Sedation and analgesia of the difficult case

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Gaining the upper hand – sedation and analgesia of the difficult case

David Bardell BVSc CertVA DipECVAA PGCert(LTHE) FHEA MRCVS

What do we mean by ‘difficult’?

In the case of providing sedation and/or analgesia to our “difficult” patients these can include adequate access to the animal, dealing with temperamentally uncooperative animals, effective administration of the required drugs, animals which do not respond to our treatment in the anticipated way, providing sedation and/or analgesia in circumstances which are outside our normal range of practices or the use of unfamiliar pharmacologic agents. However the myriad of different possible aspects which converge to present us with the ‘difficult’ case can be distilled practically into 3 basic questions

  • How can I physically get the drugs into the horse?
  • What can I give to achieve the effect I want?
  • What drugs/equipment do I have available?

horse-in-drain

Accessibility and drug administration

If we anticipate problems in drug administration, is this because the animal is unhandled, nervous, in pain or dangerous? Animals that are wilfully malicious are fortunately rare but a perceived threat, unfamiliar routine or surroundings or pain can result in potentially dangerous behaviour, particularly if the animal is unhandled or of a particularly nervous disposition. The animal will need to be confined somewhere that allows some sort of access but where it is not in danger of causing itself, or any personnel, any injury. The approach taken will vary depending on which of the above reasons are relevant to that animal and the urgency with which the intervention is required but at all times the safety of any people involved must be the absolute over-riding concern. It is perfectly permissible to go away and come back another day when the owner has managed to get a headcollar on the horse. A quiet, patient approach may be all that is required in some instances and a competent handler is a definite advantage in any circumstances. If pain is a contributing factor, the provision of effective analgesia may be all that is required and make sedation irrelevant. However, the animal will need to receive some form of pharmacological agent to facilitate examination or performance of a procedure.  Decreasing the level of auditory and visual stimuli can also be useful to maximise the chances of successful sedation. However if the eyes are covered care should be exercised as suddenly touching the horse can result in a dramatic startle response if the horse is unaware of the presence of a handler.

remote-location

Intravenous (IV) administration is preferred where possible as uptake is independent of patient factors which affect absorption by other routes, giving a bioavailability of 100% and therefore most likely to achieve a reliable effect. However, IV preparations of drugs are generally more expensive than other formulations, sterility must be ensured, frequent repeated dosing may be required, initially high plasma concentrations may produce adverse effects, there may be no IV preparation available or licenced for use or IV administration may be contra-indicated. Equally IV administration requires close and safe access to the patient which with some horses may simply not be possible.

Intramuscular (IM) injection may give a bioavailability approaching 100% and may give a fairly rapid onset of action although typically onset is delayed. Uptake is influenced by the perfusion at the site of injection which will vary between muscle groups and will be reduced in hypotensive or vasoconstricted animals, or if injection is made into fat or fascia. These factors can mean that the effect is unpredictable and can lead to overdosing if dosing is repeated.  Drug administration by this route may cause pain, haematoma or abscessation and some drugs are contra-indicated by IM injection as they can cause tissue necrosis. Where drugs can be given either by the IV or IM route, higher doses are often required IM to achieve equivalent effect compared with IV administration. Equally this method requires that the animal can be approached close enough to perform needle puncture although this may well be possible in animals where IV access is impossible. Also in favour of this route is the fact that drugs can be formulated in depot preparations, increasing the duration of effect, so reducing the need for frequent dosing. Animals which become agitated and potentially dangerous when conventional IM injection is carried out or which can be approached from outside a stable but become potentially dangerous when the stable is entered can still relatively easily be dosed this way using a cheap and simple remote injection device. This consists of nothing more than a syringe, 16 or 18 gauge 1½ inch needle and a variable number of lengths of polyethylene manometer tubing. Any tubing can be used but medical manometer tubing has a low internal volume, is non-compliant and comes in standard lengths which can be connected depending on the circumstances (Clutton 1997). The drug to be injected is drawn into the syringe (ideally the smallest syringe capable of holding the appropriate volume plus a small volume of air is used (the amount of air must be at least that of the volume of the tubing, so will therefore depend on how many lengths of tubing are used).  The manometer tubing is then connected firmly to the syringe, the needle attached to the free end and the tubing filled with drug. All the operator then has to do is get close enough to place the needle which can be done from behind a barrier or over the stable door and injection can be performed from a safe distance. Needle placement should be done purposefully and the syringe plunger pressed as soon as the needle is embedded. It is important to hold the syringe vertically with the outlet pointing down so that the air is expelled last to ensure it flushes residual drug from the tubing. The tubing is then pulled to retrieve the needle.

If manual needle placement cannot be achieved a pole syringe (either commercially available or home-made) can be used. Although these are often heavy, clumsy pieces of equipment and commercial versions are quite expensive (approximately £500 at time of writing; DANiNJECT), they do permit IM injection without getting closer than 2m from the animal and injection is effected by compressed gas depression of the syringe plunger making delivery very rapid. There is also no equipment dead-space potentially reducing injected drug volume. However some animals will panic when approached with one and they make a formidable weapon if propelled back towards the handler by a well-aimed kick.

For very fractious, dangerous or unapproachable animals, the use of a dart gun may be considered for drug delivery. This however will require that a suitable licenced and experienced individual is available which may not be the case, although we have found that wildlife capture specialists and local zoos are often very obliging in this respect. Because of the requirement to restrict the volume of drugs delivered by this method to that which can be contained within a dart, highly concentrated and/or potent drugs are often required, the handling of which often has additional safety implications. The use of small volumes will also maximise the chance of successful delivery. There is obviously the disadvantage of missed shots, failed dart delivery, inaccuracy of dart placement, dart induced trauma and public safety. Blow-pipes may provide a low trauma alternative, but the author has no experience of using them.

Subcutaneous drug delivery may occur through poor attempted IM technique. Kinetics of absorption are again dependant on blood flow to the area which may be affected by pathological conditions or even ambient temperature. Some drugs are supplied in depot preparations for human use designed for this route of administration (antipsychotic medications, insulin, heparin and contraceptives) but, other than contraceptive implants, the author is unaware of the application of any of these to veterinary species.

If no injectable route is practical or feasible, per os administration may be used. Here two different mechanisms of drug uptake can be exploited, oral and transmucosal, depending to some degree on how approachable the animal is.

Oral medication will be very familiar from chronic pain management, typically using long term non-steroidal anti-inflammatory drugs (NSAIDs). Following oral administration, drug uptake is across the mucosa of the gastro-intestinal tract, where, unless there are specific transport mechanisms for the drug concerned, only unionised drugs will have any significant uptake. Oral administration is generally the least efficient method of drug delivery resulting in the lowest and most unpredictable bioavailability as this is affected by the physical and chemical properties of the drug, the pH within the gut lumen, the surface area available for absorption, interactions with feed components or other concurrently administered drugs and first pass metabolism. Drugs can be either administered directly (there are several NSAIDs as well as acepromazine marketed and licenced for administration in this way), mixed in feed or diluted into drinking water. Where voluntary intake in food or water is expected however, palatability issues become important in ensuring an adequate dose is received.

oral-admin

Alternatively, some drugs can be absorbed readily across the mucous membranes within the oral cavity (also the nasal cavity and rectum). Although this route is often very effective, only the alpha 2 agonist detomidine is licenced and marketed in a gel formation specifically for this route. The advantages of this method are that it results in rapid uptake and avoids the first pass metabolism which enterally absorbed drugs are subject to.  Variability results from loss of any delivered drug which may be swallowed or spat out so dosing can be rather imprecise, and administration by this route obviously restricts use to those drugs which only require a small total dose to be given (either highly concentrated formulations or highly potent drugs) and requires that the animal is amenable to this method.

Other methods of drug administration which are applicable more specifically to provision of analgesia are discussed below.

Transdermal drug delivery systems have been developed for a number of classes of drugs in the human market and include patches, creams and gels for external application designed to have either systemic or local effects. Transdermal drug absorption avoids first pass metabolism and gives the potential for prolonged drug administration with minimal intervention. However drug uptake is highly dependent on sustained contact with the skin and that the area of application is healthy and has a good blood supply. Several human preparations have been evaluated in veterinary species and a specific veterinary formulation of fentanyl (licenced for use in dogs) is now available (Recuvyra; Eli Lilly UK).

Epidural drug administration is becoming more commonly employed and a number of drugs can be given by this route, providing the opportunity for a more regional effect. Depending on the characteristics of the drug, there will be varying systemic uptake and onset and duration of effect may differ significantly from that familiar from systemic administration. Local anaesthetics, alpha 2 agonists, opioids, ketamine and tramadol have all been reported in the horse by this route. For prolonged analgesia, epidural catheters can be placed which offer the potential for extended targeted pain management. Commercial kits for this procedure are available. The catheter requires very careful management, with maintenance of patency and sterility being the main problems.

Diffusion catheters are another method of providing targeted pain relief. These are available commercially or can be improvised from narrow gauge plastic tubing or intravenous cannulae. The use of these for prolonged perineural administration of local anaesthetic has been investigated experimentally in horses (Driessen et al 2008) with some success. Alternatively the catheter can be implanted at the surgical site during wound closure allowing local anaesthetic to be instilled directly for post-operative pain management. This approach has been successfully used at the author’s hospital for orthopaedic cases.

Achieving the desired effect

  1. adequate depth and duration of sedation

This is necessary to render the horse calm and easy to handle. It limits the release of catecholamines, minimises their antagonistic effects to anaesthetic agents. Ideally animals to be sedated will be calm before the sedation is given and then be left quietly until the full effect of the drugs has been developed. Whilst every effort should be made to minimise the stress to the animal in advance, with difficult animals this may well not be achievable. It is important to note that in excited or unhandled animals effects can be unsatisfactory, particularly as drugs may have to be administered by the IM, oral or oral transmucosal (OTM) routes. Higher doses than are commonly employed may be required and combination of agents to utilise synergistic or additive effects will also help, but some animals will never achieve a satisfactory level of sedation to allow close approach or interventions (Clutton 1997). The risk to the animal of an adverse event will also increase when using high doses of sedatives. Owners should be appraised of these concerns prior to starting.

Even biddable horses may require sedation which falls outside of the range of conventional drugs if extended periods of restraint are needed, requiring the use of unfamiliar and unlicenced preparations, or using conventional pharmaceutical agents in unconventional ways.  Below is a summary of some agents potentially useful to achieve sedation and anxiolysis in horses.

Phenothiazines

Anxiolytic rather than sedative with mental calming effects (antidopaminergic action) typically without producing drowsiness. Also produce a weak anticholinergic effect and anti α1-adrenergic and antiserotonergic effects. Useful but unreliable effect, but synergistic with other sedative agents. Some horses can become profoundly sedated, others mildly so, whilst some will exhibit no obvious effect. Paradoxical excitement reaction with profuse sweating, trembling and restlessness has been reported following 0.5mg kg-1 acepromazine IM which lasted approximately 40 minutes (MacKenzie and Snow 1977). For maximum benefit to be obtained, should be administered to the horse whilst it is calm and then given 45 minutes to achieve effect before proceeding with further interventions.

Anti-adrenergic effects produce peripheral vasodilation resulting in hypotension and use is therefore contraindicated in hypovolaemic horses. There is the potential for increased heat loss and care should be taken if using in foals.

Phenothiazines have no intrinsic analgesic activity except for methotrimeprazine but have been shown to potentiate the analgesic properties of other drugs.

Acepromazine – 0.01-0.05mg kg-1 IV/IM;  0.15-0.25mg kg-1 PO. Available as 2, 5 and 10mg mL-1 solutions for injection as well as tablet and 35mg mL-1 oral paste/gel preparations.

Promazine – 0.40-1.0mg kg-1 IV/IM, 1-2mg kg-1 PO. No licenced preparations.

Chlorpromazine – no licenced preparations and not recommended in horses; profuse sweating, severe ataxia and collapse has been reported at 1mg kg-1 IV, although effects were reversed by administration of 0.1mg kg-1 IV methylamphetamine (Jones 1963).

Fluphenazine –  no licenced preparations. A long-acting phenothiazine used in human schizophrenia patients with poor compliance for oral medication where intramuscular injections of the enanthate or decanoate ester are administered every 2-3 weeks . Used as a long acting tranquilliser to relieve anxiety in horses subject to stressful situations such as prolonged confinement or separation from companions where a dose of 0.1mg kg-1 IM reported to be successful for up to 30 days. Extrapyramidal side effects can occur and can be severe. Brewer et al (1990) reported onset of adverse behavioural signs 16hr after administration of 0.1mg kg-1 IM which lasted for approximately 60hrs. Kauffman et al (1989) reported intermittent extra-pyramidal effects, seizures and periods of somnolence evident 12hrs after administration of 0.1mg kg-1 IM which required barbiturate sedation to control for the following 24hrs.

Perphenazine – no licenced preparations. This has five times the potency of chlorpromazine and is available as 100mg  mL-1 solution for injection(perphenazine enanthate; Kyron Laboratories SA). Onset of action takes approximately 16hrs with effect lasting for 4-5 days. Used in antelope for relocating; no ataxia.

Butyrophenones

Show similarities in receptor activity to phenothiazines, with potent antidopaminergic activity. Also have antiadrenergic, antiserotonergic, antihistaminergic and anticholinergic activity.

Azaperone 0.4-0.8mg kg-1 IM. Not licenced in horses. Onset within 10 minutes, peaking at 20-60 minutes and lasting 2-6hrs (Serrano and Lees 1976). Sweating, salivation, mastication and slight muscle tremors are reported at these doses.  MacKenzie and Snow (1977) found 0.7-0.9mg kg-1 IM produced better and more consistent sedation than 0.5mg kg-1 acepromazine IM or 2.0mg kg-1 xylazine IM, with effects evident within 20 minutes and slight signs of sedation still detectable 24hrs later. They reported side effects as above and mild transient excitement in one horse at these doses. Paradoxical excitement/panic reported in horses after 0.29-0.57mg kg-1 IV (Dodman and Waterman 1979) with ataxia, salivation, sweating, muscle tremors and vocalisation occurring within 30 seconds and lasting up to 5 minutes before sedation became evident.

Available as 40mg mL-1 (Stresnil; Elanco), 30 and 50mg mL-1 (Wildlife Pharmaceuticals Inc; wildpharm.com) solutions for injection.

Fluanisone and droperidol have been marketed with a veterinary license in combination with fentanyl for use in small animals but adverse behavioural effects and aggression has been reported following droperidol use in dogs.

Haloperidol – no licenced preparations but reported at 0.5mg kg-1 IV for treatment of self-mutilation syndrome in horses, accompanied by sedation for approximately 2 hours after administration (Dodman et al 2004). Used for transportation of nervous animals (Cervidae) prior to relocation, where the oral form is given 1 hour prior to effect required (personal communication).

Human preparations Dolpin oral solution 10mg 5mL-1 (Pinewood ) Haldol injection 5mg mL-1 (Janssen-Cilag).

Haloperidol 20mg mL-1 and oral powder (Wildlife Pharmaceuticals Inc; wildpharm.com).

 

Benzodiazepines

None licenced for veterinary use in any species. Commonly used with ketamine for induction of anaesthesia in the horse to provide enhanced muscle relaxation, but not recommended to be used alone due to risk of disinhibition and excitement reactions in adult horses. Useful sedative in foals up to approximately 4-6 weeks of age.

Diazepam 0.1-0.3mg kg-1 IV only, gives mild to heavy sedation with recumbency at higher doses. Human preparations typically 5mg mL-1 supplied as 2mL vials.

Midazolam can be given IV or IM at 0.1-0.5mg kg-1 (higher doses IM). Human preparations typically 5mg mL-1 supplied as 2mL vials; a more concentrated form, 50mg mL-1 is available for wildlife immobilisation (Wildlife Pharmaceuticals Inc; wildpharm.com).

 

Thioxanthines

Zuclopenthixol – no licenced veterinary preparations. Long acting anti-schizophrenia drug used in patients who show poor compliance with oral medication where a dosing interval 2-3 weeks is used. Used for prolonged sedation in zoo and wildlife relocation where effect takes 12 hours to develop following IM injection and lasts approximately 72hrs.

Human preparation 50mg mL-1 (Clopixol – Acuphase; Lundbeck UK).

 

Alpha 2 adrenoceptor agonist

The mainstay of equine sedation, these give reliable sedation with muscle relaxation and analgesia. Wide range of actions (intended and otherwise) due to extensive distribution of receptors (centrally and peripherally) and variable selectivity for α2 receptor subtype. Generally sympatholytic therefore increase parasympathetic tone. Currently three are licensed for use in horses and all provide variable duration (20-90 minutes) but potentially profound sedation. It is important to be aware that even profoundly sedated horses can still be roused and bite or kick accurately. Sedation can be extended by repeat dosing or by administering as a continuous IV infusion (although this is outside their licencing range). Drugs more suited to this method of delivery are those with a rapid onset and short duration of action, making xylazine and medetomidine pharmacokinetically more appropriate for this method, but continuous infusions of xylazine, detomidine, romifidine and medetomidine have all been reported in the horse.

Xylazine – 0.2-1.1mg kg-1 IV; up to 2-3mg kg-1 by the IM route (Clarke and Hall 1969) –  unlicensed by the IM route. Produces sedation of approximately 20 minutes duration. Commercial licenced veterinary preparations available are 20 and 100mg mL-1 solution for injection. Also available as a dry powder for reconstitution, supplied in 500mg vials (Rompun Dry Substance; Bayer) and 300mg mL-1solution for injection from specialist wildlife immobilisation suppliers (Wildlife Pharmaceuticals Inc; wildpharm.com).

For continuous infusion sedation a loading dose of 0.5 – 0.75mg kg-1 IV is given. Then 500mg xylazine is added to a 500mL bag 0.9% NaCl and infusion started, aiming for approximately  12µg kg-1 min-1 (for a 500kg horse start at about 2 drops per second,  assuming a standard giving set delivering 20 drops per mL). The infusion rate can then be adjusted according to the effect observed. Once the infusion has been terminated, the horse should be able to safely be walked back to its box after 10-15 minutes.

Detomidine – 5-20µg kg-1 IV; 20-40µg kg-1 IM; 40-60µg kg-1 OTM. Sedation for approximately 60-90 minutes. Available as a 10mg mL-1 solution for injection and 7.6mg mL-1 oral gel licensed for use in horses. Note-  not all injectable preparations are licensed by the IM route; injectable formulation very effective (though unlicensed) transmucosally. The most potent of the licenced  α2 agonist drugs therefore the volume required is small. For this reason, of the conventional sedative agents, making it eminently suitable for remote IM injection.

For continuous infusion sedation a loading dose of 6µg kg-1 detomidine is given IV. Then 12mg detomidine is added to a 500mL bag of 0.9% NaCl and infusion started once full sedation has developed aiming for approximately  0.1µg kg-1 min-1 (for a 500kg horse, start at about 4 drops per second and titrate to effect). Usually you can approximately halve the initial infusion rate once an appropriate level of sedation has been achieved.

Romifidine 40-100µg kg-1 IV; up to 120µg kg-1 IM (only licenced in horses by the IV route). Sedation for approximately 90 minutes. Supplied as a 10mg mL-1 solution for injection licenced for use in horses. Anecdotally this gives the least degree of ataxia of the licenced alpha 2s.

For continuous infusion sedation a loading dose of 80µg kg-1 IV is followed by an infusion of 30µg kg-1 hour-1. This resulted in stable plasma levels of romifidine and adequate sedation as judged by the posture adopted by the animals, but no surgical interventions were carried out (Ringer et al 2012). These authors described that in comparison to their xylazine infusion protocol (above) this provided slightly less ataxia, less response to auditory stimuli, but longer time period to achieve maximal sedation and recovery after terminating the infusion (Ringer et al 2013).

Medetomidine is currently unlicensed for use in horses but there is a substantial body of research about its use and effects in this species. Bryant et al (1991) compared the sedation produced by 5 and 10μg kg-1 IV with 1 mg kg-1 xylazine IV. At 10μg kg-1 sedation was similar to xylazine but produced more severe and prolonged ataxia with one animal falling over. At 5μg kg-1 less sedation was evident but a similar degree of ataxia to 1 mg kg-1 xylazine. Concentrated preparations are available for use with wildlife immobilisation; 40mg mL-1 (Kyron Laboratories SA) and 10mg mL-1 (Zalopine; Orion); 10, 20 and 40mg mL-1(Wildlife Pharmaceuticals Inc; wildpharm.com).

A continuous infusion protocol for prolonged sedation has been described in experimental ponies using a loading dose of 5µg kg-1 IV followed by an infusion of 3.5µg kg-1 hour-1 with effective reversal after 2 hours using 60µg kg-1 atipamezole IV. A high incidence of conduction block arrhythmias and some ataxia was reported (Bettschart-Wolfensburger et al 1999).

Dexmedetomidine is currently unlicenced for use in horses. At 3.5µg kg-1 IV produces sedation equivalent to 7µg kg-1 medetomidine and 1mg kg-1 xylazine in horses (Bettschart-Wolfensberger et al 2005).

Chloral hydrate

For horses which cannot be approached and for which no remote injection technique is available, this may be a useful drug as it can be administered in the drinking water. Accurate doses are difficult to find but Wright (1958) states that 20-70g dissolved in drinking water will be consumed by 75% of horses provided that other sources of water have been withheld for 24-36hrs previously, or it may be mixed with feed to improve voluntary intake. Unfortunately he does not state what size of animal he is referring to or what effect this is intended to achieve. He does however go on to state that oral administration results in highly unpredictable response due to variable absorption and first pass metabolism. To illustrate this he states that a dose of 100-120mg kg-1 administered IV as a 20% solution will produce smooth excitement free induction of general anaesthesia, lasting a few minutes, whilst double this dose may be necessary to achieve sufficient sedation to make handling safe and effective following oral administration. It may however allow the animal to be approached closely enough to permit additional sedative drugs to be given. It should be pointed out that chloral hydrate is extremely irritant if perivascular injection occurs and is not licenced.

Opioids

These are more usefully employed to provide an analgesic component if pain is a consideration and are discussed more fully in the analgesia section below. The sedative effect of opioids is not equivalent to that seen with small animals, however they may potentiate the sedative effects of other agents (acepromazine and alpha 2 agonists particularly). Butorphanol and buprenorphine are licenced specifically for this indication.

Butorphanol is supplied in the standard equine licenced form as 10mg mL-1 solution for injection and licenced for potentiation of sedation at 20µ kg-1 IV. It is also available as 30 and  50mg mL-1 solutions (Wildlife Pharmaceuticals Inc; wildpharm.com).

Buprenorphine (Vetergesic; Alstoe) is licenced for the potentiation of sedation at a dose of 5µg kg-1 IV. There is also evidence of sedation being achieved by 6µg kg-1 buprenorphine administered by the oral transmucosal (OTM) route (Walker 2007).

The very potent opioids carfentanil and etorphine are utilised in wildlife immobilisation usually in combination with various other agents. Handling these drugs has serious safety implications as they are rapidly absorbed across human skin and mucous membranes with potentially fatal results.

Etorphine used alone at doses of up to 4.6μg kg-1 IM was ineffective in Welsh ponies, but when combined with acepromazine and hyoscine (5.4-6.0μ kg-1/140μg kg-1/110μg kg-1) was effective at immobilising wild zebra (King and Klingel 1965). Provided commercially in combination with acepromazine as Immobilon (Novartis) (2.25/10mg mL-1) with diprenorphine 3.0mg mL-1solution antagonist. Shown to be an effective immobilising agent in horses at doses of 22.5μg kg-1 and 100μg kg-1 IM (0.5mL per 50kg bodyweight (Jenkins et al 1972)). Excitement prior to recumbency, muscle tremor, spasm and tachycardia are reported. Intravenous administration at the same dose results in more rapid, excitement free immobilisation (Hillidge and Lees 1971). Adverse effects including muscle spasm, tremors, severe arterial hypoxaemia (Hillidge and Lees 1975), excitement reactions (Rafferty 1972, Hillidge and Lees 1974))and fatality (Lane 1974)have been reported in horses following IV administration of the diprenorphine antagonist.

Also available as a single agent (M99; Novartis) containing etorphine 9.8mg mL-1 (the only form currently available in UK) supplied with reversal agent diprenorphine 12mg mL-1 (M5050; Novartis). Other concentrations are available from specialist suppliers;  etorphine 1 and  10mg mL-1 (Wildlife Pharmaceuticals Inc; wildpharm.com).

Carfentanil is currently not available or licensed in UK but may be available elsewhere as a 3mg mL-1 solution for injection (Wildlife Pharmaceuticals Inc; wildpharm.com).

Rauwolfia Alkaloids

Reserpine – a potent alkaloid which exerts its effects by blocking neuronal storage of norepinephrine, dopamine and serotonin. Reported doses are 0.005 – 0.02mg kg-1 IV or IM (McCann et al 1988). Not licenced.

A reduction in spontaneous learned behaviour patterns were demonstrated after 0.01mg kg-1 IV. Maximal response was reached at 3-5 days with effect lasting for 6-10 days (Shults et al 1982). Side effect observed were sweating, depression, ptosis of the upper eyelid and diarrhoea, all of which resolved within 3 days. McCann et al (1988) found 0.005mg kg-1 IM resulted in a lower heart rate and ‘emotionality’ in unhandled yearlings during periods of handling.

Drug combinations

Combining drugs to utilise the synergistic or additive effects that may occur also potentially allows the dose of each component to be reduced, limiting the risk of adverse events and counteracting some of the less desirable effects produced by one or more of the constituents.

The more common combinations are acepromazine with an opioid and alpha 2 agonists with an opioid. Depending on the circumstances other combinations may be necessary or more useful.

For profound sedation in difficult horses the combination of acepromazine (30µg kg-1), detomidine (20µg kg-1) and butorphanol  (50µg kg-1)IM has been used with some success at the author’s institution. These drugs are mixed together in the same syringe prior to injection, with administered volume equating to approximately 1mL per 100kg bodyweight.

Zoletil 100(Virbac) is a commercially available preparation containing a combination of tiletamine (250mg) and zolazepam (250mg) as a dry powder with 5mL water for reconstitution. This has proven to be very safe in primates, carnivores and ursids for immobilisation but is not recommended in equidae due to its long effect and poor recoveries (personal communication). It is not licensed in UK.

The combination of butorphanol (30μg kg-1), detomidine (30μg kg-1) and etorphine (7μg kg-1) in equidae (zebra) gives a quick and satisfactory immobilisation with quick and steady recoveries. The effects can also be antagonised using atipamezole (0.15mg kg-1 split IM/IV) and naltrexone 0.167 mg kg-1 IV (personal communication).

BAM is a commercially available combination of 27.3mg mL-1 butorphanol, 9.1mg mL-1 azaperone and 10.9mg mL-1 medetomidine (Wildlife Pharmaceuticals Inc; wildpharm.com) which has been used in cervidae and zebra. In antelope and deer success is reported at a dose of 1mL per 30-47kg.

  1. provision of analgesia

For the maximum benefit to be obtained from an analgesic protocol two concepts need to be considered.

Pre-emptive analgesia – in theory this limits the degree to which peripheral and central sensitisation will be induced. This principle is hard to substantiate in practice. In the field of human pain relief the evidence is poor and even weaker in the veterinary field.

Multimodal analgesia – utilising analgesic drugs which act in a synergistic or additive fashion and incorporating those that act at as many of the stages in the nociceptive pathway as possible will allow doses of each individual drug to be reduced, minimising the risk of undesirable side effects whilst achieve a profound level of overall analgesia.

Relies on two factors:

  • Identifying the four stages in the nociceptive pathway
  • Transduction – conversion of a noxious stimulus into an electrical signal
  • Transmission – conduction of that signal to the central nervous system
  • Modulation – how the incoming signal is processed and ‘dealt with’
  • Perception – involvement of higher centres and consciousness
  • Knowledge of mode of action of analgesic drugs available, both site of action and receptor types involved
  • Synergism between drug classes due to similar effector pathways and/or location of receptors
  • Different drugs within the same class may have synergistic, additive or antagonistic actions due to differing receptor activity

 

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Conventional Analgesic Drugs

Non Steroidal Anti-inflammatory Drugs

Those currently available in the UK for use in horses are:

  • Phenylbutazone
  • Flunixin meglumine
  • Ketoprofen
  • Carprofen
  • Meloxicam
  • Vedaprofen
  • Suxibuzone
  • Metamizole
  • Firocoxib

There are several others. Many are available for administration by injection (IV) and per os as powders and/or pastes. Action is by inhibition of cyclo-oxygenase enzymes and thereby interruption of the arachidonic acid cascade that results in production of prostaglandins and thromboxanes. These substances are potent inflammatory mediators, which result in sensitisation and recruitment of peripheral nociceptors. Action is largely peripheral involving the transduction phase although a central action has also been proposed. Choice largely comes down to familiarity, availability and cost as these are often used for chronic as well as acute pain management. Anecdotally, some horses will respond better to one than another so it may be worth trying an alternative if response is unsatisfactory. Data sheets tend to advise leaving 24 hours between dosing if changing to an alternative.

Opioids

 Versatile drugs as can be administered by the IV, IM, OTM, transdermal, epidural and intra synovial routes. Action is primarily central at the modulation stage and mediated by kappa and mu receptor subtypes spinally and supraspinally (Hellyer et al 2003). Currently only butorphanol, pethidine and buprenorphine are licensed for use in horses in the UK. Morphine, methadone and pethidine are mu receptor agonists, buprenorphine is a partial mu agonist, whilst butorphanol is a mu antagonist and kappa agonist. Spinally mediated analgesia is by inhibition of Substance P release from the terminals of primary afferent C fibres in the dorsal horn (Bertone and Horspool). This reduces signal transmission to higher centers via the spinothalamic tract. Opioid receptors are also present outside the CNS in tissues such as the myenteric plexus and synovial membranes, and expression is upregulated in inflammatory states.

 Butorphanol – 0.025-0.1mg kg-1 IV.  Moderate analgesic, better for visceral than somatic pain. Analgesia reported as excellent or good in clinical colic cases using 0.1mg kg-1 IV (Stout and Priest 1986). Duration of effect generally short, only 15-30 minutes for somatic pain (Kalpravidh et al 1984), whilst Muir and Robertson (1985) demonstrated visceral analgesia for 45 minutes using a caecal distension model. However longer durations have been reported with Kalpravidh et al (1984) claiming 120 minutes and even up to 240 minutes (Kalpravidh et al 1984). Increase heart rate and locomotor activity may be seen.

Butorphanol administration has also been described as a constant rate infusion for post-operative analgesia following colic surgery at 13-23μg kg-1 hr-1 with reduced locomotor signs evident compared with single bolus administration (Sellon et al 2001; 2004). Used as a constant rate infusion of 13μg kg-1 hr-1 for 24hrs post coeliotomy, horses showed reduced weight loss, more ‘normal’ behaviour patterns, longer time to first defaecation, shorter period of hospitalisation and lower client bills (Sellon et al 2004).

Pethidine (meperidine): 2mg kg-1 IM.  Used at 1mg kg-1 IM shown to improve lameness scores in experimentally induced lameness but only at 2-3hrs post administration (Foreman and Ruemmler 2013). Short duration analgesia (<30 minutes) reported in caecal balloon model (Muir and Robertson 1985). Large volume needed to be injected due to low potency and can cause pain on injection. Pethidine should only be given by the IM route due to potential for histamine release.

Buprenorphine: 5-10µg kg-1 IV.  Analgesic dose stated as 10μg kg -1 IV. The data sheet recommendation for buprenorphine also states that it should only be administered after an intravenous sedative agent.  Somatic analgesia of 6hrs duration documented following 10μg kg-1 IV (Carregaro et al 2007). Good OTM absorption and sublingual dose of 6μg kg-1 produced noticeable sedation and analgesia lasting up to 12hrs in a case of musculoskeletal pain (Walker 2007). Locomotor excitement and cardiovascular stimulation have been reported (Carregaro et al 2006, 2007, Messenger et al 2011).

Fentanyl and methadone have recently been licensed in the UK for use in small animals and Lmethadone (L-Polamivet) is licensed for use in horses in some countries.

Experimentally fentanyl administered by intravenous infusion has little evidence of antinociceptive effect as assessed by thermal threshold testing or colorectal and duodenal distension. Mild transient excitement was reported at the highest fentanyl infusion rate (Sanchez et al 2007). Comparative pharmacokinetics of intravenously and transdermally administered fentanyl were described by Maxwell et al (2003) who showed a rapid uptake by the transdermal route with all horses exceeding the 1ng mL-1 plasma level (maintained for 32 hours). This plasma level is consistent with that reported to provide analgesia in other species. Orsini et al (2006) examined the pharmacokinetics of transdermal fentanyl using commercially available patches targeted to deliver 60μg kg-1 and found a large variation in onset of absorption (0 to 5 hours), time to peak concentration (8.5-14.5 hours) and maximum plasma concentration achieved (0.67-5.12ng mL-1). One third of the horses failed to achieve the 1ng mL-1 plasma concentration considered to be analgesic. A large variation in onset, maximum concentration (0.1-28.7ng mL-1) and time to maximum concentration (8-24 hours) has also been demonstrated in neonatal foals treated with fentanyl patches designed to deliver 100μg hr-1 (Eberspacher et al 2008).  The site of patch application has been shown to affect rate and uptake of transdermally delivered fentanyl (Mills and Cross 2007). Combination therapy with NSAIDs has been reported in clinical cases refractory to NSAID treatment alone (Thomasy et al 2004). Again, a large variation in maximum concentration and time to achieve this were reported but some, although weak, evidence of analgesic effect was claimed. A solution of fentanyl (50mg mL-1) has recently been licenced for transdermal use in dogs where it is claimed to provide analgesia for a minimum of 4 days post-application (Recuvyra; Elanco) but this has not been evaluated in horses at the time of writing.

In our hospital, methadone and morphine (0.1-0.2mg kg-1) are also frequently used, both systemically (IM and IV) and epidurally. Epidurally, morphine (0.1–0.2 mg kg-1 (Sysel et al 1996, Goodrich et al 2002) has a slow onset (up to 6 hours), and a duration of around 5 hours (Natallini and Robinson 2000), but can possibly last up to 12 – 18 hours. Pethidine (0.8mg kg-1) has faster onset (12 minutes) and duration up to 4 to 5 hours (Skarda and Muir 2001). Methadone (0.1mg kg-1) has an onset of around 15 minutes and lasts about 5 hours (Olbrich and Mosing 2003). It has been shown that epidurally administered butorphanol does not result in detectable analgesia (Natalini and Robinson 2000) suggesting that the horse does not possess kappa receptors in the spinal cord. It is then logical to assume that kappa agonists will only have a supraspinal effect.  It is important to ensure that preservative free solutions are used where possible.

Morphine has also been demonstrated to provide analgesia following experimentally induced synovitis at a dose of 0.05mg kg-1 administered intra-articularly (Lindegaard et al 2010).

Alpha 2 adrenergic agonists

Traditionally used as sedative and premedication agents, these compounds can also provide a useful contribution to analgesia. Duration and quality of analgesia is controversial (England and Clarke 1996) depending on the experimental methods employed or the clinical situation being evaluated. Analgesic effects peak later than sedative effects and may be equivalent, shorter or longer in duration (Rohrbach et al 2009, Dirikolu et al 2006, Elfenbein 2009). One recent study aiming to compare the analgesic effects of the above three agents at doses causing equivalent levels of sedation used a combination of electrical stimulation and mechanical pressure (Moens et al 2003). This study demonstrated an antinociceptive effect of all three agents which differed in quality and duration not only between the different agents but also with the type of stimulus. All agents produced maximum analgesic effect at 15 minutes post injection with effect gone at 60 minutes. Analgesic effects are generally thought to last one third to a half of the duration of the sedative effects. Mechanism of analgesia is similar to and synergistic with that of the opioids. Both classes of drug act via G-protein coupled receptors to alter adenylate cyclase activity and are found in similar locations in the central nervous system (Hellyer et al 2003).

 Xylazine has proven to be an excellent short acting analgesic in equine colic (England and Clarke 1996). Caecal distension model demonstrated visceral analgesia superior to that provided by morphine, butorphanol or flunixin (Kalpravidh et al 1984) and pethidine and butorphanol (Muir and Robertson 1985). Sedative and analgesic effects reported to last up to 105 and 240 minutes (Kalpravidh et al 1984).

Detomidine claimed to provide better analgesia than xylazine, butorphanol or flunixin when behavioural and physiological  parameters (heart and respiratory rates) assessed in clinical colic cases (Jochle et al 1989) but very high doses used (up to 40μg kg-1) so response may have been obtunded by sedation. Colorectal distension demonstrated visceral analgesia for 15 and 165 minutes at 10 and 20μg kg-1, but only for 15 minutes at 20μg kg-1 with duodenal distension. No change in somatic threshold was observed at either dose (Elfenbein et al 2009).

Due to the uncertainty of duration of analgesic effect, preoperative administration of these agents may result in them contributing little (detomidine, romifidine) or nothing (xylazine) to intraoperative analgesia. Consideration can be given to repeated administration during surgery. These drugs however all have profound effects on the cardiovascular system which should also be taken into account.

Epidurally, xylazine (0.17mg kg-1) diluted to a final volume of 10 mL with 0.9% NaCl is safe and effective (LeBlanc et al 1998). Higher doses (0.22 and 0.25mg kg-1) have also been reported with no adverse effects (Skarda and Muir 1996, LeBlanc and Carron 1990). Detomidine (30µg kg-1) in combination with 0.2mg kg-1 morphine produces analgesia (Skarda and Muir 1996, Sysel et al 1996, Goodrich et al 2002) and reduces post-operative lameness after hindlimb surgery (Sysel et al 1996, Goodrich et al 2002). High lipid solubility facilitates systemic absorption from the extradural space, especially of detomidine (Skarda and Muir 1996), causing sedation. Loss of tail and perineal muscle tone may become evident due to local anaesthetic-like properties (particularly with xylazine). The onset is characteristically rapid (approx 12 minutes), and duration of effect is 2.5-3.5 hours (LeBlanc et al 1998, Skarda and Muir 1996).

Local Anaesthetic Agents

 Local anaesthetics are a very versatile group of drugs and have the potential to completely abolish pain rather than just obtund it. They are however not specific for sensory neurons so care must be taken as undesirable motor nerve blockade can occur if incorrectly used. They can be administered perineurally, directly infiltrated into tissues, topically (especially useful for ophthalmic conditions), epidurally, intra-articularly and systemically. Mepivacaine, lidocaine and procaine are all licenced for use in the horse in the UK. Of these, all are supplied in combination with adrenaline except for mepivacaine. Lidocaine without adrenaline is also available from pharmaceutical suppliers as a 2% solution for injection and as a 0.2% solution in 5% glucose for IV infusion (Fresenius Kabi Ltd), but not licenced for use in horses. Other compounds commonly used but not licensed are

  • Bupivacaine
  • Proxymetacaine
  • Prilocaine

Incorporation of local and regional anaesthesia pre-, intra- or post-operatively will, if successful, interrupt the transmission stage of nociceptive input and provide complete anaesthesia of the surgical field. Obviously not all sites of pain or surgery will be amenable to this technique, but where applicable it will be of considerable benefit. Lidocaine can also be administered by continuous IV infusion (loading dose of up to 2mg kg-1 followed by 50µg kg-1 min-1 CRI) and has been shown to have MAC sparing effects during general anaesthesia (Doherty and Frazier 1998, Dzikiti et al 2003). Some analgesic effect has also been demonstrated using this dosing regimen in conscious horses following IV infusion (Robertson et al 2005) principally related to thermal threshold testing (somatic pain) but a mild response was recorded to visceral pain induced by distension of duodenal and rectal balloons. In our hospital lidocaine CRI is frequently used intraoperatively and occasionally post operatively following laparotomy if more conventional analgesic medication is inadequate.

Although there is no evidence  of direct pro-kinetic effect (Brianceau et al 2002, Milligan et al 2007, Rusiecki et al 2008) a reduction in post-op ileus and reflux volume has been shown in lidocaine treated horses (Cohen et al 2004; Malone et al 2006, Torfs 2009). This is possibly due to the drug’s anti-inflammatory properties. It may also limit ischaemia-reperfusion injury of jejunum (Cook et al 2008, Guschlbauer et al 2010).

Epidurally, local anaesthetics can produce anaesthesia for perineal surgery where complete sensory block is required but motor block will not cause problems. Care needs to be taken with the total volume injected to avoid craniad spread which may impair motor function to the hindlimbs (Goodrich et al 2002, Olbrich and Mosing 2003). Preservative free preparations of bupivacaine 0.5%, lidocaine 2% and mepivacaine 2% solutions (5-10mL) have been used by the author. Mepivacaine (Intra-Epicaine; Dechra) is licenced for use in horses by this route.

Transdermally: patches containing 5% lidocaine in a gel base are used to treat a range of chronic neuropathic and musculoskeletal pain in humans, with systemic uptake having been proven. Application of two 700mg patches to the limbs of horses for 12 hours failed to demonstrate any systemic uptake in a study by Bidwell et al (2007). Interestingly injecting 20mg lidocaine subcutaneously to facilitate jugular cannula placement did result in detectable levels of lidocaine in the blood. Any effect from the patches would be local rather than systemic. Variable systemic uptake was shown by Andreoni and Giorgi (2009) using twice the number of patches per horse applied for 24 hours. If the skin was subjected to an alcohol scrub prior to patch placement there was a tendency for a more rapid and pronounced but less sustained uptake, whilst the application of lidocaine cream showed a much greater and less variable uptake. Antinociceptive effects were assessed by pricking the area under the patch at removal. No difference in skin sensation was demonstrated between horses which had had a patch applied and control animals, but was significantly reduced after cream application.

Intra-articular anaesthesia: mepivacaine (Intra-Epicaine; Dechra) is licenced for use in horses by this route and is used fairly regularly at the author’s hospital following arthroscopic surgery. Preservative free preparations should be used.

The administration of lidocaine, mepivacaine and bupivacaine has also been reported by continuous perineural infusion at 3-10mL hr-1 (Driessen et al 2008). Some beneficial effect was shown in these experimental horses, although diffuse oedema developed in some limbs which necessitated discontinuation of the infusions.

Other Analgesic Agents

 Anticholinergic drugs

Not generally perceived to have analgesic properties in their own right but acepromazine and hyoscine butylbromide (butylscopolamine) have been shown to increase pain threshold for ~2 hours in colorectal (but not duodenal) distension model of visceral pain (Sanchez et al 2008). Although colorectal distension may be more related to urge to defaecate rather than pain, visceral pain can produce reflex spasm so there is some rationale for the use of antispasmodic drugs (pethidine also has antispasmodic properties).

Ketamine

This dissociative anaesthetic agent has potent analgesic effects at subanaesthetic doses. NMDA receptor activity may counteract central sensitization so making it potentially of particular use in the management of chronic as well as acute pain. Infusions of 0.4 and 0.8mg kg-1 hr-1 have been shown to be tolerated well in conscious horses, with excitement seen at 1.6mg kg-1 hr-1, although no somatic analgesia was demonstrated by Fielding et al (2006).  Peterbauer et al (2008) did demonstrate analgesic properties in conscious horses after 0.6mg kg-1 IV bolus followed by 20µg kg-1 min-1CRI. Analgesic properties as inferred from MAC sparing capability in anaesthetised horses was shown by Muir and Sams (1992). Analgesia is mainly somatic rather than visceral and is mediated by a number of mechanisms including its action as an NMDA receptor antagonist in the spinal cord. The short duration of the action of ketamine as a bolus limits its use as a preoperative analgesic but makes intra- and post- operative administration a possibility. Be aware that in the horse ketamine has an active metabolite (norketamine) which can result in accumulation.

Epidurally: Doses of 0.5, 1.0 and 2.0mg kg-1 have been shown to provide analgesia lasting 30 to 75 minutes (De Segura et al 1998).

Tramadol

Not licenced in the horse but the pharmacokinetics and pharmacodynamics of intravenously, intramuscularly and orally administered tramadol in horses have been investigated (Shilo et al 2007, Cox et al 2010, Dhanjal et al 2009, Knych et al 2012a 2012b, Giorgi et al 2007, Stewart et al 2011). Tramadol is a synthetic analogue of codeine which has been used in the management of acute and chronic moderate to severe pain in humans. It is a centrally acting analgesic that has agonist activity at mu-opioid receptors and also inhibits the reuptake of norepinephrine and serotonin. Minimum plasma tramadol levels which provide analgesia in people vary greatly between 100 and 600ng mL-1, with much of the analgesic effect of tramadol being attributed to the M1 metabolite (O-desmethyltramadol) which has 200 times the affinity for the mu opioid receptor than the parent drug. In people there is genetically predetermined variation in the ability to produce this metabolite, making some individuals poorly responsive to the drug. It is unknown whether this is also true in horses, although a large individual variation in plasma concentrations of MI (and several other metabolites) has been demonstrated (De Leo et al 2009, Knych et al 2012, Giorgi et al 2007). Oral bioavailability following a 5mg kg-1 dose has been reported as approximately 65% in fasted horses, increasing to approximately 85% in fed horses (Giorgi et al 2007), whilst Shilo et al (2007) reported only 3% following 2mg kg-1 administered to fasted horses. Knych et al (2012) used doses of 3, 6 and 9mg kg-1 PO which showed a very wide variation in plasma levels, with only the 9mg kg-1 dose consistently achieving plasma concentrations within the human analgesic range. No adverse events were reported apart from 1 horse at the higher dose which showed mild signs of colic and increased pacing behavior. Intramuscular administration of 2mg kg-1 resulted in rapid and complete absorption with attainment of useful plasma concentrations and no adverse effects (Shilo et al 2007). Cox et al (2010) and Shilo et al (2007) reported side effects including ataxia, muscle twitching and sweating for 15 minutes after 2mg kg-1 IV and Giorgi (2007) reported confusion, agitation, tremor and tachycardia after 5mg kg-1 IV but not PO. Dhanjal et al (2009) reported side effects following 2mg kg-1 IV and were unable to demonstrate an antinociceptive effect using a noxious thermal stimulus. Guedes et al (2012) administered 5mg kg-1 PO q 12hrs to horses with chronic laminitic pain and showed only weak evidence of analgesia, whilst ketamine showed a much greater effect. Its use has been described by epidural administration where 1mg kg-1 produced analgesia after 30 minutes with effects lasting for 4 hours (Natallini and Robinson 2000).

Gabapentin

 Originally used as an adjuvant anticonvulsant, it was subsequently shown to be effective in treating a range of chronic pain syndromes in people. It is a structural analogue of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) but has no affinity for GABAA or GABAB receptors, nor is it metabolized to GABA or a GABA agonist. Multiple mechanisms of action have been proposed including AMPA receptor antagonism, activating ATP sensitive potassium channels and hyperpolarization activated cation current (Ih) channels and binding to the α2δ subunit of voltage dependent calcium channels thereby reducing neurotransmitter release (Kong and Irwin 2007). Of these proposed mechanisms the latter currently is thought to be the major mode of action. Pharmacokinetics of a single dose of 5mg kg-1 PO (Dirikolu et al 2008) and 20mg kg-1 PO and IV (Terry et al 2010) have been evaluated in horses. No adverse events were noted after either dose or route of administration although sedation was evident for 1 hour after the IV dose. Rapid but poor absorption (compared with humans, rats, dogs and monkeys) followed PO administration with a bioavailability of only 16% following the higher dose. Not licensed for veterinary species but there is a case report of its use in a heavily pregnant mare with suspected neuropathic pain (Davis et al 2007) at 2.5mg kg-1 PO q 8hrs with increasing dosing interval over 6 days with apparent beneficial effect and no detriment to the fetus.

Paracetamol (acetaminophen)

Not a typical NSAID, the exact mechanism of action is undetermined but thought to act centrally on serotonergic, opioid, nitric oxide and cannabinoid pathways as well as effects on prostaglandin production (Sharma and Mehta 2013). Used as a marker of gastric emptying in horses (Doherty et al 1998) at dose of 20mg kg-1 body weight delivered via nasogastric tube. Use as an adjunctive analgesic medication at 20mg kg-1 PO q 12hrs reported in a laminitic pony showing pain refractory to NSAIDs, lidocaine and morphine analgesia (West et al 2011). Veterinary licensed oral preparations available for dogs (in combination with codeine) and pigs in the UK (not horses). Injectable formulations available.

Bisphosphonates

Bisphosphonates have been shown to reduce pain in human patients with osteoarthritis and cancer pain and improve joint mobility. These drugs inhibit osteoclast proton secretion, reducing the acidity of the microenvironment associated with bone resorption, so reducing activation of acid sensitive ion channels in sensory neurons. Osteoblast secretion of vascular endothelial growth factor is also inhibited as a result of tiludronate’s direct anti-inflammatory effect, inhibiting cytokine release from activated macrophages (Silvina and Barbara 2014). Tiludronic acid (Equidronate; Ceva) is licenced for treatment of inflammatory and degenerative joint disease in horses at a dose of 1mg kg-1 by intravenous infusion over 30 minutes. Improvement in lameness of horses suffering from bone spavin (Gough et al 2010) and navicular disease (Denoix et al 2003) has been demonstrated in tiludronate treated horses.

Availability

Lack of availability of drugs or equipment may require some imaginative thinking. This may necessitate using conventional sedative or analgesic medications in unfamiliar or novel ways and using unfamiliar and unconventional medications in difficult circumstances. Often there is no easy answer; some horses cannot be brought to a state of adequate sedation to successfully perform a required procedure which may necessitate having to resort to general anaesthesia for the safety of all concerned. If the situation is non-urgent there is no shame in postponing and trying again another day when all parties have had a chance to calm down, and a different approach can be applied.

Achieving satisfactory analgesia can be extremely difficult in chronic pain states as the nervous system undergoes maladaptive changes. The key is in understanding the types of pain that may be present and the mode of action of the drugs that are available for treatment. In this way therapeutic plans can be formulated which incorporate the most appropriate drugs and target as many aspects of the pain pathway as possible. The number of drugs available for use in horses is limited, however new attributes are being realized for drugs that have been commonly used for other indications, although the evidence of safety and efficacy of applying these in the horse is often lacking. One example of this is the use of tricyclic antidepressants for chronic pain management in people. It is also important to remember that adjunctive therapies may provide additional relief. These may range from simple bandaging, hot and cold compresses or using ice, to massaging, physiotherapy or acupuncture.

The World Health Organisation ‘pain ladder’ provides a useful framework to follow for pain management (www.who.int/cancer/palliative/painladder/en/). Originally this was designed to provide a guideline for the management of cancer pain in people but is now much more widely applied. It suggests a graded approach to administration of analgesic agents combined with adjuvant therapies. It is also important to keep an open mind.

 

References

  • Andreoni VA and Giorgi M. Evaluation of plasma detectable concentrations of two lidocaine transdermal formulations and their analgesic effect in the horse. J Equine Vet Sci (2009) 29; 681-686.
  • Bertone JJ and Horspool LJI (Eds) Equine Clinical Pharmacology. (2004) Saunders.
  • Bettschart-Wolfensberger R, Clarke KW, Vainio O, Shojaee Aliabadi F and Demuth D. Pharmacokinetics of medetomidine in ponies and elaboration of a medetomidine infusion regime which provides a constant level of sedation. Res Vet Sci (1999) 67; 41-46.
  • Bettschart-Wolfensberger R, Freeman SL, Bowen IM, Aliabadi FS, Weller R, Huhtinen M, and Clarke KW. Cardiopulmonary effects and pharmacokinetics of IV dexmedetomidine in ponies. Equine Vet. J. (2005) 37 (1) 60-64.
  • Bidwell LA, Wilson DV and Caron JP. Lack of systemic absorption of lidocaine from 5% patches placed on horses. Vet Anaesth and Analg (2007) 34; 443-446.
  • Brewer B, Hines MT, Stewart JT and Langlois JF. Fluphenazine induced Parkinson-like syndrome in a horse. Equine Vet J (1990) 22(2); 136-137.
  • Brianceau P, Chevalier H, Karas A, Court MH, Bassage L, Kirker-Head C, Provost P and Paradis MR. Intravenous lidocaine and small intestinal size, abdominal fluid and outcome after colic surgery in horses. J Vet Int Med (2002) 16 (6); 736-741.
  • Bryant CE, England GC and Clarke KW. Comparison of the sedative effects of medetomidine and xylazine in horses. Veterinary Record (1991) 129; 421-423.
  • Carregaro AB, Teixeira Neto FJ, Beier SL and Luna SP. Cardiopulmonary effects of buprenorphine in horses. Am J Vet Res (2006) 67 (10); 1675-1680.
  • Carregaro AB, Luna SPL, Mataqueiro MI and Queiroz-Neto A. Effects of buprenorphine on nociception and spontaneous locomotor activity in horses. Am J Vet Res (2007) 68 (3); 246-250.
  • Clarke KW and Hall LW. Xylazine-a new sedative for horses and cattle. (1969) Vet Rec 85(19); 512-517.
  • Clutton RE. Remote intramuscular injection in unmanageable horses. In Practice (1997) 19; 316-321.
  • Cohen ND, Lester GD, Sanchez LC, Merritt AM and Roussel AJ. Evaluation of risk factors associated with development of post-operative ileus in horses. J Am Vet Med Assoc (2004) 225 (7); 1070-1078.
  • Cook VL, Jones Shults J, McDowell M, Campbell NB, Davis JL and Blikslager AT. Attenuation of ischaemic injury in the equine jejunum by administration of systemic lidocaine. Equine Vet J (2008) 40 (4); 353-357.
  • Cox S, Villarino N and Doherty T. Determination of oral tramadol pharmacokinetics in horses. Res Vet Sci (2010) 89; 236-241.
  • Davis JL, Posner LP and Elce Y. Gabapentin for the treatment of neuropathic pain in a pregnant horse. Journal of the American Veterinary Medical Association (2007) 231 (5); 755-758.
  • De Leo M, Giorgi M, Saccomanni G, Manera C and Braca A. Evaluation of tramadol and its main metabolites in horse plasma by high performance liquid chromatography/fluorescence and liquid chromatography/electrospray ionization tandem mass spectrometry techniques. Rapid Commun Mass Spectrom (2009) 23; 228-236.
  • Dhanjal JK, Wilson DV, Robinson E, Tobin TT and Dirokulu L. Intravenous tramadol: effects, nociceptive properties and pharmacokinetics in horses. Vet Anaesth and Analg (2009) 36; 581-590.
  • Denoix J-M, Thibaud D and Riccio B. Tiludronate as a new therapeutic agent in the treatment of navicular disease: a double blind placebo controlled clinical trial. Equine Vet J (2003) 35 (4); 407-413.
  • Dirikolu L, McFadden ET, Ely KJ, ElkHoly H, Lehner AF and Thompson K. Clonidine in horses: identification, detection and clinical pharmacology. Vet. Therap (2006) 7 (2); 141-155.
  • Dirikolu L, Dafalla A, Ely KJ, Connerly AL, Jones CN, ElkHoly H, Lehner AF, Thompson K and Tobin T. Pharmacokinetics of gabapentin in horses. J Vet Pharmacol and Therap. (2008) 3(2); 175-177.
  • Dodman NH and Waterman AE. Paradoxical excitement following the intravenous administration of azaperone in the horse. Equine Vet J (1979) 11(1); 33-35.
  • Dodman NH, Shuster L, Patronek GJ and Kinney L. Pharmacologic treatment of equine self mutilation syndrome. Intern J Appl Res Vet Med (2004) 2(2); 90-98.
  • Doherty TJ and Frazier DL. Effect of intravenous lidocaine on halothane minimum alveolar concentration in ponies. Equine Veterinary Journal (1998)30 (4); 300-303.
  • Doherty TJ, Andrews FM, Provenza MK and Frazier DL. Acetaminophen as a marker of gastric emptying in ponies. Equine Vet J (1998) 30(4); 349-351.
  • Driessen B, Scandella M and Zarucco L. Development of a technique for continuous perineural blockade of the palmar nerves in the distal equine thoracic limb. Vet Anaesth and Analg (2008) 35; 432-448.
  • Dzikiti TB, Hellebrekers LJ and van Dijk P. Effects of intravenous lidocaine on isoflurane concentration, physiological parameters, metabolic parameters and stress related hormones in horses undergoing surgery. Journal of Vet Med A Physiol Pathol Clin MED. (2003) 50 (4); 190-195.
  • Eberspacher E, Stanley SD, Rezende M and Steffey EP. Pharmacokinetics and tolerance of transdermal fentanyl administration in foals. Vet Anaesth and Analg (2008) 35; 249-255.
  • Elfenbein JR, Sanchez LC, Robertson S, Cole CA and Sams R. Effect of detomidine on visceral and somatic nociception and duodenal motility in conscious adult horses. Vet Anaesth and Analg (2009) 36 (2); 162-172.
  • England GCW and Clarke KW. Alpha 2 adrenoceptor agonists in the horse – a review. British Veterinary Journal (1996) 152; 641-657.
  • Fielding CL, Brumbaugh GW, Matthews NS, Peck KE and Roussel AJ. Pharmacokinetics and clinical effects of a subanaesthetic continuous rate infusion of ketamine in awake horses. Am J Vet Res (2006) 67 (9); 1484-1490.
  • Foreman JH and Ruemmler R. Efficacy of intramuscular meperidine hydrochloride versus placebo in experimental foot lameness in horses. Equine Vet J (2013) 45 (S45); 48-53.
  • Giorgi M, Soldani G, Manera C, Ferrarini P, Sgorbini M and Saccomanni G. Pharmacokinetics of tramadol and its metabolites M1, M2 and M5 in horses following intravenous, immediate release (fasted/fed) and sustained release single dose administration. J Eq Vet Sci (2007) 27 (11); 481-487.
  • Gomez de Segura et al. Epidural injection of ketamine for perineal analgesia in the horse. Vet Surg (1998) 27; 384-391.
  • Goodrich LR et al. epidural morphine and detomidine decreases post-operative hindlimb lameness in horses after bilateral stifle arthroscopy. Vet Surg (2002) 31; 232-239.
  • Gough MR, Thibaud D and Smith RKW. Tiludronate infusion in the treatment of bone spavin: a double blind placebo controlled trial. Equine Vet J (2010) 42 (5); 381-387.
  • Guedes AGP, Matthews NS and Hood DM. Effect of ketamine hydrochloride on the analgesic effects of tramadol hydrochloride in horses with signs of chronic laminitis associated pain. Am J Vet Res (2012) 73; 610-619.
  • Guschlbauer M, Hoppe S, Geburek F, Feige K and Huber K. In vitro effects of lidocaine on the contractility of equine jejunal smooth muscle challenged by ischaemia-reperfusion injury. Equine Vet J (2010) 42 (1); 53-58.
  • Hellyer PW et al. Comparison of opioid and alpha 2 adrenergic receptor binding in horse and dog brain using radioligand autoradiography. Veterinary Anaesthesia and Analgesia (2003) 30 (3); 172-182.
  • Hillidge CJ and Lees P. Preliminary investigations of the actions of Immobilon in the horse. Vet Rec (1971) 89; 280-281.
  • Hillidge CJ and Lees P. Fatality after Revivon. Vet Rec May 18th 1974 p476.
  • Hillidge CJ and Lees P. Influence of the neuroleptic combination of etorphine and acepromazine on the horse: blood gases and acid-base balance. Eq Vet J (1975) 7(3); 148-154.
  • Jenkins JT, Crooks JL, Charlesworth C, Blaine GF and Ling CM. The use of etorphine-acepromazine (analgesic-tranquilliser) mixtures in horses. Vet Rec (1972) 90; 207-210.
  • Jochle W, Moore JN, Brown J, Baker GJ, Lowe JE, Fubini S, Reeves MJ, Watkins JP and White NA. Comparison of detomidine, butorphanol, flunixin meglumine and xylazine in clinical cases of equine colic. Equine Vet J (1989) 21 (S7); 111-116.
  • Jones RS. Methylamphetamine as an antagonist of some tranquilising drugs in the horse. Vet Rec (1963) 75(4) 1157-1159.
  • Kalpravidh M, Lumb WV, Wright M and Heath RB. Analgesic effects of butorphanol in horses: dose-response studies. Am J Vet Res (1984) 45 (2); 211-216.
  • Kalpravidh M, Lumb WV, Wright M and Heath RB. Effects of butorphanol, flunixin, levorphanol, morphine and xylazine in ponies. Am J Vet Res (1984) 45 (2); 217-223.
  • Kauffman VG, Soma L, Divers TJ and Perkons SZ. Extrapyramidal side effects caused by fluphenazine decanoate in a horse. J Am Vet Med Assoc (1989) 195(8); 1128-1130.
  • King JM and Klingel H. The use of the oripavine derivative M99 for the restraint of equine animals and its antagonism with the related compound M285. Res Vet Sci (1965) 6 (4); 447-455.
  • Knych HK, Corado CR, McKemie DS, Scholtz E and Sams R. Pharmacokinetics and pharmacodynamics of tramadol in horses following oral administration. J Vet Pharmacol Therap (2012) 36; 389-398.
  • Knych HK, Corado CR, McKemie DS and Steffey EP. Pharmacokinetics and selected pharmacodynamics effects of tramadol following intravenous administration to the horse. Equine Vet J (2013) 45; 490-496.
  • Kong VKF and Irwin MG. Gabapentin: a multimodal perioperative drug? British Journal of Anaesthesia (2007) 99(6); 775-786.
  • Lane JG. Fatality after Revivon. Vet Rec May 18th 1974 p476.
  • LeBlanc PH and Carron JP. Clinical use of epidural xylazine in the horse. Eq Vet J (1990) 22; 180-181.
  • LeBlanc PH et al. Epidural injection of xylazine for perineal analgesia in horses. J Am Vet Med Assoc (1998) 193; 1405-1408.
  • Lindegaard C, Thomsen MH, Larsen S and Andersen PH. Analgesic efficacy of intra-articular morphine in experimentally induced radiocarpal synovitis in horses. Vet Anaesth and Analg (2010) 37 (2); 171-185.
  • MacKenzie G and Snow DH. An evaluation of chemical restraining agents in the horse. Vet Rec (1977) 101; 30-33.
  • Malone E, Ensink J, Turner T, Wilson J, Andrews F, Keegan K and Lumsden J. Intravenous continuous infusion of lidocaine for treatment of equine ileus. Vet Surg (2006) 35 (1); 60-66.
  • Maxwell LK, Thomasy SM, Slovis N and Kollias-Baker C. Pharmacokinetics of fentanyl following intravenous and transdermal administration in horses. Equine Vet J (2003) 35; 484-490.
  • McCann JS, Heird JC, Bell RW and Lutherer LO. Normal and more highly reactive horses. II. The effect of handling and reserpine on the cardiac response to stimuli. App Animal Behaviour Science (1988) 19; 215-226.
  • Messenger KM, Davis JL, LaFevers DH, Barlow BM and Posner LP. Intravenous and sublingual buprenorphine in horses: pharmacokinetics and influence of sampling site. Vet Anaesth and Analg (2011) 38 (4); 374-384.
  • Milligan M, Beard W, Kukanich B, Sobering T and Waxman S. The effect of lidocaine on post-operative jejunal motility in normal horses. Vet Surg (2007) 36 (3); 214-220.
  • Mills PC and Cross SE. Regional differences in transdermal penetration of fentanyl through equine skin. Res Vet Sci (2007) 82; 252-256.
  • Moens Y et al. A comparison of the antinociceptive effects of xylazine, detomidine and romifidine on experimental pain in horses. Veterinary Anaesthesia and Analgesia (2003) 30; 183-190.
  • Muir WW and Robertson JT. Visceral analgesia: effects of xylazine, butorphanol, meperidine and pentazocine in horses. Am J Vet Res (1985) 46 (10); 2081-2084.
  • Muir WW and Sams R. Effects of ketamine infusion on halothane minimal alveolar concentration in horses. American Journal of Veterinary Research (1992) 53 (10); 1802-1806.
  • Natalini CC and Robinson EP. Evaluation of the analgesic effects of epidurally administered morphine, alfentanil, butorphanol, tramadol and U50488H in horses. American Journal of Veterinary Research (2000) 61 (12); 1579-86.
  • Olbrich VH and Mosing M. A comparison of the analgesic effects of caudal epidural methadone and lidocaine in the horse. Vet Anaesth and Analg (2003) 30; 156-164.
  • Orsini JA, Moate PJ, Kuersten K, Soma LR and Boston RC. Pharmacokinetics of fentanyl delivered transdermally in healthy adult horses – variability among horses and its clinical implications. J Vet Pharmacol Therap (2006) 29; 539-546.
  • Petebrauer C Larenza PM, Knobloch M Theurillat R, Thormann W, Mevissen M and Spadavecchia C. Effects of low dose infusion of racemic and S-ketamine on the nociceptive withdrawal reflex in standing ponies. Vet Anaesth and Analg (2008) 35 (5); 414-423.
  • Rafferty GC. Hazards of immobilization. Vet Rec April 8th 1972 p 430.
  • Ringer SK, Portier KG, Fourel I, Bettschart-Wolfensberger R. Development of a romifidine constant rate infusion with or without butorphanol for standing sedation in horses. Vet Anaesth and Analg (2012) 39; 12-20.
  • Ringer SK, Portier KG, Fourel I and Bettschart-Wolfensberger R. Development of a xylazine constant rate infusion with or without butorphanol for standing sedation of horses. Vet Anaesth and Analg (2012) 39; 1-11.
  • Robertson SA, Sanchez LC, Merritt AM and Doherty TJ. Effects of systemic lidocaine on visceral and somatic nociception in conscious horses. Equine Veterinary Journal (2005) 37 (2); 122-127.
  • Rohrbach H, Korpivaara T, Schatzmann U and Spadavecchia C. Comparison of the effects of the alpha-2 agonists detomidine, romifidine and xylazine on nociceptive withdrawal reflex and temporal summation in horses. Vet Anaesth and Analg (2009) 36 (4); 384-395.
  • Rusiecki K, Nieto JE, Puchalski SM and Snyder JR. Evaluation of continuous infusion of lidocaine on gastrointestinal tract function in normal horses. Vet Surg (2008) 37 (6); 564-570.
  • Sanchez LC, Robertson SA, Maxwell LK, Zientek K and Cole C. Effect of fentanyl on visceral and somatic nociception in conscious horses. J Vet Int Med (2007) 21; 1067-1075.
  • Sanchez CL, Elfenbein JR and Robertson SA. Effect of acepromazine, butorphanol or N-butylscopolammonium bromide on visceral and somatic nociception and duodenal motility in conscious horses. Am J Vet Res (2008) 69 (5); 579-585.
  • Sellon DC et al. Pharmacokinetics and adverse effects of butorphanol administered by single intravenous injection or continuous intravenous infusion in horses. American Journal of Veterinary Research (2001) 62; 183-189.
  • Sellon DC et al. Effects of continuous rate intravenous infusion of butorphanol on physiologic and outcome variables in horses after celiotomy. Journal of Veterinary Internal Medicine (2004) 18; 555-563.
  • Serrano L and Lees P. The applied pharmacology of azaperone in ponies. Res Vet Sci (1976)20; 316-323.
  • Sharma CV and Mehta V. Paracetamol: mechanisms and updates. Continuing Education in Anaesthesia, Critical Care and Pain (2013) doi: 10.1093/bjaceaccp/mkt049.
  • Shilo Y, Britzi M, Eytan B, Lifschitz T, Soback S and Steinman A. Pharmacokinetics of tramadol in horses after intravenous, intramuscular and oral administration. J Vet Pharmacol Therap (2007) 31; 60-65.
  • Silvina S and Barbara AC. Bisphosphonates: pharmacology and clinical approach to their use in equine osteoarticular diseases. J Eq Vet Sci (2014) doi:10.1016/j.jevs.2014.01.009.
  • Shults T, Combie J, Dougherty J and Tobin T. Variable interval responding in the horse: a sensitive method of quantitating effects of centrally acting drugs. Am J Vet Res (1982) 43 (7); 1143-1146.
  • Skarda RT and Muir WW. Comparison of antinociceptive, cardiovascular and respiratory effects, head ptosis and position of pelvic limbs in mares after caudal epidural administration of xylazine and detomidine hydrochloride solutions. Am J Vet Res (1996) 57; 1338-1345.
  • Skarda RT and Muir WW. Analgesic, hemodynamic and respiratory effects induced by caudal epidural administration of meperidine hydrochloride in mares. Am J Vet Res (2001) 62; 1001-1007.
  • Stewart AJ, Boothe DM, Cruz-Espindola C, Mitchum EJ and Springfield J. Pharmacokinetics of tramadol and metabolites O-desmethyltramadol and N-desmethyltramadol in adult horses. Am J Vet Res (2011) 72; 967-974.
  • Stout RC. and Priest GT. Clinical experience using butorphanol tartrate for relief of abdominal pain in the horse. Equine Colic Research, Proceedings of the second Symposium at the University of Georgia, Lawrenceville, NJ: Veterinary Learning Systems Vol 2 1986.
  • Sysel AM et al. Efficacy of an epidural combination of morphine and detomidine in alleviating experimentally induced hindlimb lameness in horses. Vet Surg (1996) 25; 511.
  • Terry RL, McDonnell SM, van EPS AW, Soma LR, Liu Y, Uboh CE, Moate PJ and Driessen B. Pharmacokinetic profile and behavioural effects of gabapentin in the horse. J Vet Pharmacol and Therap (2010) 485-494. doi: 10.1111/j.1365-2885.2010.01161.x.
  • Thomasy SM, Slovis N, Maxwell LK and Kollias-Baker C. Transdermal fentanyl combined with nonsteroidal anti-inflammatory drugs for analgesia in horses. J Vet Int Med (2004) 18; 550-554.
  • Torfs S, Delesalle C, Dewulf J, Devisscher L and Deprez P. Risk factors foe equine post-operative ileus and effectiveness of prophylactic lidocaine. J Vet Int Med (2009) 23 (3); 606-611.
  • Walker AF. Sublingual administration of buprenorphine for long term analgesia in the horse. Veterinary Record (2007) 160; 808-809.
  • West E, Bardell D, Morgan R and Senior JM. Use of acetaminophen (paracetamol) as a short term adjunctive analgesic in a laminitic pony. Vet Anaesth and Analg (2011) 38(5); 521-522.
  • Wright JG. Anaesthesia and narcosis in the horse. Vet Rec 1958 70(16); 329-336.

From Abstracts in Equine Veterinary Journal Volume 30, Issue S27, Nov 1998, Pages: 49–64.

Pharmacological aids to behaviour modification in horses

SUE M. McDONNELL

University of Pennsylvania School of Veterinary Medicine, New Bolton Center, 382 West Street Road, Kennett Square,

Pennsylvania 19348, USA.

Very little systematic research has been done on pharmacological aids to behaviour modification in horses. Nonetheless, a number of treatment regimens are used effectively, usually in combination with other management and/or systematic behaviour modification

approaches. The following is an outline of agents and the most commonly recommended treatment regimens known to the author in North America for use with horses. Certainly many more agents are used by owners and trainers, particularly in the racing and show horse industries, but accurate information is difficult to obtain. These notes are meant to supplement the presentation. Use of these treatments is not recommended to clinicians without further

detailed discussion of pharmacology, indications, contraindications, expected course of treatment and effects and adverse side-effects with veterinary behaviour clinicians experienced with the particular regimen.

  1. To control oestrus cycle-related performance and temperament problems in mares
  2. a) Progesterone to inhibit oestrus and ovulation.

progesterone in oil (150-300 mg i.m. every other day)

altrenogest (22 mg orally daily)

cattle steroid implants (usually progesterone-oestrogen combinations)

medroxyprogesterone acetate (effectiveness controversial)

megestrol acetate (effectiveness controversial)

  1. b) Prostaglandin F2α to hasten luteolysis to shorten diestrus (label recommended regimen for luetolysis).
  2. c) HCG to hasten ovulation and shorten oestrus.

 

  1. To subdue unwanted stallion-like behaviour in stallions or geldings
  2. a) Progesterone in oil (15C300 mg i.m. every other day).
  3. b) Altrenogest (22 mg orally daily).
  4. c) Cattle steroid implants (usually progeterone-oestrogen combinations).
  5. d) Reserpine (2.5-10 mg s.i.d. or divided bid. orally up to 30 days).

 

  1. To reduce stereotypies (weaving, pacing, circling, self-mutilation, behavioural head-shaking, pawing)
  2. a) Imipramine/clomipramine (500-1000 mg i.d. orally in grain).
  3. b) 1-tryptophan (1-3 g to t.i.d. orally in grain).
  4. c) Naloxone, naltrexone, nalmefene opiate antagonists (not used widely).

 

  1. To improve spirit and/or induce stallion-like behaviour in stallions, mares, geldings
  2. a) Androgens
  3. b) Oestrogen (high doses of oestrogens can have androgenic behavioural effects)
  4. c) Anabolic steroids

 

  1. To improve libido in stallions
  2. a) Anxiolytics for inhibited sexual behaviour.
  3. b) Testosterone (80 mg aqueous subcutaneously every 1-2 days).
  4. c) GnRH (stallions) 50 μg subcutaneously 2 h and again 1 h before breeding.
  5. d) Yohimbine (15-30 mg orally b.i.d., not used widely in stallions).

 

  1. To improve maternal behaviour

Reserpine (2.5-5.0 mg orally s.i.d. to bid. for 3 4 days; can premedicate known poor mothers for a few days before expected parturition)

 

  1. Inducdmaintain oestrus in ovariectomised stimuludmount mare for semen collection
  2. a) Oestradiol cypionate (1/4 mg-1/2 mg subcutaneously every other day).
  3. b) Oestradiol benzoate (1-2 mg subcutaneously daily).

 

  1. To calm nervous, fearful, or generally hyperactive horses (long-term)
  2. a) 1-tryptophan (1-3 g b i d . to t.i.d. orally in grain).
  3. b) Fluphenazine decanoate (25-35 mg m. every 3 weeks).
  4. c) Reserpine (2.5-10 mg i.d. or divided b.i.d. orally).

 

References

diazepam (0.05 mgkg slow i.v., maximum 20 mg, 5 min before breeding)

Brendemuehl, J.P. (1996) Personal communication. Tuskegee University, Alabama, USA.

Dodman, N.H., Shuster, L. er al. (1988) Use of a narcotic antagonist (nalmefene) to suppress self-mutilation behaviour in a stallion. J. Am. vet. med. Ass. 192, 1585-1587.

Dodman, N.H., Shuster, L. ef al. (1987) Investigation into the use of narcotic antagonists in the treatment of a stereotypic behaviour pattern (crib-biting) in the horse. Am.

Houpt, K.A and McDonnell, S.M. (1993) Equine stereotypies. Comp. con?. Educ. pract. Vef. 15, 1265-1272.

Pozor, MA., McDonnell, S.M. ef al. (1991) GnRH facilitates copulatory behaviour in geldings treated with testosterone. J. Reprod. Ferf. Suppl., 44, 666-667.

McDonnell, S.M., Kenney, R.M. ef al. (1985) Conditioned suppression of sexual behaviour in stallions and reversal with diazepam. Physiol. Behav. 34,951-956.

McDonnell, S.M., Kenney, R.M. er al. (1986) Novel environment suppression of sexual behaviour and effects of diazepam. Physiol. Behav. 37,503-505.

McDonnell, S.M., Gracia, M.C. and Kenney, R.M. (1987) Pharmacological manipulation of sexual behaviour in stallions. J. Reprod. Ferf. Suppl., 35,4549.

McDonnell, S.M.. Diehl, N.K. ef al. (1989) Gonadotrophin releasing hormone (GnRH) aEects precopulatory behaviour in testosterone-greated geldings. Physiol. Behnv. 45, 145.149.

Lizzie Barnard

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