximately 3 weeks prior to the trial. During this 3-week period, calves were acclimated to the cattle yards, race and crush and were provided ad libitum access to molasses lick blocks. The lick blocks are described in Example 1 above.

[00221] 2.1 Treatments and experimentaldesign

[00222] The experiment was conducted over 14 days with measurements taken on day -1 (pre castration), 0 (day of castration) and days 1, 2, 3, 6, 9 and 13 post-castration. The calves remained within their treatment groups throughout the entire trial. The bull calves were randomly allocated to one of 3 treatment groups: surgical castration only (negative control, NC), surgical castration with subcutaneous meloxicam injection (Metacam20@ 20mg/mL at 0.5mh/kg; M) or surgical castration with meloxicam lick block (ML). The steers, rubber ring castrated within 48 hours after birth, were allocated to the positive control (PC) group and were completely healed well before the experiment. All castrated calves were treated with Tri-Solfen@ (Animal Ethics Pty Ltd), as described in 2.2. The calves were held on pasture in 0.2ha in their respective treatment groups with ad libitum access to water, hay and molasses lick blocks (unmedicated for PC, NC and M groups) for the duration of the experiment. (The unmedicated molasses lick block is the same as the medicated lick block described in Example 1, except without the pain relieving agent meloxicam.) The ML group were given access to the meloxicam lick blocks on day -1 and had continued access until day 6 when the blocks were removed and replaced with unmedicated molasses lick blocks. The lick blocks were weighed using a scale on days -1, 0, 1, 2, 3 and 6. Each calf was allocated a number from 1 to 40, spray painted on their sides and back with cattle tail paint (Leader Products Pty Ltd, Craigiebum, VIC) for visual identification throughout the experiment.

[00223] 2.2 Castrationandpainmitigation

[00224] All calves were administered an intramuscular sub-sedative dose of Ilium Xylazil @ (Troy Laboratories Australia) at of 0.05mg/kg liveweight, a minimum of 5 minutes prior to castration. This was injected into the rump of each calf while in the race before entering the crush to ensure time for standing sedation to take effect, identified by dribbling, delayed ocular response and slow movement. A sub-sedative dose was given so that the calves would remain standing during and post procedure. For castration, calves were restrained in the head bale, standing in the crush with the left hind leg tied forward using a rope to minimise movement. Approximately 1mL of local anaesthetic lignocaine (Ilium Lignocaine-20@, Troy Laboratories Australia) was infiltrated into the scrotal skin, and 2.5mL injected into the spermatic cord and testis via the neck of the scrotum, a minimum of 3 minutes prior to excision. While restrained in the crush, calves in the M group were administered 0.5mg/kg of meloxicam subcutaneously to the neck immediately before castration.

[00225] All calves were surgically castrated by the same skilled technician using a sterile scalpel. The testes were held in the proximal section of the scrotum while a transverse incision was made around the entire circumference of the lower third of the scrotum, removing the tip. Each testis was individually pulled through the scrotum to expose the spermatic cord and associated blood vessels, which were then severed by scraping with the scalpel to reduce blood loss by promoting clotting. Five calves from the NC group were castrated with this method, however, due to the size of the testes, concern for haemorrhage prompted a change in method. The remainder of the calves were castrated by making a medial incision from the mid to distal end of the scrotum on the lateral side of either teste. Each testis was held in the distal section of the scrotum by the technician to keep the skin taut and prevent the teste from retracting. The testes were removed in the same manner as previously described and 1mL of topical anaesthetic

(Tri-Solfen@) was administered directly into each scrotum onto the retracting spermatic cord tissue to induce anaesthesia and haemostasis [7].

[00226] 2.3 Blood sampling and analysis

[00227] Blood samples were collected via jugular venepuncture from calves in the ML and M groups for plasma meloxicam concentration (PMC) analysis. The calves were restrained in the head bale of the crush for blood sampling, with their heads held to the right or left to access to the jugular vein. Side of sampling was alternated across days. Samples were taken on day 0 from ML calves only, then both ML and M calves on days 1, 2, 3, 6, 9 and 13. Blood samples were collected in a lithium heparin tube and were immediately inverted to mix the lithium heparin anticoagulant with the blood and were then stored on ice until centrifuging, within 2 hours after collection. Samples were centrifuged at 1500 revolutions per minute for 10 minutes. The plasma was then pipetted from the top section of the blood sample, being cautious to not to draw up the buffy coat or red blood cells. Two aliquots of each sample were transferred to 3ml Eppendorf tubes. The samples were labelled with the calf number and date, then frozen at -200 C immediately. The samples were analysed by high performance liquid chromatography (HPLC)

[25].

[00228] 2.4 Medicated lick block analysis

[00229] Medicated lick blocks from the ML group were weighed on days -1, 0, 1, 2, 3 and 6, then replaced with a non-medicated molasses block after day 6. The differences in block weight were used to calculate the approximate amount of meloxicam consumed on the group level.

[00230] 2.5 Wound morphology

[00231] Scrotal diameter was measured using Craftright@ digital callipers (Bunnings Group Ltd, Australia) at the widest part of the scrotum. Measurements were conducted on days 1, 2, 3 6, 9 and 13 on calves in the NC, M and ML treatment groups.

[00232] Digital photographs were taken on days 1, 2, 3, 6, 9 and 13 of calves in treatments NC, M and ML for wound healing scoring. Wounds were scored for healing on a scale from 1 to (Table 1, 6.1). A score of 1 indicated that the incision had closed and a score of 5 indicated an open wound with exudate. Infrared thermographs (IRT) were taken using a FLIR E50 camera (FLIR® Systems Inc.) to measure wound temperature. Infrared photographs were taken on days

1, 2, 3, 6, 9 and 13 of calves in treatments NC, M and ML. FLIR Tools Software (FLIR® Systems Inc.) was then used to determine the maximum scrotal temperature from the infrared images, analysing the entire area within the frame.

[00233] For both wound measurements, photographs were taken caudal to the scrotum as the calves were restrained in the crush with their left leg tied forward, providing a clear image of the entire scrotum. A square 20x2cm frame was used for the infrared photos to ensure the distance from the wound was constant for accurate temperature validation. The frame was rested against the thigh of the calf with the camera aligned with the top and bottom of the frame.

[00234] 2.6 Weight

[00235] All calves were weighed on day -1, 9 and 13 of the trial using Gallagher@ cattle scales (Gallagher Group Ltd, Hamilton, New Zealand).

[00236] 2.7 Behaviour

[00237] Calf behaviour was recorded via visual observation of animals in the observation pens for the duration of the experiment. The same 3 observers performed all behavioural observations throughout the experiment and were blinded to treatment. Behaviours were recorded according to a customised ethogram adapted from the literature (Table 2, 6.1) [3,7,10,26-20]. The observers were blinded to treatment and rotated between groups, achieving in total approximately 4 to 8 observations per calf, per day. Behaviours were recorded via instantaneous sampling at 30 second intervals. Behaviours were analysed as mutually exclusive and recorded binomially as either 0 if the behaviour did not occur or 1 if the behaviour did occur. Observations were conducted from 11:30am until 1:30pm on day -1, 2, 3, 6, 9 and 13, and from 11:30am to 1:30pm and 2:00pm to 4:00pm on day 0 and 1. Data from day 0 was measured as AM and OPM. Data from day 1 was combined.

[00238] 2.4 StatisticalAnalysis

[00239] All data was collated in Microsoft Excel 2019 (Microsoft Corporation, Washington, USA) and stacked for analysis. The weight data was converted into the percentage of change in weight from baseline weights and between timepoints. The percentage change in weight (PCW) was calculated using the following formula in Microsoft Excel® 2019:

[00240] intial weight-new weight X 100

% intitalweight

[00241] Statistical analyses were conducted using statistical software, Genstat@ 1 8 edition (VSN International, Hemel Hempstead, UK). Plasma meloxicam concentration (PMC), scrotal temperature and diameter and PCW data was input to Genstat@ and checked for normality using the "distribution plots" function. This produced a Q-Q plot and Anderson-Darling (AD) statistic and critical value. If the AD statistic > AD critical value for 5% confidence, the data is not normal

[31]. The PMC was not normally distributed and was therefore transformed using Loge. A normality test of the transformed data was then performed using the distribution plots function, confirming the transformed data was normally distributed. The PCW data was checked for outliers using the box-plot function in Genstat@. Seven weights in total were removed from the data set as outliers: 4 from day -1, 2 from day 9 and1 from day 13 which improved normality. One outlier was removed from the scrotal temperature data, as the thermograph was not positioned to capture the entire scrotum. Transformed PMC, scrotal diameter, scrotal temperature, and PCW were analysed using restricted maximum likelihood (REML) in Genstat@. The fixed model for each test was Treatment (PC, ML, M and NC where applicable) x day (0, 1, 2, 3, 6, 9 and 13 where applicable). The random model used was calf ID number. PMC, scrotal temperature and diameter, and PCW data were first tested for a significant interaction between treatment and day and non-significant terms were then dropped from the model to determine the effect of treatment and day. The model predicted means which were used for a pairwise comparison using least significant differences (LSDs). The predicted means and the standard error of the difference (PMC, scrotal diameter, and temperature) or standard error of the means (PCW) were reported, along with their significant pairs. The predicted means and standard error of the difference of the transformed PMC data were back-transformed using the exponential function in Microsoft Excel®2019. For all statistical tests a P value of <0.05 was considered as significant, and 0.05<P<0.1 was considered a statistical trend.

[00242] Wound scoring data was stacked using Microsoft Excel® 2019 and was analysed using an ordinal logistic regression (OLR). An initial OLR was performed only on NC calves in Genstat@ to determine any difference between the two different castration methods. For this analysis, the response factor was wound score and the model to be fitted was castration method. A significant difference was found between the two methods, so the 5 calves that had been castrated by the initial method (removing the distal end of the scrotum) were removed from the analysis. The wound scores of the remaining 5 NC calves were analysed against the ML and M data using an ordinal logistic regression (OLR) in R@ (R Foundation for Statistical Computing, Vienna, Austria) within the ordinal package. The fixed effects were treatment, day and observer and the random effect was the calf ID number. Post-hoc analysis using Tukey's comparisons were used to determine pairwise significance. An inter-observer reliability test was also performed to test the wound scoring system for repeatability between 2 observers. For all analyses, a P value <0.05 was considered significant.

[00243] Behavioural data was stacked and combined in Microsoft Excel® 2019. Head turning, tail flicking and leg movements including stomping or kicking were amalgamated into a single behaviour due to the low frequency of each individual behaviour. These behaviours had been previously validated for pain by numerous authors and in this study, were collectively referred to as "pain associated behaviours" [3,26-30]. Abnormal and normal positional and locomotive behaviours were combined (i.e., normal lying and abnormal lying were amalgamated to "lying"). Additionally, pain associated behaviours and abnormal positional/locomotive behaviours were amalgamated as "abnormal" and maintenance or comfort behaviours including eating, grooming, defecating, and ruminating were amalgamated with normal positional/locomotive behaviours and were analysed as "normal". All behaviours were analysed by week, except for eating, which was analysed by observation timepoint. Observations prior to castration/sham castration (day -1) were referred to as "week -1", observations made on day 0 to 3 were amalgamated to "week 1", and observations made on day 6-13 were amalgamated to "week 2". Behavioural data were analysed using a generalised linear mixed model (GLMM) in GenStat with a binomial distribution to determine the effect of treatment and timepoint (day or week). The model to be fitted was treatment (PC, ML, M and TA) x day (-1, 0AM, OPM, 1, 2, 3, 6, 9 and 13) or week (-1, 1, 2). Behaviours werefirst tested for a significant interaction between treatment and day and non-significant terms were then dropped from the model to determine a significant effect of treatment and/or day. The predicted means presented represent the percentage of time spent performing the behaviour. For all statistical tests a P value of <0.05 was considered as significant. LSDs were used for pairwise comparisons of model predicted means to determine significance using Microsoft Excel 2019 and were presented with the standard error of the means (s.e.m.).

[00244] 3. Results

[00245] 3.1 Infection and morbidity

[00246] Eight calves were treated throughout the study for bleeding or infection. Only 1 calf (from M group) was observed to still be bleeding slightly on day 1 and was subsequently treated with TA, which contains haemostatic agent. This same calf was later treated on day 6 for infection. Infection was characterised by foul smell and a putative exudate and was treated with topical antimicrobial Alamycin@ (Norbrook Laboratories, Tullamarine, VIC). One calf from the NC group was treated for infection on day 3, 6 and 9. An additional calf from the NC group was also treated for infection on day 9. Five calves from the ML group were treated for infection throughout the trial, 3 on day 6 and 2 on day 13. The two treated on day 13 were also administered an injection of Alamycin@.

[00247] 3.2 Plasma meloxicam concentration

[00248] There was an interaction between treatment and day for PMC (P=<0.001; Table 3, 6.2). There was a significant difference in PMC between treatment groups on all days except day 1, with concentration being greatest in the ML group on all days. Meloxicam concentration was significantly greater on day 1, 2, 3, and 6 than days 0, 9 and 13. The PMC of M calves reduced with each subsequent day after day 1.

[00249] 3.2 Medicated Lick Block Consumption

[00250] Throughout the duration of the experiment, the 10 ML calves consumed a total of 15.5kg of the lick block. The concentration of meloxicam in the lick block was1000mg/kg. Based on the total lick block consumed and assuming that consumption was equal between calves, it is estimated that each calf consumed approximately 6.34mg/kg over the duration of access, equating to 0.9mg/kg/day. This is an approximation as individual intake of each calf was not measured.

[00251] 3.3 Wound Morphology

[00252] No differences in wound healing were seen for treatment (P=0.314), day (P=0.429) or their interaction (P=0.686). There was no difference in scoring between two observers (P=0.110).

[00253] 3.3.1 Scrotal Diameter

[00254] There was a significant difference in scrotal diameter between days (P=0.015). No differences in scrotal diameter were seen for treatment (P=0.205) or the interaction between treatment and day (P=0.678).

[00255] 3.3.2 Scrotal Temperature

[00256] No differences in temperature were seen for treatment (P=0.981), day (P=0.093) or their interaction (P=0.062). There was a statistical tendency to significance for the interaction between treatment and day, with scrotal diameter being lower in meloxicam treated calves for 6 days post castration (Table 2, 6.2)

[00257] 3.4 Percentageof Change in Weight

[00258] There was an interaction between treatment and day for the percentage of change in weight (P=0.044; Table 5, 6.2). PC and M calves gained significantly more weight between day -1 and day 9 compared to ML and NC calves. From day -1 to day 13, M and NC calves lost significantly more weight than PC calves. There was no significant difference in the percentage of change in weight between treatments from day 9 to day 13, with all groups losing weight. The change in weight from day -1 to 9 compared to day 9 to 13 was significantly greater in PC and M calves than ML and NC calves.

[00259] 3.5 Behaviour

[00260] Behaviours that occurred too infrequently for statistical analysis were combined, and behaviours that only had an effect of time have not been included.

[00261] 3.5.1 Eating

[00262] There was an interaction between treatment and day for eating (P=<0.001; Table 6, 6.2). Eating was observed significantly more on day -1 than all other days for every treatment. Eating was observed significantly more in ML calves immediately after castration(OAM)than PC, M and NC calves. Eating behaviour was significantly reduced in ML calves from day 6 to day 9 and 13.

[00263] 3.5.2 PositionalandLocomotive Behaviour

[00264] Lying and locomotion differed between treatments (Table 7, 6.2). Lying was observed more in PC calves compared to all castrated calves. ML calves displayed significantly less lying than M and NC calves and performed more locomotion than all other treatment groups.

[00265] 3.5.3 Abnormal and Normal Behaviour

[00266] There was an interaction between treatment and time for normal and abnormal behaviour (Table 8, 6.2). There was no significant difference between treatments in week -1. In week 1, abnormal behaviour was observed less, and normal behaviour was observed more in PC calves as compared to castrated calves. There was no significant difference between castrated calves during week 1. In week 2, abnormal behaviour occurred more, and normal behaviour occurred significantly less in NC calves compared to all other treatment groups. Abnormal behaviour was observed more in week 2 as compared to week 1 in PC calves, concurrent to a reduction in normal behaviour. Conversely, abnormal behaviour was reduced from week 1 to week 2 in M calves, with normal behaviour increasing. There was no difference between week 1 and 2 for ML and NC calves.

[00267] 4. Discussion

[00268] This Example is the first to evaluate the administration of meloxicam via a medicated lick block to establish pre-emptive analgesia and maintain long-term analgesia. Physiological and behavioural responses to surgical castration were evaluated in calves to determine the efficacy of meloxicam delivered via the novel medicated lick block versus traditional administration by injection. Therapeutic concentrations of meloxicam were established and maintained from day 0 until day 9, with the lick block removed on day 6. Weight loss was minimised over the duration of the experiment in calves that received the medicated lick block compared to other castrated calves. The instance of eating was increased in ML calves immediately after castration compared to all other treatment groups and was reduced after removal of the medicated lick. Locomotion was greater in ML calves compared to all other treatment groups. Behavioural and physiological data indicates that the administration of meloxicam via a medicated lick block is efficient for providing pre-emptive and long-term analgesia in surgically castrated calves.

[00269] The successful administration of meloxicam via a medicated lick block enabled therapeutic concentrations of the drug to be established pre-emptively and sustained long-term, without human interference. The therapeutic concentration of meloxicam for cattle is estimated the half-maximal effective concentration (EC5)of meloxicam in equines and canines; 0.2pg/mL and 0.7pg/mL, respectively [24,32,34]. PMC after 19 hours of access to the lick was 0.64pg/mL. The PMC of M calves one day after administration was 1.31 pg/mL, which was not significantly different to the PMC of ML calves on that day. The PMC on the subsequent days for M calves was significantly reduced from day to day. The efficacy of SC meloxicam has been shown to last up to 72 hours, as was seen in M calves in this study, with a PMC of 0.26pg/mL, 3 days after castration [3]. The medicated lick block was removed on day 6. The PMC of M calves 3 days post-removal was 0.42pg/mL, still within therapeutic range. The PMC of M calves peaked on day 2 and remained high until the lick block was removed on day 6. The elevated concentration and maintenance of therapeutic concentration after lick block removal can be attributed to the long elimination half-life and slower absorption of oral meloxicam [15,22,24].

[00270] The recommended dose of PO meloxicam in cattle is 1.0mg/kg (Solvet, Alberta Veterinary Laboratories, Canada), compared to 0.5mg/kg OTM and SC (Boehringer Ingelheim Vetmedica, Germany). Over the 7 days of ad libitum access to the medicated lick, each calf consumed approximately 0.9mg/kg/day, based on the group average weight, assuming consumption was equal between calves. A previous, unpublished study explored the palatability of molasses lick blocks medicated with meloxicam. This study found no significant difference between consumption of medicated and unmedicated licks, suggesting that palatability is unaffected by the addition of meloxicam [35]. A study evaluating the administration of1.0mg/m meloxicam PO found that the maximum concentration (Cmax), 3.10pg/mL, was established 12 hours after administration [18]. In the present study, the suboptimal daily intake of meloxicam indicates that meloxicam delivery via the medicated lick block is reduced. The slower uptake of meloxicam via the medicated lick block is advantageous for continued administration, reducing the potential for toxicity. Hence, the delivery of meloxicam via a medicated lick block is a safer mode of delivery for continued administration.

[00271] Wound characteristics such as temperature, oedema and the degree of healing can inform about the inflammatory response. The recruitment and action of inflammatory cells produce the physical signs of inflammation: redness, heat, oedema (swelling), pain and can lead to loss of function [36,37].

[00272] Scrotal oedema can be measured as an indication of inflammation and healing in surgically castrated calves [3,10]. Oedema is the accumulation of extracellular fluid caused by increased vascular permeability or inadequate lymphatic drainage and subsides after approximately 14 days [21,38,39]. In this study, there was no significant treatment effect for scrotal swelling between castrated calves. These findings are consistent with other studies examining scrotal swelling of surgically castrated calves, finding no significant difference between castrates [10,20]. A significant difference in scrotal diameter was observed in a study that compared 30 surgically castrated calves, half receiving oral meloxicam and half receiving no pain relief [3]. The greater sample size may have improved the statistical power of the experiment, leading to a significant outcome.

[00273] Increased wound temperature is an indication of inflammation and can be easily and accurately measured non-invasively through the infrared thermography (IRT) [40-42]. The increase in wound temperature during acute inflammation can be attributed to the rapid influx of leukocytes and proliferation of macrophages [43]. There was a statistical tendency toward significance for the interaction between treatment and day (P=0.062). This trend describes the reduction of scrotal temperature in meloxicam treated calves for 6 days post-castration. This trend is supported by a study evaluating TA and OTM meloxicam, finding that scrotal temperature was significantly reduced in calves that received meloxicam compared to no pain relief or TA alone, indicating that comparison to sham castrated bulls could improve the statistical power [10]. Ultimately, there was no effect of multiple versus single dose of meloxicam.

[00274] Wound healing occurs in four non-exclusive stages: haemostasis, inflammation, proliferation, and remodelling [44,45]. In this study, wound healing was scored on the closure of the incision, visibility or protrusion of flesh, degree of wound dermatitis and the presence of exudate [19,10]. No effect of treatment was observed for wound healing. The healing of surgical castration wounds has been shown to take approximately 4 to 9 weeks [19]. Therefore, for a better indication of healing between treatment groups, healing should be evaluated over a longer period. This would highlight the long-term effects of pre-emptive and continued administration of meloxicam compared to a single dose.

[00275] The metabolisable energy and crude protein demand of a calf with an average daily gain (ADG) of 1.Okg/d is almost double that of a calf at maintenance [46]. Pain and inflammation from surgical castration has been shown to reduce feed efficiency for up to 14 days post castration, ultimately effecting their percentage of change in weight (PCW) [47]. The PCW was reduced in all castrates from day 1 to 13, with weight loss minimised in ML calves compared to other castrated calves. From day 9 to day 13, all calves lost weight, indicating that weight loss in this period is likely an effect of environment. The calves were kept in their respective groups on the same 0.2ha pasture throughout the entire duration of the experiment, diminishing the state of the pasture. For a better indication of the effect of treatment on weight, a greater sample size and longer measurement period is required.

[00276] Physiological measures of pain and inflammation can be unreliable as they are generally not specific and can be influenced by stress [48]. The analysis of behaviour enables a better understanding of pain and discomfort, informing of the animal's wellbeing as an expression of their mental and physical state.

[00277] Cattle have been known to spend up to 13 hours a day eating, with the rest of the day mostly comprised of ruminating and resting [49]. Therefore, any marked reduction in eating behaviour is considered as abnormal [25,50]. Eating occurred significantly more prior to castration in all treatment groups. This was expected as the calves had been off feed for several hours prior and had just been moved onto fresh pasture. Immediately after castration, eating was significantly reduced in PC, M and NC calves compared to ML calves, indicating that the administration of meloxicam prior to castration alleviated some degree of pain. The reduction in eating seen in PC calves immediately after sham castration may be an effect of stress or sedation. Four hours after castration, eating behaviour increased in PC and M calves compared to ML and NC calves. The increase in eating for M calves corresponds with the Tmax (time to reach maximum concentration) of SC meloxicam, of approximately 3.7 hours [51]. This delay was alleviated in the ML group by allowing access to the lick 19 hours before castration [12,18]. The increase in eating behaviour of ML and M calves in the hours after castration aligns with results from a similar study, finding that eating behaviour was significantly increased in calves that received NSAID flunixin meglumine at castration, compared to calves that received no pain relief [25]. In the present study, eating behaviour reduced in all treatment groups from day 6 to day 13. This pattern correlates with the reduction in PCW. Eating was reduced from day 6 to day 9 in ML calves, where there was no difference in other treatments. This timeframe correlates with the removal of the medicated lick on day 6. These findings demonstrate that the pre-emptive analgesia is preferable to peri-operative analgesia for the alleviation of pain and inflammation resultant of surgical castration.

[00278] Positional and locomotive behaviours can inform about comfort or pain experienced by cattle [26,52,53]. A significant effect of treatment was seen for both lying and locomotion. A relationship between lying and comfort in cattle has been established in numerous studies examining the effects of meloxicam and surgical trauma including dehorning, caesarean section, and castration [27,54,55]. Lying occurred significantly more in PC calves compared to castrates, as expected. Lying occurred less in ML calves compared to M and NC calves. The low instance of lying in ML calves may be explained by their greater display of locomotion compared to all other calves. The increase in locomotion and reduction in lying is consistent with a study evaluating oral meloxicam in surgically castrated calves, demonstrating that movement is also an indication of comfort or reduced pain [3]. These results show that pre-emptive and continued administration of meloxicam reduced post-operative pain more effectively than a single dose of meloxicam. More frequent behavioural observations or continuously logging accelerometer data is important for a clearer effect of treatment.

[00279] The comparison of abnormal and normal behaviour enabled a better understanding of the effect of pre-emptive versus peri-operative and single versus multiple doses of meloxicam. The interaction between treatment and week for both normal and abnormal behaviour demonstrates the efficacy and duration of the various pain relief options. Sham castrated calves displayed less abnormal behaviour and more normal behaviour than castrated calves in week 1. ML calves displayed less abnormal behaviour and more normal behaviour than M and NC calves, although this was not significant. By week 2, there was no difference in abnormal or normal behaviour between PC, ML and M calves. This indicates that meloxicam is effective for reducing the instance of abnormal behaviour and increasing normal behaviour. Topical anaesthetic (TA) has been shown to significantly reduce pain associated behaviours in surgically castrated calves, displaying no significant difference to uncastrated controls [7]. Conversely, the singular or combined administration of TA and OTM meloxicam in surgically castrated calves showed an intermediate pain response compared to uncastrated controls, with no significant difference between treatments [10]. Inconsistencies in results between studies is likely the result of different observational methods. The TA study qualified pain on a scale depending on the severity of the abnormality of behaviour, whereas the TA and OTM study recorded duration and frequency. In this study, behaviour was recorded by only frequency, therefore highlighting a limitation of these results. For a better understanding of the treatment effects, abnormal behaviour should be rated on a scale and the duration of each behaviour should be recorded. Additionally, the statistical power of the experiment could be improved with a greater sample size. The results of this study ultimately demonstrate the efficacy of meloxicam delivered via medicated lick block for alleviating pain.

[00280] Toxicity to continuously administered meloxicam has been observed in numerous species, although has not been evaluated in cattle in the literature [56-59]. Meloxicam is often the preferred NSAID for animal treatment due to the long duration of efficacy and COX-2 specificity for the inhibition of prostaglandin [60,61]. COX-2 is preferred over COX-1 as it is mainly expressed at sites of inflammation, however, COX-2 also plays an important role in production of prostaglandin for homeostasis of the central nervous system, renal system, gastrointestinal system, bones, female reproductive tract and cardiovascular system [59,62-64]. Toxicity to meloxicam often manifests as gastrointestinal ulceration or perforation and impaired renal function [57-60]. Experimentally induced meloxicam toxicity in rats at a dose of 2.3mg/kg/day for 28 days led to renal, hepatic, myocardial and neuronal necrosis [58]. In horses, a dose of 0.6mg/kg PO meloxicam every 24 hours for 6 weeks was well tolerated with no adverse effects, whereas horses that were administered 3 and 5 times this dose experienced gastrointestinal damage, renal damage and bone marrow abnormalities [56]. These findings indicate that research into the toxicity effects of long-term meloxicam administration in cattle is critical to prevent adverse health effects.

[00281] 5. Conclusions

[00282] The administration of meloxicam via a medicated lick block successfully enabled pre-emptive and continuous administration of meloxicam in Bos taurus calves. The concentration of meloxicam ingested was sufficient to reduce the extent pain and inflammation resultant of surgical castration, to the same degree or superior to traditional pain relief methods. No adverse effects of the medicated lick block were observed.

[00283] Ultimately, this technology has great potential to change pain relief for livestock husbandry procedures, enabling pre-emptive and long-term action. Animal welfare should be a priority for all producers, and the implementation of this delivery system could make it a reality.

[00284] 6. Tables

[00285] 6.1 Research Methods

[00286] Table 2: Ethogram

BEHAVIOUR DESCRIPTION POSITION/LOCOMOTION NORMAL STANDING Calf stands passively or actively with muscles relaxed, head may be held in relaxed frame, ears may be held loose ABNORMAL STANDING Calf stands stationary, possibly hunched back, legs may be trembling or stretched out, body may be trembling, may be shifting weight between hind legs (easing quarters), head may be held low NORMAL LYING Calf may lie ventrally or laterally, legs may be folded underneath or partially, head may be up or folded towards body ABNORMAL LYING Calf lies laterally with hind legs entirely or partially extended, lateral recumbency, forelimbs may be extended, head may be flat on the ground NORMAL MOVING Calf moves in forward locomotion, takes even steps, weight bearing on all 4 limbs, even cadence, relaxed muscles, hindfoot replaces forefoot ABNORMAL MOVING Calf may walk with a hunched back, trembling legs, small, short steps, tiptoeing, walking on knees, falling over, stiff gait, spreading of hind legs or dragging feet, hindfoot may not replace forefoot ACTIVITY TAIL FLICKING Calf flicks its tail in one motion or1 continuous motion

EAR FLICKING Calf flicks one or both ears

KICKING OR STAMPING Calf may kick at belly/groin, may kick backwards, stomping fore or hind leg. Definitive lifting and replacing of the foot not associated with walking HEAD TURNING Calf turns its head to side of body, may place head under leg towards wound VOCALISATION Calf vocalises GROOMING Licking self MAINTENANCE GRAZING Calf grazes, ingests feed- pasture, hay or lick DRINKING Calf ingests water DEFECATION/URINATION Calf defecates or urinates RUMINATING Chewing cud, salivation

[00287] Table 3: Wound scoring scale - See Figure 1.

[00288] 6.2 Results

[00289] Table 3: predicted means and standard error of the means (s.e.m.) for plasma meloxicam concentration (pg/mL) ML= meloxicam lick block and TA; M= meloxicam injection and TA. Values with different superscripts differ significantly (P=<0.05). Lowercase superscripts (a c) represent significance within a treatment; uppercase b superscripts (A B, c) represent significance between treatments.

Predicted means s.e.d Day ML M 0 0.64a^ g 1.35 1 1. 9 9 b± 1.3 4 1.31ag 1.34 2 3 . 9 9 cA g 1.34 0.56bB+1.34 3 3 .4 0cA c1.34 B. 2 6 cB1.34 6 3 .7 0cA 0. 41.34 4 dB+1.34 9 0.42a ±1.34 0.01eB+1. 8 1 13 0.05A± 1.36 O.OOB± 0.00

[00290] Table 4: Predicted means and standard error of the means (s.e.m.) for scrotal temperature by treatment PC= sham castration; ML= meloxicam lick block; M= meloxicam injection; NC= negative control.

Predicted means ±s.e.m. Day ML M TA 1 38.14 0.24 38.3 0.24 38.7 0.24 2 38.28 0.24 38.28 0.24 38.54 0.27 3 38.59 0.24 38.39 0.24 39.04 0.24 6 38.82 0.24 38.57 0.24 38.84 0.24 9 38.5 0.24 38.68 0.25 38.02 0.24 13 38.73 0.24 38.61 0.24 38.3 0.24

[00291] Table 5: Predicted means and standard error of the means (s.e.m.) for the percentage of change in weight. PC= sham castration; ML= meloxicam lick block; M= meloxicam injection; NC= negative control. Values with different superscripts differ significantly (P=<0.05). Lowercase superscripts (a b c) represent significance between treatments; uppercase superscripts (A B C) represent significance within treatments; values with no superscript are not significant from any other value.

Treatment Predicted means ±s.e.m. Day-i to day 9 Day 9 to day 13 Day 1 to day 13 PC . 4 5 0 aA 0 .0 1 B ± 0 0 1 aA ML 0 .7 7 ' 0.01 -0.8 0.01 -0 0 .3 3 ab g 0.01 M 1 .5 3 abA±0.01 B ±0.01 1 7 bB±0.01 NC -1.27' 0.01 -0.9 ±0.01 -1.64' 0.01

[00292] Table 6: Predicted means and standard error of the means (s.e.m.) for eating. PC= sham castration; ML= meloxicam lick block; M= meloxicam injection; NC= negative control. Values with different superscripts differ significantly (P=<0.05). Lowercase superscripts (a b, c)

represent significance within a treatment; uppercase superscripts (A, B C) represent significance between treatments; values with no superscript are not significant from any other value.

TIMEPOINT PC ML M NC Predicted means s.e.m. -1 0.98± 0.02 1.00e± 0.00 1.00e± 0.00 1.00e± 0.00 OAM 0 . 1 8 abA g 0.07 0 . 5 3 aB±0.08 0 . 9 aA±0.07 0 1 2 aA±0.06

OPM 0 .0 6 aA±0.03 0 13 bA±0.04 0 3 6 abB+0.06 0 . 4 aA±0.04

1 0 .2 8 bcA g 0.05 0 .5aB0.06 0 3 8 bAB 0.05 0 .5 8 bB g 0.05 2 0 .4 6 cdA g 0. 0 5 0 .2 7 cB 0 04 0 47 bcA 0. 0 5 0.4cAB 3 0. 5 8 d0.05 0.57a s 0.05 0 .5 4 cd 0.05 0 .5 3 b 0.05 6 0.83e 0.07 0.70a s 0.06 0 .6 5 d0.07 0 .7 8 d 0.05 9 0 .7 8 eA g 0. 0 5 0 .2 1 bcB 0 07 dA bdA 0.05 13 0 .4 1 dA0.08 0 1 3 bB 0.05 0 .2aB0.06 0 4 8 bcA±0.08

[00293] Table 7: Predicted means and standard error of the means (s.e.m.) for lying and locomotion. PC= sham castration; ML= meloxicam lick block; M= meloxicam injection; NC= negative control. Values with different superscripts differ significantly (P=<0.05).

Lying P=<0.001 Locomotion P=0.018 Predicted means s.e.m. PC 0.2la g 0.02 0.09a g 0.01 ML 0.10b 0.01 0.14 b 0.01 M 0. 17° 0.02 0.10a g 0.01 NC 0. 16° 0.0 1 0.10a g 0.01

[00294] Table 8: Predicted means and standard error of the means (s.e.m.) for abnormal and normal behaviour. PC= sham castration; ML= meloxicam lick block; M= meloxicam injection; NC= negative control. Values with different superscripts differ significantly (P=<0.05). Lowercase superscripts (a b, c) represent significance between treatments; uppercase superscripts

(A B, C) represent significance within treatments; values with no superscript are not significant from any other value.

Abnormal P=0.002 Normal P=<0.001 Week Week -1 1 2 -1 1 2 PC 0 . 0 0 A± 0 1 2 aB± 0 2 4 aC A aB 0.75 aC 0.00 0.02 0.04 0.02 0.02 ±0.04 ML 0 .0 0 A 0 2 9 bB 0 2 4 aB 0 . 9 5 A ±7bB g 0.75aB 0.00 0.02 0.04 0.03 0.02 ±0.04 M 0 . 0 0A g 0 .3 5 bB 0 2 2 aC 1 0 0 A 0 .6 5 bB 7 aC 0.00 0.03 0.04 0.00 0.03 ±0.04 bB 0 9 7A 0 6 8 bB B NC 0 .0 0 A± 0 3 2 bB± 0 3 9

0.00 0.03 0.04 0.02 0.03 ±0.04

[00295] In the present specification and claims, the word 'comprising' and its derivatives including 'comprises' and 'comprise' include each of the stated integers but does not exclude the inclusion of one or more further integers.

[00296] Reference throughout this specification to 'one embodiment' or 'an embodiment' means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, the appearance of the phrases 'in one embodiment' or 'in an embodiment' in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more combinations.

[00297] In compliance with the statute, the invention has been described in language more or less specific to structural or methodical features. It is to be understood that the invention is not limited to specific features shown or described since the means herein described comprises preferred forms of putting the invention into effect. The invention is, therefore, claimed in any of its forms or modifications within the proper scope of the appended claims (if any) appropriately interpreted by those skilled in the art.

[00298] REFERENCES

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Claims

1. A method of providing pre-emptive and ongoing pain relief to an animal following a ) surgical or animal husbandry procedure, said method comprising the step of providing the animal access to a medicated supplement comprising at least one type of pain relieving agent, whereby the animal is able to self-medicate prior to undergoing the surgical or animal husbandry procedure and continue to self-medicate following the procedure.

2. Use of a medicated supplement comprising at least one type of pain relieving agent in the manufacture of a medicament for providing pre-emptive and ongoing pain relief treatment to an animal following a surgical or animal husbandry procedure, wherein said treatment comprises providing the animal access to the medicament such that the animal is able to self-medicate prior to undergoing the surgical or animal husbandry procedure and continue to self-medicate following the procedure.

3. A medicated supplement comprising at least one type of pain relieving agent for use in providing pre-emptive and ongoing pain relief to an animal following a surgical or animal husbandry procedure, said use comprising the step of providing the animal access to the medicated supplement such that the animal is able to self-medicate prior to undergoing the surgical or animal husbandry procedure and continue to self-medicate following the procedure.

4. A medicated supplement for an animal comprising at least one type of pain relieving agent, capable of providing pre-emptive and post-surgical or animal husbandry procedure pain relief to the animal when the animal self-medicates prior to undergoing the surgical or animal husbandry procedure and following the procedure.

5. A method of manufacturing a medicated supplement for an animal comprising at least one type of pain relieving agent, capable of providing pre-emptive and post-surgical or animal husbandry procedure pain relief to the animal when the animal self-medicates, said method comprising the step of combining ingredients, including supplement ingredients and at least one type of pain relieving agent, to form the medicated supplement.

6. The method of claim 1, the use of claim 2, the medicated supplement of claim 3 or 4, or the method of claim 5, wherein the at least one type of pain relieving agent is an analgesic agent and/or an anti-inflammatory agent.

7. The method, use or medicated supplement of claim 6, wherein the at least one type of pain relieving agent is acetaminophen, aspirin, salicylic acid, methyl salicylate, choline salicylate, glycol salicylate, 1-menthol, camphor, mefenamic acid, fluphenamic acid, indomethacin, diclofenac, alclofenac, ibuprofen, ketoprofen, pranoprofen, fenoprofen, sulindac, fenbufen, clidanac, flurbiprofen, indoprofen, protizidic acid, fentiazac, tolmetin, tiaprofenic acid, bendazac, bufexemacpiroxicam, phenylbutazone, oxyphenbutazone, clofezone, pentazocine, mepirizole, hydrocortisone, cortisone, dexamethasone, fluocinolone, triamcinolone, medrysone, prednisolone, flurandrenolide, prednisone, halcinonide, methylprednisolone, fludrocortisone, corticosterone, paramethasone, betamethasone, naproxen, suprofen, piroxicam, diflunisal, meclofenamate sodium, carprofen, flunixin, tolfenamic acid, meloxicam, salicylate, diflunisal, salsalate, propionic acid derivative, acetic acid derivative, enolic acid derivative, anthranilic acid derivative, selective COX-2 inhibitor, sulfonanilide, clonixin, licofelone, or H-harpagide in Figwort or Devil's Claw.

8. The method, use or medicated supplement of claim 7, wherein the at least one type of pain relieving agent is meloxicam.

9. The method of any one of claims 1, 5, 6, 7 and 8, the use of any one of claims 2, 6, 7 and 8, or the medicated supplement of any one of claims 3, 4, 6, 7 and 8, wherein the medicated supplement comprises about 1000 mg of pain relieving agent per about 1kg of medicated supplement.

10. The method of any one of claims 1, 5, 6, 7, 8 and 9, the use of any one of claims 2, 6, 7, 8 and 9, or the medicated supplement of any one of claims 3, 4, 6, 7, 8 and 9, wherein the medicated supplement is in the form of a lick block.

11. The method, use or medicated supplement of claim 10, wherein the lick block is a medicated molasses lick block.

12. The method, use or medicated supplement of claim 11, wherein the medicated molasses lick block comprises the following ingredients (all weight/weight):

about 40-55% molasses, preferably about 50%;

up to about 5% hydrated lime, preferably about 5%;

about 5-20% magnesium oxide, preferably about 5-10%, more preferably about 5%; about 5-10% water, preferably about 10%; up to about 5% phosphoric acid, preferably about 5%; and the at least one type of pain relieving agent, quantity to suit, preferably about 0.1-0.2%.

13. The method, use or medicated supplement of claim 11, wherein the medicated molasses lick block comprises the following ingredients (all weight/weight):

about 24% vegetable oil, preferably about 2%;

about 40-55% molasses, preferably about 50%;

about 2 to 10% salt, preferably about 5%;

about 5 to 10% phosphate (e.g. di-calcium phosphate), preferably about 5%;

up to about 5% hydrated lime, preferably about 5%;

about 5 to 20% magnesium oxide, preferably about 5-10%, more preferably about 5%;

up to about 2% minerals, preferably about 1-2%, more preferably about 2%;

up to about 10% water, preferably about 5-10%, more preferably about 10%;

up to about 5% phosphoric acid, preferably about 5%; and

the at least one type of pain relieving agent, quantity to suit, preferably about 0.1-0. 2 %.

14. The method, use or medicated supplement of claim 11, wherein the medicated lick block comprises the following ingredients (all weight/weight):

about 2% vegetable oil;

about 50% molasses;

about 5% salt;

about 5 % di-calcium phosphate;

about 5% hydrated lime; about 5% magnesium oxide; about 2% minerals; about 10% water; about 5% phosphoric acid; and the at least one type of pain relieving agent, quantity to suit, preferably about 0.1%.

15. The method of any one of claims 1and 5 to 14, the use of any one of claims 2 and 6 to 14, or the medicated supplement of any one of claims 3, 4 and 6 to 14, wherein the surgical or animal husbandry procedure is selected from a surgical incision, a major abrasion, a major bum, mulesing, shearing, castration, spaying, tail docking, ear tagging, ear notching, de-horning, crush dehoming, scoop dehoming, hot iron disbudding, branding, hot iron branding or marking.

16. The method, use or the medicated supplement of claim 15, wherein the surgical or animal husbandry procedure is castration.

17. The method of any one of claims 1and 5 to 16, the use of any one of claims 2 and 6 to 16, or the medicated supplement of any one of claims 3, 4 and 6 to 16, wherein the animal is a farm animal, livestock or ruminant, preferably a sheep, a head of cattle, pig, horse, buffalo, goat or yak.

18. The method of claim 1, the use of claim 2, or medicated supplement of claim 3, further comprising a step of topically administering to the animal an anaesthetic or analgesic composition prior to, during, as part of, or following the surgical or animal husbandry procedure.

19. The method of any one of claims 1and 5 to 18, the use of any one of claims 2 and 6 to 18, or the medicated supplement of any one of claims 3, 4 and 6 to 18, wherein the animal self premedicates for a period of about 7-10 days prior to the surgical or animal husbandry procedure, and self-medicates for a period of about 1 to 3 weeks after the surgical or animal husbandry procedure.

20. The method of any one of claims 1 and 5 to 19, the use of any one of claims 2 and 6 to 19, or the medicated supplement of any one of claims 3, 4 and 6 to 19, wherein:

the medicated supplement establishes pre-emptive analgesia and maintains long-term analgesia; the medicated supplement reduces inflammation and ameliorates pain responses; and/or the animal continues to self-medicate throughout some, most or an entire inflammatory period following the procedure, without human interference.