2Pain and its Management in Animals

Mogoa E.GM. and P.M.F. Mbithi,Department of Clinical Studies, University of Nairobi, College of Agric. and Vet. Sciences,P.O. Box 29053, Nairobi, Kenya.

AbstractPain is a perception, an unpleasant experience associatedwith actual or potential tissue damage. It is usually causedby mechanical, chemical or thermal stimulation ofspecialised pain receptors (nociceptors)in tissues. Inroutine veterinary practice, such acute insults causingintense stimulation encountered include tissue traurna..including surgery, burns and fractures. As veterinarypractitioners, we are ethically obliged to prevent painand suffering where possible and alleviate it, should itoccur, as it contributes to increased morbidity andmortality. In order to do this, we need to be able to assess.pain in animals and manage it appropriately. Painassessment can be made based on anthropomorphism,behavioural responses of the patient and clinical signs.The behavioural and physiological responses thataccompany pain such as vocalization, withdrawal reflex,guarding of the affected area and increased activity ofthe sympathetic nervous system are measurable. Paincontrol in animals can be achieved through limitation ofnociceptor stimulation, interruption of peripheraltransmission, inhibition of nociceptive transmission at thelevel of the spinal cord, modulation of brain pathways bysystemic administration of analgesics or, through'balanced' or 'multimodal' analgesia by simultaneous useof a number of the above strategies. Although theselection and techniques of administration of individualanalgesic drugs vary, local and opioid analgesics, non-steroidal anti-inflammatory drugs, tranquilizers and othercombination therapies when used appropriately cancontrol pain and alleviate suffering in animalsexperiencing pain. This paper looks at pain and itsmanagement in animals.

IntroductionPain has been defined by the International Associationfor the Study of Pain (lASP) as 'an unpleasant sensoryor emotional experience associated with actual orpotential tissue damage or described in terms of suchdamage' (Short, 1995; Muir, 1998). It can be present inmild and severe forms (quality) and in acute and chronicforms (temporal). There is no dispute that all mammalshave the anatomical and physiological pathways requiredfor the perception of pain and learn to avoid painful stimuli(Morton and Griffiths, 1985). .One of the noblest goals of medicine is the alleviation ofpain and suffering. Although knowledge and techniquesto control pain exist in both human and veterinarymedicine, in many instances, clinicians do not utilize them(Tranquilli and Raffe, 1989;-Carroll, 1996). In humanmedicine, relieving chronic pain and pain associated withsurgery and trauma has become an importantsubspecialty of anaesthesiology and intensive care(Tranquilli and Raffe, 1989). .One of the most important treatment decisions to makeas veterinarians is whether to control pain in patientsundergoing surgery. Indeed, pain and inflammatory~-----------------------------------------------

responses are induced by surgical procedures andanaesthesia related muscle ischaemia. These produce aseries of behavioural, neurophysiological, endocrine.metabolic and cellular responses (stress response) whichinitiate, maintain and amplify the release of pain andinflammatory mediators (Muir, 1998).Because non-verbal animals are incapable of describingpain, veterinarians are left with the task of evaluatingpatients for assorted signs of pain. Animals in pain exhibitboth physiological and behavioural signs which shouldbe used inclusively to assess pain. The most recognizedbehavioural manifestation of pain is vocalization. whichincludes crying, howling, barking, growling, purring ormoaning. Other behavioural and clinical indications orpain include changes in posture or facial expression.guarding or protecting a limb, self-mutilation. dilatedpupils, salivation, muscle rigidity or weakness. andchanges in sleeping and eating patterns.In the management of pain in animals, considerationought to be given to the location of the pain, painmechanisms involved in transmission, the mechanismsof action of the medication chosen, and its potential toblock or alleviate the source, or recognition of thepainfulcondition (Short, 1995). To control pain in animals. man)techniques are available and these include limitation ofnociceptive stimulation, interruption of peripheraltransmission, inhibition of nociceptive transmission at thelevel of the spinal cord, modulation of brain pathways or.through a combination of any of these techniques. Allthese techniques use the many drugs avai lable for controlof pain, by administering them locally or systemically(Quandt and Rawlings, 1996). Medication for control ofpain can be chosen from non-steroidal anti-inflammatorydrugs (NSAIDs), corticosteroids, op io ids. alpha,-adrenergic agonists, anaesthetics and other centralnervous system (CNS) response altering agents (Short.1995).

Terms used to define and describe painSeveral terms are used to define and describe pain.Noxious stimulus is a stimulus (mechanical, chemical orthermal) of sufficient intensity to threaten or overtlycause tissue damage. Nociception is the process of painperception via pain receptors (nociceptors). Hyperalgesiarefers to increased response or hypersensitivity to anoxious stimulus, either at the site of injury (primary) orin surrounding undamaged tissues (secondary).Hyperaesthesia refers to increased sensitivity to non-noxious stimuli. Allodynia is pain produced by non-noxiousstimuli. Pre-emptive analgesia deals with the preventionor minimization of pain by administering analgesics priorto pain production or prior to introduction of a noxiousstimulus as in surgery, ifpain already exists. Pre-emptiveanalgesia is aimed at provision of therapeutic interventionin the advance of pain in order to prevent or minimizethe central nervous system response to noxious stimuli(Muir, 1998).

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Classification of painPain can be classified into 'physiological' or 'clinical'.Pain is considered to be 'physiological' when it operatesto protect the body by warning of contact with tissuedamaging stimuli (Woolf and Chong, 1993) and this typeof pain is produced by stimulation of nociceptorsinnervated by high threshold A-delta (Group III) andunmyelinated C (Group IV) fibres. 'Clinical' pain isproduced by peripheral tissue injury or damage to thecentral nervous system (Woolf and Chong, 1993). Thisclinical pain is categorized as inflammatory or neuropathic.Inflammatory pain can either be visceral or somatic inorigin. Visceral pain is poorly localized, cramping orgnawing and may be referred to cutaneous sites far fromthe site of injury. Somatic pain on the other hand is easilylocalized, can be aching, stabbing or throbbing andgenerally is acute. This includes cutaneous or incisionalpain after operations. This pain is frequently referred toas superficial, when involving the skin or deep, wheninvolvingjoints, muscles and the periosteum. Neuropathicpain results from damage to peripheral nerves or thespinal cord and is described as burning, stabbing andintermittent, often unresponsive to treatment. Bothinflammatory and neuropathic pain can produce allodynia,hyperalgesia and central nervous system and peripheralsensitization to external stimuli. Idiopathic pain, which ispain that persists in the absence of an identifiable organicsubstrate is often excessive and accentuated by activationof the sympathetic nervous system due to emotionalstress (fear) or excitement (Muir, 1998).

Pain-processes and the resultant effectsPain' perception and nociception can be considered toinvolve four primary physiological processes oftransduction, transmission.modulation and perception.Noxious stimuli are transduced into electrical impulsesby peripheral pain receptors and subsequently transmittedthroughout the sensory nervous system. These electricalimpulses are modulated by endogenous systems, whichinclude the serotonergic, cholinergic, noradrenergic andopioid systems in the dorsal horn of the spinal cord and,then transmitted to the brain from where emotional,behavioural and physiological responses are initiated.Mechanical, chemical, or thermal activation of smalldiameter high-threshold A-delta and C sensory nervefibres normally produces pain. Several chemicalmediators of pain and inflammation are recognized.These include histamine, serotonin, bradykinin,leukotrienes, prostaglandins (PGF2, PGI2, PGE2),

interleukins (IL- I, IL-6), neutrophil-chemotactic peptides,nerve growth factor (NGF) and neuropeptides includingsubstance P (Levine et al., 1993; Woolf and Chong,1993). Their role is in the enhancement of the excitabi lityof sensory nerves and postganglionic sympathetic nervefibre activity leading to peripheral sensitization,hyperalgesia and allodynia. On the other hand,inflammation increases the sensitivity of peripheralterminals of A-delta and C-fibres which causes someA-beta fibres to express substance P and stimulate thesynthesis and release of nerve growth factor (NGF),' apeptide which increases the synthesis of substance Pand calcitonin gene related peptide (CGRP). This process,stimulates the release of histamine and leukotrienes and

is associated with the development of sensoryhyperexcitabi Iity and hyperalgesia. The consequent resultof these inflammatory and tissue chemical responses isthe development of diverse but interrelated positivefeedback loops, which enhance neural sensitivity andintensify the pain response (Muir, 1998).After transduction, electrical impulses are transmittedto C-fibre terminals in the dorsal horn where theexcitatory neuropeptides (tachykinins), substance P,neurokinin A (NKA), CGRP and the amino acid glutamateare released to activate post-synaptic tachykinin (NK

"NK,), CGRP and glutamate (N-methyl-D-aspartate[NMDA]; amino-hydroxy-methyl isoaxalepropionic acid[AMPA]; Kinate [KAJ) receptors. Cumulative increasesin the number of electrical impulses produced in the dorsalhorn cells and large motor neurons of the ventral horn illresponse to increased C-fibre stimulus frequencyeventually results in increase in excitability of the spinalcord neurons and central nervous system leading tocentral sensitization, hyperalgesia and allodynia (Muir.1998).

Assessment of painPain can be assessed based on one or a combination ofseveral criteria. The criteria include anthropomorphism,unprovoked behaviour, behavioural responses to externalstimuli, and clinical signs. Anthropomorphism(extrapolation from human experience) relies on the factthat if a procedure will cause pain in a human, then it islikely to do so in our patients. From this, the Iikely severityof untreated pain from a surgical procedure may bepredicted on the basis of the extent of damage to thetissues and anatomical site of the proposed surgical injury.Unprovoked behaviour relies on responses to pain thatinclude vocalization; restlessness; attempts to escape;changes in normal sleeping patterns; changes in appetite:changes in temperament including increased anxiety andwithdrawal, guarding or protecting the affected area andturning the head towards the painful stimulus; selfmutilation including biting, chewing or scratching of thepainful area and, lameness including limb disuse, unusualposture (e.g. hunched up) and, slow movement.Behavioural responses to external stimuli includeassessing animal responses when interacting with humansand their response to gentle handling of the surgical siteor source of pain. The use of clinical signs to judgewhether an animal is in pain is only useful for acute pain.The clinical signs that can be used include increased heartrate and blood pressure, peripheral vasoconstriction andpall our of mucous membranes, cardiac arrythmias.sweating in some species, hyperventilation and reductionin peristalsis (Morton and Griffiths, 1985). Increasedplasma catecholamine and cortisol concentration andincreased systolic blood pressure have been shown tobe very useful in predicting post-operative pain in cats(Morton and Griffiths, 1985; Smith et. al., 1996).

Justification for pain therapyPain treatment isjustified for several reasons.(i) Treatment or alleviation of pain reduces patient

suffering.(ii) Pain increases morbidity, the cost of patient care

and occupies time better spent on more productivework.

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· (iii) Pain increases patient risk during anaesthesia asmore drugs are required to maintain a stable planeof anaeshtesia.

(iv) Pain exaggerates the inflammatory response,which in turn increases the production of painneurotransmitters (substance P, CGRP) andincreases the excitability of sensory neurones.

(v) Pain produces a catabolic state, suppresses theimmune response and promotes inflammationwhich delays wound healing and predisposes thepatient to infection and intensified medical care.

In addition to the above, special consideration should begiven to post-operative pain, although it is thought that itdoes not serve any useful purpose. This is because, post-operative pain causes sympathetic stimulation, increasedcardiac output and cardiac work, elevation of bloodpressure, increase in catabolic hormones and musclespasm, all ofwhich contribute to increased morbidity andmortality.

Pain therapyStrategies for pain controlPain can be controlled by interventions aimed at differentpoints in the pain transmission pathway. Several or acombination of these interventions can be employed.Limitation of nociceptor stimulation can be achieved bygentle handling of tissues to minimize tissue trauma duringsurgery. Administration of non-steroidal anti-inflammatorydrugs (NSAIDs) that inhibit cycle-oxygenase pre-operatively ensures reduced production of prostaglandinsand other substances that sensitise the nociceptors.Interruption of peripheral neural transmission can beachieved through local infiltration oflocal anaesthetics,nerve blocks or intravenous regional anaesthesia.Inhibition of nociceptive transmission at the spinal cordcan be achieved by systemic, epidural or subarachnoidadrninistrationpf opioids and alpha, -adrenergic agonistsand epidural 6r subarachnoid administration of localanaesthetics. Modulation of brain pathways to controlpain entails systemic administration of opioids, alpha -adrenergic agonists.and to a lesser extent some NSAID~.'Balanced' or 'multimodal' approach to pain controlinvolves the simultaneous use of the above strategies tomaximize pain control with minimal doses of drugs. Forexample, infiltration of the surgical site with localanalgesics can be combined with systemic administrationof a NSAID or an opioid. Similarly, epidural administrationof a mixture of a local anaesthetic and an opioid togetherwith systemic administration ofa NSAID can maximizepain control. Combination therapies have been found tobe the most useful and rational.

Specific pain therapiesAmong the wide variety of pharmacological and non-pharmacological therapies avai lable for the managementof pain in animals are local and regional anaesthesia, useof systemic drugs and, analgesic adjuncts.

Examples of useful local anaesthetics are lidocaine,mepivacaine and bupivacaine.

Sedatives. Alpha;z-adrenergic agonists (xylazrne,detomidine, romifidine), opioids (butorphanol, morphine)and tranquilizers (acepromazine) modulate centralnervous system signal processing thus interfering withnociceptive inputs. The alpha.sagonists that are widelyused in horses for provision of analgesia include xylazine(0.5-1.0 mg/kg, intravenous), detomidine (0.01-0.02 mgJkg, intravenous), medetomidine (0.01-0.02 mg/kg.intravenous), and romifidine (0.04-0.08' rug/kg.intravenous) (Muir, 1998).

General anaesthetics. Dissociative anaesthetics(phencyclidine, ketamine) are non-competitive N-methyl-D-aspartate (NMDA) antagonists producing dosedependent prevention of hyperalgesia and allodynia, inaddition to amnesia while injectable anaesthetics(thiopentone, propofol) and ?nhalation anaesthetics(halothane, isoflurane, sevoflurane) interfere with corticalsignal processing. It is generally accepted that adequatelyanaesthetised patients cannot experience pain as corticalsignal processing is depressed. However, the magnitudeof nociceptive input may vary considerably for differentsurgical procedures resulting in a variety of physiologicalresponses especially in heart rate, blood pressure andsympathetic outflow, suggestive of increased nociceptiveinputs that may require adjunctive pain therapy (Muir,1998).

Non-steroidal anti-inflammatory drugs (NSAIDs).The most popularly used NSAIDs are phenylbutazone.ketoprofen, carpoprofen and flunixin meglumine. Theiranalgesic effects arises majorly through inhibition ofcyclo-oxygenase-I (COX-I) activity. They are used invarious animal species to control pain (Table I). OtherNSAIDs in use include ibuprofen, ibufenac, alclofenan.phenoprofen, naproxen and diclofenac (Short, 1995).Most of them have the known potential forgastrointestinal ulceration and renal toxicity (Quandt andRawlings, 1996; Muir, 1998).

Corticosteroids. Corticosteroids reliefpain through thereduction of inflammatory processes, especially softtissue damage, stabilization of cell membranes and thereduction of oedema without significant central nervoussystem activity (Short, 1995). The most commonly usedcorticosteroids are hydrocortisone, dexamethasone, andmethylprednisolone. Most often, the use of steroids inhorses is by intra-articular injection although systemicadministration is also widely practiced in other species.However, the use of intra-articular injection ofcorticosteroids can cause reduction in cartilaginous tissueresponses because of interference with circulation ortissue perfusion (Short, 1995).

Local anaesthetic drugs. These can be used in regionaland local anaesthetic techniques including epiduralanaesthesia and various specific nerve blocks to blocknerve electrical activity and therefore block transmissionof pain signals (Quandt and Rawlings, 1996; Muir, 1998).€)--------------------------------- The Kenya Veterinarian

Opioids. Opioids activate opioid receptors producinggood to excellent analgesia. Of the commonly usedopioids, butorphanol, morphine and fentanyl produceanalgesia with minimal or no sedation when administeredin low dosages. The most potent opioids (e.g. fentanyl)are less likely to develop tolerance than less potent opioids

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(e.g. butorphanol). Their use in various animals to controlpain is well documented (Short, 1995; Smith et aI., 1996;Muir, 1998). Dosages of the more commonly used opioidsfor the provision of analgesia in various animal speciesare shown on Table 2. Opioids or opioid and localanaesthetic mixtures can be injected into the epiduralspace to provide excellent long-lasting analgesia in variousanimal species (Quandt and Rawlings, 1996).

Combination therapy.The combination or sequential administration of analgesicsthat act by different mechanisms (multimodal therapy)is often advocated in order to maximize analgesic drugeffects (Muir, 1998). Examples of these are theadministration of two major analgesics - NSAID withan opioid or an opioid with an alpha-agonist. Thesefrequentl~ produce supra-additive or synergistic analgesiceffects with the advantage of reduced individual drugdosages thereby reducing the potential for drug relatedside effects. Synergism or supra-additivity has beendemonstrated when local anaesthetics are combined withopioid or dissociative anaesthetics and when NSAIDsare combined with opioids (Henrik and Dahl, 1993). Thecombination of morphine with xylazine in horses forexample, produces excellent sedation, euphoria andpotent analgesia allowing for most medical and minorsurgical procedures to be completed without the needfor further administration of an injectable or inhalantanaesthetic (Muir et. al. 1979b).Administration of adjunctive drugs (tranquilizers) inconjun~tion with major analgesic drugs may potentiateanalgesic effects and produces additional calming effects.Some examples of these include acepromazine andmeperidine or acepromazine and xylazine (Muir, 1979a,b).Several of the m~jor ~pioid and alpha-agonist analgesicscan be antagonised Incase of adverse effects on theiradministration which is a distinct advantage over othergroups of drugs. However, it is important to note thatreversal or antagonism of adverse effects may antagonisethe drug's analgesic activity (Muir, 1998).

Pre-emptive analgesia.The deliberate administration of analgesic drugs 24-48~ours before extensive soft tissue or orthopaedic surgeryIn order-to pre-empt or minimise the response to painhas a number of advantages in that:(i) the ~umber and amount of anaesthetic drugs

required to produce and maintain surgicalanaesthesia is reduced,

(ii) it helps to stabilise the maintenance phase ofanaesthesia,

(iii) the total amount of analgesic drugs required tocontrol pain both intra-and post-operatively isreduced, and

(iv) the overall patient morbidity associated withsurgery and anaesthesia is decreased (Muir, 1998).

The most commonly used pre-emptive analgesics in thehorse for short term pain therapy are combinations oflow dosages of opioids with NSAIDs or alpha, -agon ists.

Long term pain therapy.Conti~ued or long term administration of analgesic drugsfor pain ther~py where necessary poses special problemsfor the vetennary surgeon. Long term use of opioids maylead to tolerance in addition to the development ofconstipation and urine retention (Quandt and Rawlings,1996). Long term use of alpha -agonists can predispose!o i.mpaction or constipation.

2Prolonged use of Cox-I

inhibitors has the potential for producing gastrointestinalulceration or renal toxicity (Short, 1995). Drugs thatproduce analgesia by two distinctly separate mechanismsare li~ely to be synergistic. For example, although thexylazlne.an~ ketamine combination produces synergisticanalgesia, It also produces synergistic respiratorydepression. In this case, the dosages of each should bereduced to avoid this potential outcome. It should be notedt~at the development of side effects is almost always adirect consequence of inadequate consideration of thedrug's toxic effects, dose-response characteristics andpatient status prior to drug administration (Muir, 1998).

Table I. Dose rate and route of administration for commonly used NSAIDs as analgesic agents. (The duration of action fore each drug is shown below each dose).1eIS

ddnIC

S.)f.IeDr

ngedceedyl)ids

ian

DRUG DOG CAT HORSE PIG SHEEP/GOAl CATTLE

Aspirin 10-20PO Max. 10PO(mglkg) 8-20 hours 48 hhours

_Ketoprofen 2IY,IM,SC 2SC 2IV(mg/kg) 24 hours 24 hours 24lioursCarprofen 4 IV,SC U:IIV(mglkg) Not 1M 24 hours

24 hoursFlunixin IIV l.lIV 2.2 deep 1M 2.2fV(mglkg 24 hours 24 hours 12 hours 24 hoursPhenylbutazone 10PO 5PO(mglkg) 8-12 hours 24 hours

3.QIV12 hours

1M Intramuscular; IV - Intravenous: SC = Subcutaneous; PO = Oral; NR = Not Recommended.

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Table 2.

Haemodynamic and respiratory effects ofaxylazine-acetylpromazine drug combination in horses. AmericanJournal of Veterinary Research, 40, 1518-1522.

Muir, W.W., 1998.Anaesthesiaand pain management in horses.Equine Veterinary Education, 10 (6), 335-340.

Quandt, E.J. and RC Rawlings, 1996. Reducing postoperativepain for dogs: Local anaesthetic and analgesic techniques.Compendium on Continuing Eductation 18 (2), 10 I-II I.

Short, E.C, 1995. Equine pain: Use of non-steroidal anti-inflammatory drugs and analgesics for its prevention andcontrol. Equine Practice, 17 (10), 12-22.

Smith, D.J., S.W. Allen., E.J. Quandt, L.R. Tackett, 1996.Indicators of postoperative pain in cats and correlation withclinical criteria. American Journal 0/ Veterinary Research,57(11),1674-1678.

Tranquilli, J.W and RM. Raffe, 1989. Understanding pain andanalgesic therapy in pets. Veterinary Practice, 680-686.

Woolf, CJ. and M. Chong, 1993. Preemptive analgesia- treatingpostoperative pain by preventing the establishment of centralsensitization. Anaesthesia and Analgesia, 77, 362-379.

Dose rate ~nd route .of administration for commonly used opioids as analgesic agents.(The duration of action for each drug is shown below each dose).

DRUG DOG CAT HORSE PIG SHEEP/GOAT CATTLEMorphine 0.2~.5 0.05-0.1(mglkg) IM,SC IM,SC

3-4 hours 3-4 hours0.1 epidural 0.1 IV10-23 hours 0.1 epidural

Pethidine 2~5IM,SC 2-5 IM,SC 2-4 1M 21M 200mg total 1M 21M(mz/kz) 1-2 hours 1-2 hours 15 minutes 4 hoursFentanyl 5-10 IV NR(u/kg) 20 minutesBuprenorphine 10-15 5-10 5-101M 51M(~g) IV,IM,SC IV,IM,SC to 10 hours to 12 hours

6-8 hours 6-8 hoursButorphanol 0.05-0.2 IV 0.05-0.2 IV 0.022 1M(mglkg) 0.2-0.5 1M 0.2-0.5 1M 2-4 hours

1-2 hours 1-2 hoursCodeine 1-2 PO NR(mglkg) to 6 hoursMethadone 0.25-0.5 O.2-O.3SC(mglkg) IM,SC 4 hours

4 hoursSource. Unnamed, (1996).1M = Intramuscular; IV = Intravenous; SC = Subcutaneous; PO = Oral; NR = Not Recommended.

References

Carroll, L.G, 1996. How to manage perioperative pain.Veterinary Medicine, 353-357.

Guidelines for the management of Pain in Veterinary Practice,1996. Australian Veterinary Practitioner, 26 (4), 206-209

Henrik, K. and J.B. Dahl, 1993. The valve of'multimodal' or'balanced analgesia' in postoperative pain treatment.Anaesthesia and Analgesia, 77, 1048-1056.

Levine, J.D., H.L Fields and A.I. Basbaum, 1993. Peptides andthe primary afferent nociceptor. Journal of-Neurology, 13,2273-2286.

Morton, B.D. and M.H.P. Griffiths, 1985. Guidelines on therecognition of pain, distress and discomfort in experimentalanimals and an hypothesis for assessment. VeterinaryRecord,116,431-436.

Muir, W.W., R.T. Skarda and W.C Sheehan, 1979a.Haemodynamic and respiratory effects ofaxylazine-morphine sulphate in horses. American Journal of VeterinaryResearch, 40, 1417-1420.

Muir, W.W., R.T. Skarda and W.e. Sheehan, .1979b.

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