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Musk, G. and Raisis, A. (2012) Analgesia for patients with

neurological disease. In: Platt, S. and Garosi, L., (eds.) Small Animal Neurological Emergencies. Manson Publishing Ltd,

London, pp. 557-569.

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INTRODUCTION

Pain is defined by the International Association for theStudy of Pain as an unpleasant sensory and emotionalexperience associated with actual or potential tissuedamage or expressed in terms of such damage. Recogni-tion of the presence of pain and assessment of the severityof pain are essential for optimal management and areintegral steps towards appropriate treatment of pain inanimals with (and without) neurological disease. Poorlymanaged pain is a significant contributor to morbidityand mortality, has adverse welfare implications anddelays the return to normal function. Good painmanagement relies on regular pain assessment andincludes the administration of analgesic drugs (419).

The aims of pain treatment are to:• Inhibit the neuroendocrine stress response, which

may compromise recovery.• Maintain tissue perfusion.• Allow restful sleep.• Encourage mobility.• Improve appetite.• Attenuate peripheral and central sensitization.

A plethora of drugs exist that can be used alone or incombination to manage pain in animals with neurologi-cal disease. Analgesic therapy must be tailored to eachindividual animal based on the cause, duration andseverity of pain, the level of consciousness, the presenceof coexisting diseases and the impact of expected side-effects (420, p. 559). This chapter describes specificconsiderations for selecting analgesic agents for painmanagement of animals with acute neurological diseaseand provides examples of analgesic regimens that may besuitable for these patients. The physiology of pain andthe pharmacology of analgesic drugs are beyond the

ANALGESIA FOR PATIENTS WITH NEUROLOGICAL DISEASE

Gabrielle Musk& Anthea Raisis

SPECIFIC MANAGEMENT ISSUES Chapter 30

557

a

b

! 419 (a) A dog following hindlimb amputation withinadequate analgesia. (b) The obvious difference in thisanimal’s behaviour is demonstrated after adequateanalgesia was provided.

scope of this book, but a good understanding of both isvital to ensure optimal pain management (see Furtherreading). Furthermore, familiarity with available drugswill guide the clinician’s decision making.

Painful stimuli may cause an acute pain response andpoorly managed pain can lead to neurophysiologicalchanges that are permanent. Furthermore, certain typesof pain are particularly difficult to manage and require amultimodal approach. The clinician should be preparedto trial therapy and assess the response before commit-ting to a long-term plan. Neuropathic pain is particular-ly difficult to manage and is often not responsive toopioids. It is produced by peripheral and central sensiti-zation and may be present as allodynia or hypersensitivi-ty (Table 107). It may be continuous or sporadic and isdescribed as burning, shooting, tingling or electric innature.

Pain assessmentAccurate assessment of pain in animals is difficult. Inanimals with acute neurological disease it is even morechallenging, especially if a patient is moribund ordepressed. Conversely, physical examination may revealtachycardia, tachypnoea and hypertension, which com-plicates objective assessment of autonomic nervoussystem activity. These cases are easy to misinterpretand concern about the adverse effects of analgesic drugsmay influence clinical decision making. Given the scopeand variability of responses to painful stimuli in humanpatients, every effort must be made to perform a thor-ough pain assessment in each animal patient and treataccordingly. Furthermore, assessment of the response totherapy is essential to ensure that pain is adequately andcontinuously controlled.

In human medicine, self-reporting of pain is the goldstandard method of pain assessment. In veterinary medi-cine, pain assessment has been performed somewhatsubjectively or by applying pain scales used in humans.These include simple descriptive scales, numerical ratingscales and visual analogue scales. There are inherent lim-itations with each of these scales; they are one-dimen-sional and they have been shown to be unreliable in thesetting of acute postoperative pain in dogs. They have,however, had their place in the evolution of pain assess-ment in animals and have contributed to the understand-ing of the complexity of the pain experience.

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Table 107 Neuropathic pain

TERMINOLOGY DEFINITION

Allodynia A pain response to a non-painfulstimulus. This is usually localized to thearea of the initial injury

Hypersensitivity An exaggerated pain response to apainful stimulus. This phenomenonoccurs as a result of ‘sensitization’

Peripheral ‘Wind up’ of peripheral nociceptors sensitization leading to an exaggerated pain

response to stimulation

Central ‘Wind up’ of central nociceptorssensitization leading to generalized exaggerated

pain response to stimulation

Table 108 The multiple steps of thenociceptive pathway

TERMINOLOGY DEFINITION

Noxious stimulus A mechanical, chemical or thermalstimulus that causes pain. Pain is thesensory and emotional experienceassociated with actual or potentialtissue damage resulting from a noxiousstimulus

Transduction Processing the noxious stimulus fromthe peripheral site to the sensory nerveendings

Transmission Signalling along sensory nerves to thecentral nervous system. Sensory nervesmay be small myelinated A fibresassociated with sharp mechanical-typestimuli or unmyelinated C fibresassociated with dull, burning or longerlasting pain

Modulation Alteration of the incoming signal bysynapsing in the dorsal horn of thespinal cord. Neurotransmitters areinvolved in the propagation of ongoingimpulses in the central nervous system.Synapses within the grey matter of thespinal cord also connect with theventral horn to complete the reflex arc.This manifests as a withdrawalresponse to a noxious stimulus

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" 420 The different classes of analgesicdrugs interfere with the pain process atdifferent points and a multimodal approachis invariably most appropriate. The sites ofaction of each class of medication arehighlighted. (See also Table 108.)

The only validated pain scoring system for acute painin dogs is the Glasgow Composite Measure Pain Scale(GCMPS), which is a multidimensional scale taking intoaccount not just the intensity of pain, but its conse-quences. The GCMPS is based on psychometric princi-ples that are well established in human medicine for themeasurement of complex constructs such as intelligence,pain and quality of life. It categorizes and weights spontaneous and evoked behaviour and interactive andclinical observations (comfort, vocalization, mobility,demeanour, posture, attention to surgical wound andresponse to touch), resulting in a composite score. It ispractical in a clinical setting and easy to become familiarwith and use. As it forces the assessor to evaluate behav-iour that may be associated with pain and draw conclu-sions about whether or not the animal requires additionalanalgesia, it contributes to improved pain management.

A short form of the GCMPS for dogs suffering acutepostoperative pain has been developed for use in a clini-cal setting where the emphasis is on speed, ease of use andguidance for provision of analgesia as opposed to precisemeasurement of pain in a research environment. Theshort form comprises six behavioural categories (vocal-ization, mobility, demeanour, posture, attention tosurgical wound and response to touch). The maximum

pain score is 24 (or 20, if mobility is impossible to assess)and it is reported that a clinical decision point foranalgesia gave an intervention level of 6/24 (or 5/20 ifmobility could not be assessed).

Analgesic drugsAnalgesic drugs fall into the following categories:• Opioids.• NSAIDs.• Local anaesthetics.• Alpha-2 adrenoceptor agonists (e.g. medetomidine).• N-methyl-D-aspartate antagonists (e.g. ketamine).• Miscellaneous drugs (e.g. gabapentin, tramadol,

nitrous oxide).

Most analgesic drugs will diminish pain; they arehypoalgesic in effect, rather than entirely abolishing it.The effects are usually dose dependent and an under-standing of nociceptive pathways, pain transmission,modulation and perception, the chemical mediators ofpain and inflammation and their impact on painprocessing will help the decision-making process (420and Table 108). The different classes of analgesics interfere with the pain process at different points and amultimodal approach is invariably most appropriate.

Transmission

Local anaesthetics

Transduction

Opioids

NSAIDs

Alpha-2 agonists

Tramadol

Noxious stimulus:mechanical,chemical, thermal

Perception

Opioids

Alpha-2 agonists

Tramadol

Projection

Modulation

Opioids

NSAIDs

Alpha-2 agonists

Tramadol

INTRACRANIAL DISEASE

OverviewManagement of pain in animals with intracranial diseaseis important from a welfare perspective and because painitself may increase ICP. This occurs because of sympa-thetic nervous system-modulated increases in BP.

Considerations • Cerebral perfusion. Selected analgesic drugs and

management techniques should have little impacton regulation of CBF. Minimal depression of thecardiovascular and respiratory systems is importantfor maintaining adequate cerebral perfusion andoxygenation while minimizing secondary neuronalinjury. Hypoventilation and consequent hyper-capnia may increase CBF and therefore increaseICP, while hyperventilation and hypocapnia maycause cerebral vasoconstriction and compromiseCBF. Higher doses of opioids may contribute tohypoventilation through respiratory depression,

while pain may cause either hypoventilation if chestexcursions are uncomfortable or hyperventilation ifthe pain is poorly managed. Close monitoring ofpulmonary function and careful adjustment of dosesare required to provide appropriate analgesiawithout respiratory depression.

• Neurological assessment. Analgesic drugs oftencause tranquillization or sedation. Caution shouldbe exercised if these side-effects are likely to impedeassessment and mask neurological deterioration.Low doses of short-acting drugs are preferable anda neurological examination should be performedprior to the administration of any medication.

• Severity of pain. As nociceptors are present in themeninges and skull, the severity of pain will dependon involvement of these structures in the diseaseprocess. Animals with meningitis (421) or skullfractures (422) are expected to suffer from severepain and should be treated accordingly. Animalswith concurrent trauma to other body systems arealso expected to suffer severe pain.

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! 421 Meningitis is suspected based on the meningealenhancement present in this dorsal T1-weighted post-contrast MR image (arrows). This condition can beextremely painful. (Photo courtesy Victoria Johnson)

! 422 Radiograph of a frontal bone fracture (arrow) in adog. This lesion would be expected to contribute to thepain present in the animal following its head trauma.(Photo courtesy Victoria Johnson)

Drug selectionOpioids Opioids are often administered to patients with intra-cranial disease. A summary of the characteristics and doseregimes of commonly used opioids is presented inTable 109.

Full mu agonist opioids can be reversed in the eventof undesirable side-effects. The potential complicationsof opioid administration, particularly important toanimals with intracranial disease, include bradycardia(with potential hypotension) and respiratory depression(with associated hypercapnia). Hypotension associated

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Table 109 Opioid analgesic agents used for perioperative pain control in dogs and cats with neurological disease

AGENT ADVANTAGES DISADVANTAGES DOSE

Morphine

Methadone

Oxymorphone(US)

Hydromorphone (US)

Pethidine(meperidine US)

Fentanyl

Remifentanil

Tramadol

Buprenorphine

Butorphanol

* Where a dose range is given, the lower doses are recommended for IV administration (where specified) or IMinjection in depressed animals and the higher doses for IM administration in alert animals/animals in pain.

** Cats may have slower metabolism and may require less frequent administration.CRI = continuous rate infusion.

Excellent analgesia (full mu agonist).Can be infused intravenously

Excellent analgesia (full mu agonist).Moderate duration of action.Antagonizes NMDA receptors

Excellent analgesia (full mu agonist)

Excellent analgesia (full mu agonist)

Good analgesia (full mu agonist)

Excellent analgesia (full mu agonist).Short duration of action (15–20minutes). Suitable for infusion

Excellent analgesia (full mu agonist).Short duration of action (3 minutes).Suitable for infusion

Analgesia for moderate pain.Capsules and syrup available for oraladministration

Long duration of action (6–8 hours).May provide more analgesia thanmorphine in cats

Good sedative

0.1–0.4 mg/kg IV/IM*q2–6h** CRI: 0.05–0.1mg/kg/hour

0.1–0.4 mg/kg IV/IM*q2–6h**

0.05–0.2 mg/kg IV/IM

0.05–0.2 mg/kg IV/IM

2–5 mg/kg IM/SCq1–2h**

CRI: 3–24 µg/kg/hour;transdermal patches:2–5 µg/kg/hour

CRI: 3–24 µg/kg//hour

1–2 mg/kg PO/IM/IVq6–12h

dog: 0.006–0.01 mg/kgIV/IM/SC* q6–8h;cat: 0.005–0.01 mg/kgIV/IM q4–8h.

0.05–0.4 mg/kg IV/IM*

Nausea and vomiting may occur, but aremore likely if given to a pain-free animal.Histamine release is reported followingrapid IV injection

Pharmacokinetics in small animals unclear.May accumulate with repeated dosing

Bradycardia, respiratory depression,sedation occur at conservative doses

Hyperthermia associated with >0.1 mg/kg.Vomiting (especially with SC injection)

Potent releaser of histamine when givenIV. Pain on IM injection. Large volume.Short duration of action (1–2 hours)

High doses cause respiratory depressionand bradycardia

Short duration of action (3 minutes).Higher doses cause respiratory depressionand bradycardia

May cause nausea, vomiting, dizziness.Increases risk of seizures in susceptiblepatients. Use cautiously with head injuries

Analgesia for moderate pain (partial muagonist). Prolonged onset of action (30–60minutes)

Analgesia for mild pain (kappa agonist).Short duration of action (1–2 hours).mu receptor antagonist

with opioid-induced bradycardia is not common innormovolaemic patients with normal myocardialfunction. Often, the arterial BP remains stable orimproves as the increased time during diastole associatedwith the slight reduction in heart rate allows forimproved ventricular filling and an increased strokevolume. Conservative doses of opioids are unlikely tocause significant respiratory depression in normal dogsand cats, but in those with increased ICP the effects maybe more marked. Care should be taken and therefore theadequacy of ventilation should be closely monitored.Opioids are also reported to cause pupillary constrictionin dogs and pupillary dilation in cats (423), which has thepotential to interfere with neurological assessment. Inconscious animals these side-effects do not appear to be aproblem at the low doses used clinically. However, inanimals with CNS depression, these side-effects can beexacerbated.

Animals in severe pain, without pre-emptive analgesia (e.g. trauma)The use of short-acting reversible opioids, such asfentanyl or remifentanil, is preferred in patients in severepain. These drugs have a relatively fast onset and shortduration of action, giving them a pharmacokinetic profilesuitable for infusion. The infusion rate can thereforebe titrated to achieve the desired clinical effect. A balance

between adequate analgesia and minimal CNS, cardio-vascular and respiratory depression (and increase inPaCO2) must be achieved. Patients with high ICP maybe extremely sensitive to the sedative, cardiovascular andrespiratory depressant effects of opioids, so great careshould be taken and conservative doses should be admin-istered in the first instance. The authors have observedmarkedly reduced mentation using low infusion rates offentanyl. It is recommended that infusions of fentanylare started as low as 1 µg/kg/hour in animals with headtrauma and increased gradually to achieve the desiredlevel of pain management without causing further dete-rioration in mentation. When analgesia cannot beachieved without respiratory depression, the applicationof IPPV (manual or mechanical) will be required tomaintain normocapnia.

Animals with moderate to severe pain (e.g. postoperative period), having received pre- and intraoperative analgesiaIntermittent dosing of full mu receptor agonists (e.g.methadone, 0.1–0.4 mg/kg IM) may be adequate foranimals with severe to moderate pain. However, painmanagement can only be achieved by maintaining astable therapeutic plasma concentration of drug. This inturn ensures a stable, effective (e.g. brain or peripheralnociceptor) concentration of drug. To achieve a stableplasma concentration of opioid, an infusion that can beadjusted according to clinical effect is best. Intermittent‘bolus’ dosing will cause periods of relative overdose andperiods of relative underdose. Morphine and otheropioids that may induce emesis should not be used ifthere is any contraindication to vomiting (e.g. raisedICP). The use of tramadol for perioperative analgesia iscurrently popular, but there are only a few reports in theliterature documenting its use and efficacy in dogs.While it may be appropriate for animals in moderate tosevere pain, it is the authors’ opinion that it should bereserved for use as an adjunct to an analgesic protocol. Areported side-effect of tramadol in humans is seizures,and while this seems to be a risk for veterinary patients aswell, it is unknown how significant a problem this maybe. If the patient is receiving other medication that affectsthe reuptake of serotonin, drug interactions should betaken into account. In such cases a low dose of tramadolor an alternative analgesic drug should be used.

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! 423 Pupillary dilation in a cat after premedication with an opioid.

Animals with mild painMild pain can be managed with drugs such as buprenor-phine (0.01–0.02 mg/kg IM q4–6h) or pethidine (2–5mg/kg IM q1–2h). The appropriate interval betweendrug administrations will depend on the anticipatedduration of action of an individual drug. It is alwaysbetter to aim for a continuum of pain control, so regulardosing is important. To achieve a continuum, subsequentdoses of drug should be administered before the plasmaconcentration of the drug has decreased. Pethidine is afull mu agonist, but it does not produce analgesia compa-rable to morphine, methadone or other full mu agonists.It is often associated with an increase in heart rate as it hasan atropine-like structure. Pethidine should only begiven intramuscularly as the potential for histaminerelease following intravenous injection is high. Further-more, pain associated with intramuscular injection andthe frequent dosing required for continuous analgesiamake pethidine a less desirable option for pain manage-ment compared with other opioids.

Other agentsA summary of other agents available for use in animalswith neurological disease is presented in Table 110.NSAIDs are also useful, but if any contraindication isidentified (e.g. circulatory shock, coagulopathies, gastricmucosal bleeding, corticosteroid administration, renaldisease), they should be avoided. Ketamine shouldbe avoided in patients with intracranial disease andassociated increased ICP, as they may be exacerbated byketamine. Alpha-2 adrenoceptor agonists should be usedwith extreme caution, as their vasoconstrictive effectsmay further compromise CBF. Corticosteroid adminis-tration may contribute to pain management in certaindisease processes (e.g. meningitis or neoplasia associatedwith marked peritumoural oedema) through their anti-inflammatory action. However, corticosteroids maypotentiate neuronal ischaemia in a hypoxic environment(see Chapter 20).

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Table 110 Non-opioids used as part of pain management in animals with spinal disease

AGENT ADVANTAGES DISADVANTAGES DOSE REGIMEN

Benzodiazepines:diazepam,midazolam

Phenothiazine tranquillizers:acepromazine

Alpha-2 agonists:medetomidine,dexmedetomidine

NMDA antagonists:ketamine,amantadine

Muscle relaxation

Anxiolysis, sedation

Sedation, muscle relaxation,analgesia. Dexmedetomidine is associated with fewercardiovascular side-effectsthan medetomidine

Analgesia. May be useful to treatneuropathic pain. Interferes withcentral sensitization. Reversetolerance associated withprolonged opioid administration

Diazepam: 0.1–0.2 mg/kgIV/PO. Midazolam:0.1–0.4 mg/kg IV/IM

0.01–0.05 mg/kg IV/IM

Medetomidine: bolus,1–2 µg/kg IV up to 3–5 µg/kgIM; CRI, 0.5–3 µg/kg/hour.Dexmedetomidine: Bolus,1 µg/kg IV; CRI, 0.5–1µg/kg/hour

Ketamine: CRI,5–10 µg/kg/minute (can beused with morphine orlidocaine CRI). Amantadine:3–5 mg/kg PO q24h

Disinhibition in healthy animals.Respiratory depression in animals withunderlying respiratory disease/insufficiency

Hypotension; avoid in hypovolaemia.Contraindicated in carbamate andorganophosphate poisoning

Adverse cardiovascular effects: avoid inanimals with heart disease, hypo-volaemia. Hyperglycaemia: avoid indiabetics and head trauma. Highincidence of vomiting in cats

Dysphoria associated with accumulationof norketamine with prolonged infusion,therefore requires dose reduction withtime. Arrhythmogenic: avoid in chesttrauma. Increased skeletal muscle tonemay potentiate pain due to musclespasm. Pain on IM/SC injection. Cerebellardysfunction reported anecdotally in somebreeds of cat (Continued)

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Table 110 Non-opioids used as part of pain management in animals with spinal disease (continued)

AGENT ADVANTAGES DISADVANTAGES DOSE REGIMEN

Tricyclic antidepressants:amitriptyline

Lidocaine

Gabapentin

May be useful in the treatment ofneuropathic pain. Blocks nor-adrenaline and serotonin reuptakein the brain, increasing the effectof these neurotransmitters

Analgesia. May be useful inneuropathic pain

Supplementary analgesia forneuropathic pain

1–2 mg/kg PO q12h

Initial bolus of 2 mg/kgfollowed by 20–50µg/kg/minute

Titrate dose from 2 mg/kg upto 10–20 mg/kg PO q8–12h

Vomiting and diarrhoea, excitability,arrhythmias. Consider drug interactions ifusing anaesthetics or antiepileptics.Enhanced sedation if used with othersedating drugs

Sedation may interfere with mobility.Myocardial depression can cause hypo-tension in unstable patients. Vomitingreported. DO NOT USE IN CATS

Sedation and ataxia

SPINAL DISEASE

Considerations• Neuronal function. Aiming to preserve neuronal

function by maintaining perfusion and oxygenationis vital. Agents that cause excessive depression ofcardiovascular and pulmonary functions should beavoided. Arterial BP and adequacy of ventilation(using a capnograph) should be monitored closely.

• Pain. Pain associated with spinal disease (424) islikely to be severe, necessitating the use of potentanalgesic drug combinations by continuousinfusion.

• Anxiolysis. Anxiety in weak or paralysed animalsmay decrease the pain threshold. The judiciousadministration of anxiolytics is a useful part of painmanagement in haemodynamically stable animals.

• Muscle relaxation. The administration of musclerelaxants is useful in reducing pain associated withmuscle spasm. (Note: Do not use in animals withunstable fractures.)

• Neuropathic pain. When present, neuropathicpain is often resistant to opioid analgesia andrequires a multimodal analgesic regime.

• Multimodal analgesia. A combination of analgesicagents can be administered concurrently tooptimize pain management and minimize thefrequency and severity of side-effects associatedwith individual agents.

Drug selectionOpioidsDue to the severity of pain in most animals with spinaldisease, opioid analgesics are often the best choice. Theadvantages and disadvantages of commonly used opioidsand appropriate dose rates are described in Table109.

Animals in severe pain (e.g. spinal trauma)As previously described for animals with intracranialdisease (see above), the use of short-acting reversibleopioids, such as fentanyl or remifentanil, is preferred inanimals with severe pain (e.g. trauma victims with multi-ple organ damage and orthopaedic injury).

! 424 Animals with spinal disease, such as the one in thispicture, will be in pain and require administration ofanalgesic agents.

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The transdermal delivery of drug from a patchapplied to the skin (e.g. fentanyl patches, 425) mayprovide a useful adjunct to perioperative analgesia. It maytake up to 24 hours for therapeutic plasma concentra-tions to be achieved, so analgesia will be required untilthis time. The delay is shorter in cats than in dogs.Because there is also marked individual variation inabsorption and, therefore, plasma concentrationsachieved, fentanyl patches should not be relied on as the

Stable animals requiring intensive pain control During the immediate post-trauma or post-surgicalperiod, the continuous infusion of opioids (e.g. fentanylor morphine) is more likely to prevent breakthroughpain. Opioid infusions can be combined with otheragents to achieve multimodal pain management (e.g. anopioid in combination with ketamine and/or lidocaine).Infusion rates for each of the individual drugs areprovided in Tables 109 and 110.

e

a b

c

! 425 Steps for placement of a fentanyl patch. (a) Clipthe skin prior to placement of the patch. (b) Wipe theskin with a dry swab only. (c) Wear gloves whenpositioning the patch. In this case two patches are beingused (25 µg/hour and 50 µg/hour). (d) Ensure evenadherence to the skin with gentle digital pressure. (e) Cover the patches with a light adhesive dressing andlabel with the name of the drug and the time and date of application.

d

sole method of providing analgesia. Buprenorphinepatches are also available and should be used with thesame caveats as fentanyl patches. Patches should not becut in half. If a lower dose is required, then creating abarrier between the patch and the skin is most appropri-ate. It is best to place the patch on a clipped area of skinout of reach of the patient. The lateral thorax, dorsum orneck may be appropriate.

Stable animals requiring less intensive pain controlWhen less intensive management of the animal isrequired, intermittent administration of full mu opioidssuch as methadone or morphine can be used. Althoughvomiting is less likely in animals in pain, the use of mor-phine is generally avoided in animals with cervical injurywhere violent movements associated with vomiting cancause further injury to an unstable spinal lesion. In addition, recumbent animals that vomit may not be ableto clear vomitus from the pharynx and mouth, predispos-ing to airway obstruction and aspiration.

Other agentsA variety of other agents can be used in conjunction withopioids to improve pain management. A summary ofthese agents can be found in Tables 110 and 111.

Non-steroidal anti-inflammatory drugsNSAIDs may be used to decrease inflammatory pain andthey are potent analgesics in their own right. The cyclo-oxygenase inhibitors carprofen, meloxicam and meclo-fenamic acid are registered for perioperative use (Table111). The lipoxygenase and cyclo-oxygenase inhibitortepoxalin was available to the veterinary market, but ithas been associated with an increased incidence ofadverse side-effects.

Concurrent administration of NSAIDs and cortico-steroids is contraindicated due to increased risk of gastro-intestinal ulceration and haemorrhage, therefore the useof NSAIDs is best delayed until it has been decidedwhether the patient will benefit from corticosteroidtherapy. For animals receiving either steroids orNSAIDs, concurrent administration of gastrointestinalprotectants may help reduce the incidence of gastro-intestinal ulceration.

Muscle relaxantsBenzodiazepines (diazepam or midazolam, 0.25–0.5mg/kg PO q6–8h) may provide a useful adjunct to painmanagement in patients with stable spinal injury by alle-viating muscle spasm, which is commonly observed inanimals with spinal disease. In animals with unstablespinal lesions (e.g. fractures), skeletal muscle relaxationmay be detrimental as it reduces the splinting effects ofthe epaxial muscle.

Alpha-2 agonists, such as medetomidine, can also beused to provide muscle relaxation. In addition, theseagents are analgesic. Because of sedative and cardio-vascular side-effects, these agents are generally limited toanimals that do not have cardiovascular pathology. Theauthors have found that infusing medetomidine at1–3.5 µg/kg/hour is useful in healthy dogs that have painor anxiety that is unresponsive to other drugs. As withbenzodiazepines, these agents should be avoided inanimals with unstable spinal fractures.

AnxiolyticsAcepromazine is an extremely useful agent for anxiousanimals with spinal disease. Due to its hypotensiveeffects, the use of this agent should be limited to normo-volaemic and normotensive animals. The side-effects are dose dependent; the authors use 0.01–0.05 mg/kg to a maximum of 1 mg/kg. Acepromazine is also moreeffective if combined with an opioid (e.g. 0.03 mg/kg acepromazine with 0.3 mg/kg morphine for sedation).Trazodone can also be used for this function (see p. 545).

N-methyl-D-aspartate antagonistsKetamine is becoming increasingly popular as part of amultimodal analgesic protocol in small animals. Keta-mine interferes with the process of CNS sensitization(wind-up), which may manifest as hyperalgesia (exagger-ated pain response to a painful stimulus) or allodynia(pain response to a non-painful stimulus) from peripheraland central sensitization. It plays an extremely importantrole in the management of animals with chronic pain,animals with direct nerve trauma, amputees and traumapatients. Care is required when using this agent intrauma patients where the arrhythmogenic effects of ketamine may exacerbate myocardial contusions or

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DRUG SIDE-EFFECTS DOSE RATE: DOGS DOSE RATE: CATS

Carprofen

Meloxicam

Meclofenamic acid

ischaemia and associated arrhythmias. At higher dosesthe cardiovascular effects of ketamine can become prob-lematic (increased heart rate and BP). The authors use2–10 µg/kg/minute by infusion for analgesia (higher endof dose rate if intraoperatively and lower end if con-scious). A ‘bolus’ dose of ketamine may be incorporatedinto a premedication for cats (5–10 mg/kg) and very dif-ficult dogs (1–2 mg/kg). Dogs are more prone to the dis-sociative effects of ketamine, so lower doses should beused in this species. As part of an induction combination,ketamine can be given at 5 mg/kg with a benzodiazepine(e.g. diazepam or midazolam, 0.25–0.5 mg/kg).

Methadone may also act as an antagonist at theNMDA receptor and this is thought to be especiallybeneficial in the treatment of neuropathic pain that mayotherwise be resistant to typical opioids.

Lidocaine The effectiveness of this agent in spinal pain has not beendetermined. It should, however, be considered if pain isunresponsive to other agents. It can be administeredeither alone or in combination with morphine and/orketamine. Infusion of each drug is adjusted to optimizeanalgesia but minimize sedation. Lidocaine can depresscardiovascular function and contribute to hypotension,therefore it is essential that animals are normovolaemicand that cardiovascular function is monitored duringadministration. It should also be used cautiously in cats

and at lower doses than in dogs, as the former species ismore sensitive to the neuroexcitatory effects of lidocaine.

Lidocaine patches are also available and may be usefulfor topical analgesia prior to attempting vascular accessor for the management of incisional pain. The onset ofaction is relatively rapid. (The area should be clipped andthe patch secured in position to avoid inadvertentingestion by the patient. Care should also be taken toavoid heating the area, as this may accelerate absorptionand increase the potential for side-effects.)

TramadolTramadol is an agent with weak mu opioid agonist andnon-opioid analgesic properties. The non-opioid effectsare associated with increased noradrenaline (norepine-phrine) and 5-hydroxytryptamine (serotonin) at centralneuronal synapses, which reduces the excitability ofspinal nociceptive activity, partly via alpha-2 adrenergicactivity. The activities of the opioid and non-opioidmechanisms are synergistic, resulting in greater analge-sia than that expected for each component acting separately. The efficacy of tramadol postoperatively inhumans appears to be similar to that of µ opioid agonists.It can be administered parenterally and enterally. Com-prehensive clinical studies in animals are currentlylacking. Tramadol has a wide therapeutic margin andwhile most dosing is based on anecdotal reports it iscommon to use 1 mg/kg q12h or q8h.

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Table 111 Non-steroidal anti-inflammatory drugs

Minimal. Vomiting

Minimal. Diarrhoea

Vomiting and diarrhoea

2 mg/kg PO, SC or IV q12h or4 mg/kg q24h

0.2 mg/kg PO, SC or IV q24hthen 0.1 mg/kg q24hthereafter

1–2 mg/kg PO q24h

2 mg/kg SC once only

0.1–0.2 mg/kg PO or SConce only. 0.1 mg/kg q24hfor 3 days

Not used

NEUROPATHIC PAIN

Neuropathic pain (426) is classically less responsive toopioids and difficult to manage. It may occur in patientswith lumbosacral disease, neuropathy, nerve root traumaand a number of other conditions. Other agents that maybe useful in animals suffering neuropathic pain includeketamine, amantadine, medetomidine, lidocaine, tra-madol, gabapentin and tricyclic antidepressants. Asummary of these agents and doses rates are found inTable 110.

Gabapentin’s mode of action in the treatment ofneuropathic pain is thought to be by prevention of therelease of glutamate in the dorsal horn via interactionwith the alpha-2/delta subunit of the voltage-gatedcalcium channels. While gabapentin has been used safelyin dogs, only anecdotal reports of its efficacy have beenpublished.

NEUROMUSCULAR DISEASE

Considerations • Severity of pain. The type of NM disease will

influence the severity of pain and the choice ofanalgesic agents. Some conditions may not bepainful, so careful pain assessment is essential.

• Ventilation. Animals with NM disease frequentlyhave impaired ventilation. This may be exacerbatedby drugs that depress spontaneous ventilation (e.g. opioids).

• Vomiting. Animals with NM disease may not beable to protect their airway. In addition, vomitingmay trigger laryngeal spasm in animals withtetanus. Agents that predispose to vomiting (e.g.morphine) should be avoided.

• Sedation. The use of analgesic agents with sedativeproperties may exacerbate recumbency andimmobility in animals with NM weakness. Incontrast, sedation can be useful in animals that arehyperaesthetic (e.g. polyradiculoneuritis). (Note:Acepromazine is contraindicated in methiocarb andorganophosphate poisoning.)

Drug selectionAny of the drugs used for management of spinal pain canbe used for management of animals with painful NMdisease. The choice will depend on the stability of theanimal and the severity of the pain.

Regional and local anaesthesia in animals withneurological diseaseWhile pain associated with intracranial disease and generalized NM disease is not amenable to regionalanaesthesia, this modality may be useful for managingpain associated with trauma to other regions of the body.Regional anaesthesia may also be used in certain spinaldiseases. Regional and local anaesthesia provide the ulti-mate in analgesia if the innervation of an area can be iso-lated and completely desensitized.

In patients with chest wall trauma, intrapleural orintercostal nerve blocks are effective as an adjunct to ananalgesic regime. A maximum dose of 2 mg/kg of bupi-vacaine should be administered every 6 hours. Forintrapleural analgesia this dose may be diluted to increasethe volume or combined with NaHCO3 to minimize thediscomfort associated with the low pH of the solution.For intercostal nerve blocks, two intercostal spaces eitherside of the lesion or surgical wound should be blocked(five spaces in total). The intercostal nerves cross-inner-vate, so it is essential to block at least five spaces. Thenerve runs caudal to the rib. Epidural administration ofanalgesic drugs will provide additional analgesia inanimals with concurrent pelvic and abdominal trauma(see Further reading). Epidurals have also been used toprovide analgesia in animals with spinal fractures,although the use of local anaesthetic by this route, andconsequent motor (and sensory) blockade, should gener-ally be avoided, as motor function is an essential part ofneurological assessment. Local anaesthetic drug prepara-tions may be diluted to minimize motor blockade (e.g.0.25% bupivacaine can be diluted to 0.125%) or ropiva-caine may be used. Epidural administration of localanaesthetics should be avoided in haemodynamicallyunstable animals as sympathetic nerve blockade will

SP E C I F I C MA N A G E M E N T IS S U E S568

exacerbate hypotension. In these cases, epidural admin-istration of morphine alone (0.1 mg/kg diluted in sterilesaline to the desired volume) can still provide usefulregional analgesia. The volume of injection is a factorthat determines the degree of cranial spread of the drugand, therefore, the clinical effect. Opioids are lipophilic,so will spread cranially, but increasing the volume ofinjection will facilitate this. As a rule of thumb, 1 ml of diluted drug per 4.5 kg to a maximum of 6 ml isappropriate.

For infiltration of surgical or traumatic wounds, acombination of lidocaine with NaHCO3 (1 mmol/ml) ina ratio of 9:1 will help reduce irritation on injection.Lidocaine 2% can be combined with 0.5% bupivacainein a 1:1 ratio to provide a more rapid onset and longerduration of action.

Prior to placement of an intravenous or intra-arterialcatheter, a eutectic mixture of local anaesthetic (EMLA)cream can be applied to the site at least 30 minutesbeforehand. EMLA will facilitate painless placement of acatheter and is especially useful for arterial catheteriza-tion in conscious patients. Lidocaine patches are alsouseful in this situation. For nasal cannula or urinarycatheter placement, topical application of a local anaes-thetic, such as xylocaine or lidocaine spray, is helpful ifadministered a few minutes beforehand.

Non-specific aspects of pain management inanimals with neurological disease• Bedding should be well padded, able to wick

moisture away from the patient, easy to clean andeasy to replace as often as required.

• A comfortable ambient temperature will helpprevent hypothermia or panting.

• A urinary catheter may be necessary to preventurinary retention, especially if an epidural has beenadministered. Placement of a urinary catheter alsofacilitates the measurement of urine output, whichis useful to ensure adequate fluid therapy and renalfunction (see Chapters 31 and 2, respectively).Placement of the urinary catheter must beperformed aseptically.

• Any wounds should have regular dressing changes.If dressings are wet or odorous, they should bechanged immediately.

• Patients that require exercise should be managedcarefully by skilled personnel with a goodunderstanding of the individual patient’s history andtreatments.

• ICUs can be busy places and animals may find itdifficult to sleep quietly and rest. It is important toprovide quiet times with the lights out, so sleepdeprivation does not contribute to morbidity.

AN A L G E S I A F O R PAT I E N T S W I T H NE U R O L O G I C A L DI S E A S E 569

" 426 Neuroanatomy and neurotransmitters involved in pain pathways. Descending pathways modulate theincoming pain sensation, which stimulates glutamaterelease.

Spinothalamic tract

Descending serotonin andnorepinephrine tracts

Interneuron containingenkephalin

Opioid receptors

Dorsal root ganglion

Peripheral process