Analgesia for Anesthetized Patients · analgesic drugs and techniques. Surgical trauma and inﬂam- ... NMDA antagonists (ketamine) can be used throughout the perioperative period

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TOPICAL REVIEW

Analgesia for Anesthetized Patients
Kip A. Lemke, DVM, MSc, Dipl. ACVA, and Catherine M. Creighton, DVM
Many perioperative pain management protocols for cats and dogs are overly complex, some are ineffective, andstill others expose patients to unnecessary risk. The purpose of this article is to provide clinicians with a basicunderstanding of the pathophysiology of perioperative pain and a working knowledge of the principles ofeffective therapy. First, the concept of multimodal analgesic therapy is discussed. Next, the pathophysiology ofperioperative pain and the clinical pharmacology of the major classes of analgesic drugs are reviewed. And last,a simplified approach to managing perioperative pain in cats and dogs is presented.© 2010 Elsevier Inc. All rights reserved.

Keywords: analgesia, anesthesia, pain, dogs, cats

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ultimodal analgesic therapy has gained widespreadacceptance in the management of perioperative pain

n both dogs and cats.1-3 In recent years, a clearer understand-ng of the pathophysiology of perioperative pain has pro-ided the conceptual framework for a more rational use ofnalgesic drugs and techniques. Surgical trauma and inflam-ation produce sensitization of the peripheral nervous sys-

em, and the subsequent barrage of nociceptive input pro-uces sensitization of neurons in the dorsal horn of the spinalord. Blockade or attenuation of ascending nociceptive path-ays or activation of descending antinociceptive pathwaysy different classes of analgesic drugs usually provides betternalgesia with fewer side effects than unimodal therapy withsingle class of analgesic drugs. Because peripheral and cen-

ral neural blockade with local anesthetics are the only anal-esic techniques that can produce complete blockade of pe-ipheral nociceptive input, these techniques are the mostffective way to attenuate sensitization of the central nervousystem and the development of pathological pain.4,5 Clini-ians should also remember that atraumatic surgical tech-ique is always the most effective method to prevent periph-ral and central sensitization and the development of painostoperatively.The neuroendocrine or stress response to surgical trauma

ompromises hemostatic, metabolic, and immunologicalunction, which increases perioperative morbidity and mor-ality.6,7 Early studies in human infants undergoing cardiacurgery demonstrated that the neuroendocrine response wasignificantly reduced by intraoperative administration ofalothane and fentanyl when compared with administrationf halothane alone.8 In a subsequent clinical study, the mor-

rom the Atlantic Veterinary College, University of Prince Edward Island,harlottetown, Prince Edward Island, Canada.ddress reprint requests to: Kip A. Lemke, DVM, MSc, Dipl. ACVA, At-

antic Veterinary College, University of Prince Edward Island, 550 Univer-ity Ave, Charlottetown, PE, Canada, C1A 4P3. E-mail: [email protected].

2010 Elsevier Inc. All rights reserved.527-3369/06/0604-0171\.00/0

coi:10.1053/j.tcam.2009.12.003

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ality rate dropped from 25% to 0% in a similar group ofnfants when sufentanil was given intraoperatively and addi-ional opioids were given postoperatively.9 Perioperative usef neural blockade, in particular central neural blockade,lso attenuates the neuroendocrine response and dramati-ally reduces mortality and the incidence of major complica-ions in human patients undergoing a wide variety of surgicalrocedures.10 In this analysis of 141 clinical trials, patientsith central neural blockade had a 30% reduction in mor-

ality and a 40% to 60% reduction in major complicationsthromboembolism, hemorrhage, respiratory depression,neumonia) when compared with those without central neu-al blockade. Intraoperative use of multimodal analgesicherapy also reduces inhalation anesthetic requirements andutonomic responses to noxious surgical stimuli. These re-uctions improve cardiopulmonary function intraopera-ively and facilitate a rapid, smooth recovery from anesthesiaostoperatively.Alpha-2 agonists, opioids, N-methyl-D-aspartate (NMDA) an-

agonists, cyclooxygenase (COX) inhibitors, and neurallockade with local anesthetics are often used perioperativelys part of a multimodal strategy to manage pain.1-3 Theselasses of analgesic drugs can be incorporated easily intonesthetic and pain management plans for cats and dogsndergoing most types of surgical procedures. Alpha-2 ago-ists can be used preoperatively and postoperatively to pro-ide sedation and analgesia. Opioids can be used throughouthe perioperative period to reduce anesthetic requirementsnd to manage pain. NMDA antagonists (ketamine) can besed throughout the perioperative period to manage pain inatients with significant central sensitization and pathologi-al pain. COX inhibitors can be used postoperatively to re-uce opioid requirements and provide more effective analge-ia with fewer side effects. Peripheral and central neurallockade with local anesthetics can be used intraoperativelyo reduce anesthetic requirements and attenuate the develop-ent of central sensitization. Neural blockade can also besed postoperatively to manage pain in selected patients. A
lear understanding of the pathophysiology of pain and the
mailto:[email protected]

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Volume 25, Number 2, May 2010 71

linical pharmacology of the major classes of analgesic drugss required to use multimodal analgesic therapy safely andffectively in anesthetized patients.

athophysiology

he terminology used to describe the pathophysiology ofain is confusing, so defining a few terms relevant to theanagement of perioperative pain is important. Nociception

s defined as the neural response to a noxious stimulus. Spe-ifically, nociception includes signal transduction and nerveonduction in the peripheral nervous system, and synapticransmission, projection, and modulation of nociceptive in-ut in the central nervous system (Fig 1). Pain, on the otherand, is a complex sensation that requires integration ofociceptive and other sensory input at the cortical level. Pain

s defined as an unpleasant sensory or emotional experiencehat is associated with actual or potential tissue damage. Painan be further classified anatomically as somatic or visceralain, or temporally as acute or chronic pain. Recent neuro-natomical and functional imaging studies suggest that pains one component of an interoceptive system that is primarilyesponsible for maintaining internal homeostasis, and thathere are significant differences among species in the neuralomponents that make up this system.11

Most perioperative pain is due to surgical trauma and in-ammation. Some patients may have preexisting tissuerauma and inflammation, and others may have pain associ-ted with nerve injury. Although a small number of surgicalatients may experience both inflammatory and neuropathicain, inflammatory pain is by far the most common type oferioperative pain. The mechanisms of inflammatory painre reasonably well understood and form the basis for ratio-al, effective, multimodal analgesic therapy. Neuropathicain is relatively uncommon in surgical patients, and theechanisms of neuropathic pain are similar to those of in-ammatory pain.12,13 Consequently, clinicians should focusn understanding the pathophysiology and management of

nflammatory pain.

ociceptive Pathways

Ascending nociceptive pathways begin in the peripheralissues and project to the dorsal horn of the spinal cord, braintem, thalamus, and cerebral cortex (Fig 1). The nociceptiveathways are composed of 3 general types of neurons. Therst-order neurons are primary afferent neurons, and theseeurons are responsible for transduction of noxious stimulind conduction of electrical signals to the dorsal horn of thepinal cord. The second-order neurons are projection neu-ons, and these neurons receive input from the primary affer-nt neurons and project to the medulla, pons, midbrain, thal-mus, and hypothalamus. Third-order supraspinal neuronsntegrate input from spinal neurons and project to subcorti-al and cortical areas where pain is finally perceived. Su-
raspinal processing of afferent nociceptive input is also p
igure 1. Overview of nociceptive and antinociceptive path-ays. Surgical trauma activates mechanical, chemical, and

hermal nociceptors. Action potentials are conducted to theorsal horn of the spinal cord by primary afferent nervebers. Second-order projection neurons encode and relay sig-als to the brainstem and thalamus. Third-order neurons inhe thalamus project to the limbic system and somatosensoryortex where pain is perceived. Descending antinociceptiveathways modulate nociceptive processing at the level of thehalamus, brainstem, and spinal cord. Different classes ofnalgesic drugs act at different sites in the nociceptive andntinociceptive pathways. Multimodal analgesic therapy in-ibits processing of nociceptive input at 2 or more sites. PAG,
eriaqueductal gray; RVM, rostroventral medulla.

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72 Topics in Companion Animal Medicine

losely integrated with regulation of the autonomic nervousystem.

Primary afferent neurons are bipolar neurons. The cellodies of these bipolar neurons are located in the trigeminalnd dorsal root ganglia, and their axons project peripherallyo somatic and visceral tissues and centrally to the dorsalorn of the spinal cord. Some primary afferent neurons re-pond to noxious or high-threshold stimuli, and others re-pond to non-noxious or low-threshold stimuli (touch). Af-erent nociceptive neurons have free nerve endings thathange or “transduce” noxious mechanical, thermal, orhemical stimuli into electrical signals. Somatic tissues have aigher density of nociceptive nerve fibers and smaller recep-ive fields, whereas visceral tissues have a lower density ofociceptive nerve fibers and larger receptive fields. These an-tomical differences may account for some of the qualitativeifferences between somatic (discrete) and visceral (diffuse)ain.Primary afferent neurons are classified by axon diameter,

he presence or absence of myelination, and their response toechanical, thermal, and chemical stimuli. A� afferent neu-

ons have large, myelinated axons that conduct impulses at aelocity of greater than 30 m/sec. The free nerve endings ofhese fibers respond to non-noxious mechanical stimulitouch) but do not respond to noxious stimuli directly. A�ociceptive neurons have small, myelinated axons that con-uct impulses at a velocity of 3 to 30 m/sec. The free nervendings of these fibers contain membrane-bound receptorshat respond primarily to intense mechanical and thermaltimuli and are called mechanothermal nociceptors. C noci-eptive neurons have small, unmyelinated axons that con-uct nerve impulses at a velocity of less than 3 m/sec. The freeerve endings of these fibers contain membrane-bound recep-ors that respond to chemical as well as thermal and mechan-cal stimuli and are called polymodal nociceptors. Small, my-linated A� fibers carry the nociceptive input responsible forhe fast, sharp pain that occurs immediately after injury. Theociceptive input responsible for the prolonged dull pain thatccurs several seconds later is carried by small, unmyelinated

fibers. Silent nociceptive neurons are also present in so-atic tissues. The free nerve endings of these neurons only

espond to mechanical and thermal stimuli after they arectivated by chemical (inflammatory) mediators. This classi-cation scheme is derived from analysis of fibers that inner-ate the somatic tissues (skin). Visceral pain is qualitativelyifferent from somatic pain and is typically dull and poorly

ocalized. Visceral pain also lacks the fast and slow compo-ents that are characteristic of somatic pain.Transduction of mechanical, thermal, and chemical stim-

li by the free nerve endings of A� and C nociceptive fibers isediated by membrane-bound receptors.13-15 Most of these

eceptors are nonselective cation channels that are gatedy temperature, chemical ligands, or mechanical shearingorces. Activation of these channels increases inward conduc-ion of Na� and Ca�2 ions, which ultimately depolarizes theembrane and generates a burst of action potentials. The
echanisms of mechanical signal transduction are not well w
efined. Noxious mechanical stimuli may activate a mechan-cally gated ion channel directly, or shearing forces may re-ease adenosine triphosphate, which acts on purine receptorsP2X). Noxious chemical stimuli (H�) activate acid-sensingon channels and transient receptor potential vanilloidTRPV1) channels. Noxious heat also activates TRPV1 chan-els as well as related channels (TRPV2), and noxious coldctivates transient receptor potential menthol (TRPM8)hannels.Nociceptive afferent neurons synapse with second-order

eurons in the dorsal horn of the spinal cord. Projectioneurons and interneurons are the 2 major types of nocicep-ive neurons in the dorsal horn, and these neurons are orga-ized in layers or laminae. Neurons that mediate nociceptionre located in laminae I, II, and V. Projection neurons areocated in laminae I and V, and they have axons that crossidline and project to third-order supraspinal neurons. Pro-

ection neurons located in lamina I receive input directly from� and C nociceptive fibers and are classified as nociceptive-

pecific and polymodal nociceptive neurons, respectively.rojection neurons in lamina V receive input from both no-iceptive and non-nociceptive (A�) fibers and are classified aside, dynamic-range neurons. Interneurons are located in

amina II and also receive input from nociceptive and non-ociceptive (A�) fibers. Inhibitory and excitatory interneu-ons play a central role in gating and modulating nociceptivenput. Propriospinal neurons that project across several der-atomes are also present in the dorsal horn and are respon-

ible for segmental reflexes associated with nociception.Glutamate is the primary excitatory neurotransmitter in

he dorsal horn of the spinal cord. Nociceptive as well ason-nociceptive fibers co-release glutamate and neuropep-ides (substance P, neurokinin A, calcitonin gene–relatedeptide). With normal afferent input, glutamate bindso �-amino-3-hydroxy-5-methyl-4-isoxazolepropionoic acidAMPA) receptors located on the postsynaptic membrane ofrojection neurons. Neuropeptides bind to several types ofeceptors on the postsynaptic membrane. With intensive af-erent input, prolonged activation of AMPA and neuropep-ide receptors leads to progressive depolarization of theostsynaptic membrane and activation of additional types oflutamate receptors. Activation of a specific type of gluta-ate receptor, the NMDA receptor, plays a key role in theevelopment of central sensitization.The spinothalamic tract (STT) is the major ascending no-

iceptive pathway in carnivores and primates.11,16 Lamina, nociceptive (nociceptive-specific, polymodal nociceptive)eurons are somatotopically organized, modality-selectiveeurons with small receptive fields that convey discrete nox-ous mechanical, thermal, and chemical afferent input. Theseeurons project to the ventromedial nucleus of the lateralhalamus, which projects to the insular cortex and the sec-ndary somatosensory cortex. These neurons also project tohe mediodorsal nucleus of the medial thalamus, whichrojects to the anterior cingulate cortex. Like the dorsalorn, glutamate is an important excitatory neurotransmitter
ithin the thalamic nuclei. Lamina V, wide, dynamic-range

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eurons have large receptive fields, are not somatotopicallyrganized or modality selective, and are responsible for inte-ration of all afferent input to the dorsal horn. These neuronsroject to the motor thalamus (ventrodorsal and ventrolat-ral nuclei), which projects to the basal ganglia and the pri-ary somatosensory cortex. Axons from lamina I are con-

entrated in the lateral STT, and axons from lamina V areoncentrated in the ventral STT. The thalamus relays afferentnput from the STT and integrates this information with af-erent input from the autonomic nervous system. Projectionrom neurons in the lateral thalamus to neurons in the insularnd secondary somatosensory cortex appears to be responsi-le for the sensory-discriminative aspects of pain. Projectionrom neurons in the medial thalamus to neurons in the ante-ior cingulate cortex appears to be responsible for the moti-ational-affective aspects of pain. Projection from neurons inhe motor thalamus to neurons in the primary somatosensoryortex appears to be responsible for sensory and motor inte-ration. Direct connections between the lateral thalamus andhe dorsal margin of the insular cortex (interoceptive cortex)re more developed in primates than in carnivores.

ntinociceptive Pathways

Mammals also have descending antinociceptive pathwayshat modulate nociceptive input at spinal and supraspinalevels (Fig 1). The antinociceptive pathways begin at the su-raspinal level and project to neurons in the dorsal horn ofhe spinal cord. The periaqueductal gray matter (midbrain),ocus ceruleus (pons), and nucleus raphe magnus (medulla)re all important structures in the modulation of nociceptivenput. The periaqueductal gray matter receives direct inputrom the thalamus and the hypothalamus, and indirect inputrom the insular cortex and the anterior cingulate cortex.hese neurons in the periaqueductal gray matter send projec-

ions to neurons in the nucleus raphe magnus, which projecto the dorsal horn of the spinal cord. Neurons in the locuseruleus project directly to the dorsal horn, and they may alsoeceive input from the periaqueductal gray matter.

Endogenous opioids (endorphins, enkephalins, dynor-hins), serotonin, and norepinephrine are the primary neu-otransmitters in the descending antinociceptive pathways.xons that originate in the nucleus raphe magnus release

erotonin in the dorsal horn of the spinal cord and are calledserotonergic” neurons. Similarly, neurons that originate inhe locus ceruleus release norepinephrine in the dorsal hornnd are called “noradrenergic” neurons. Supraspinal releasef endogenous opioid peptides activates both types of neu-ons, whereas supraspinal release of release of �-aminobu-yric acid (GABA) inhibits both types of neurons. Supraspinalnhibition of descending antinociceptive pathways is medi-ted by GABAA receptors. At the supraspinal level, endoge-ous opioids not only activate descending antinociceptiveathways, but inhibit GABA-mediated inhibition of theseame pathways, which is called “disinhibition.”

Release of norepinephrine and serotonin in the dorsal horn
f the spinal cord, and subsequent release of enkephalins and
ABA by local interneurons, inhibit presynaptic calciumhannels that modulate neurotransmitter release. This inhi-ition, mediated by presynaptic noradrenergic (�2), opioid�), and GABAB receptors, limits release of glutamate andeuropeptides from primary afferent neurons, which inhibitsociceptive transmission. Release of norepinephrine, en-ephalins, and GABA in the dorsal horn hyperpolarizes pro-ection neurons, which also inhibits nociceptive trans-

ission. This inhibition is mediated by postsynapticoradrenergic (�2) and opioid (�) receptors that activateotassium channels, which leads to an outward flux ofotassium ions and hyperpolarization of the postsynapticembrane. This inhibition is also mediated by postsynap-

ic GABAA receptors that activate chloride channels,hich leads to an inward flux of chloride ions and hyper-olarization of the postsynaptic membrane. In summary,elease of norepinephrine, endogenous opioids, and GABAnhibits synaptic transmission between primary afferenteurons and projection neurons by inhibiting neurotrans-itter release and hyperpolarizing the postsynaptic mem-rane, which effectively shuts down the key synapse in theorsal horn.

eripheral and Central Sensitization

Neural plasticity is defined as the ability of the nervousystem to modify its function in response to different envi-onmental stimuli. Surgical trauma and inflammation pro-uce sensitization of the peripheral nervous system, and theubsequent barrage of nociceptive input produces sensitiza-ion of neurons in the dorsal horn of the spinal cord. Periph-ral and central sensitization of nociceptive pathways plays aentral role in the development of pathological pain.17 Pa-ients with no preexisting tissue trauma and inflammationxperience pain that is physiological or protective in natureTable 1). This type of inflammatory pain is well localized,roportionate to the peripheral stimulus, and subsides oncehe inflammatory process resolves. Patients with significantissue trauma and inflammation experience pain that isathological or debilitating in nature (Table 2). This type ofnflammatory pain is diffuse, disproportionate to the periph-ral stimulus, and continues beyond resolution of the inflam-atory process. A key concept that is often lost when trying

o understand the clinical relevance of neural plasticity is thatentral sensitization occurs secondary to surgical trauma,nflammation, and the development of peripheral sensitiza-

Table 1. Characteristics of Physiological Pain

● Protective● Discrete or well localized● No peripheral or central sensitization● Proportionate to the peripheral stimulus● Subsides once the inflammatory response resolves● Pain can be differentiated from touch
● Responds well to conventional analgesic therapy

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ion. Consequently, atraumatic surgical technique and neurallockade are far more effective than other types of analgesicherapy in limiting the development of pathological pain,lunting the stress response, preventing major complications,nd reducing mortality.18,19

Peripheral sensitization occurs as a direct consequence ofissue trauma and inflammation. Tissue trauma leads to theelease of inflammatory mediators from damaged cells (H�,�, prostaglandins), plasma (bradykinin), platelets (seroto-in), mast cells (histamine), and macrophages (cytokines).ome inflammatory mediators activate nociceptors directlybradykinin), whereas others sensitize nociceptors (prosta-landins). Activation of nociceptors also leads to antidromalr retrograde activation of nociceptive nerve fibers and re-

ease of substance P and other neuropeptides. Release ofhese neuropeptides leads to mast cell degranulation, vasodi-ation, edema, and further activation and sensitization ofociceptors. Peripheral sympathetic nerve terminals alsoontribute to activation and sensitization of nerve terminalsy releasing norepinephrine and prostaglandins. Ultimately,issue trauma and inflammation produce a “sensitizing soup”f chemical mediators that convert high-threshold nocicep-ors to low-threshold nociceptors. In other words, peripheralensitization is characterized by a reduction in the activationhreshold of peripheral nociceptors.

Central sensitization occurs as an indirect consequence ofissue trauma and inflammation and is contingent to a largeegree on the development of peripheral sensitization. Con-tant activation of sensitized peripheral nociceptors leads toustained release of glutamate and neuropeptides from affer-nt fibers. Constant activation of AMPA and neuropeptideeceptors on dorsal horn projection neurons leads to progres-ive cellular depolarization and activation of additional typesf glutamate receptors (NMDA, metabotropic). Normally,he channel of NMDA receptor complex is blocked by aagnesium plug. Progressive depolarization of the postsyn-

ptic membrane releases this plug, activates the receptoromplex, and increases inward conduction of Ca�2 ions. Thisnflux of calcium, along with activation of other types ofeceptors, leads to activation of phospholipases, polyphos-hoinosites, kinases, and other intracellular messengers.hese activity-dependent changes lead to an increase in the

Table 2. Characteristics of Pathological Pain

● Debilitating● Diffuse or poorly localized● Significant peripheral and central sensitization● Disproportionate or exaggerated response to the periph-

eral stimulus● Continues beyond resolution of the inflammatory re-

sponse● Pain cannot be differentiated from touch● Does not respond well to conventional analgesic therapy

xcitability of dorsal horn projection neurons. This initial p

hase of central sensitization is called short-term sensitiza-ion. If the inflammatory process continues for several days,ene regulatory proteins are activated, new types receptorsre expressed, and dorsal horn projection neurons becomeven more reactive to subsequent nociceptive input. Thishase of central sensitization is called long-term sensitiza-ion. Activation of NMDA receptors and the subsequent in-ux of Ca�2 also leads to the release of arachidonic acid,hich is converted to prostaglandins by COX. Prostaglan-ins act presynaptically and postsynaptically to facilitate theevelopment of central sensitization. Glial cells also appearo facilitate the development of central sensitization. Micro-lia and astrocytes normally play a supportive role in neuro-ransmission, but they are also activated by glutamate andeuropeptides released from primary afferent fibers. Acti-ated glial cells release adenosine triphosphate, glutamate,itric oxide, and cytokines, which facilitate release of neuro-ransmitters from afferent fibers and further sensitization ofrojection neurons.

linical Pharmacology

he primary goal of perioperative multimodal analgesic ther-py is to limit the development of peripheral and centralensitization, and prevent the development of pathologicalain. Effective analgesic therapy also blunts the neuroendo-rine response, reduces major complications, and improvesutcome. There are 5 major classes of analgesic drugs, andach class blocks or modulates nociceptive input at one orore sites of action (Fig 1). Alpha-2 agonists and opioids

lter the central perception of pain. Activation of supraspinalnd spinal alpha-2 receptors and opioid receptors also inhib-ts synaptic transmission in the dorsal horn of the spinal cord.issociative anesthetics (ketamine) block NMDA receptorsn projection neurons, which inhibit the development of cen-ral sensitization. Peripheral and central neural blockadeith local anesthetics also inhibits the development of central

ensitization. COX inhibitors reduce inflammation, whichimits the development of peripheral sensitization. COX in-ibitors also reduce the synthesis of prostaglandins in theorsal horn of the spinal cord, which limits the developmentf central sensitization.

elective Alpha-2 Agonists

Norepinephrine is the endogenous ligand for spinal andupraspinal alpha-2 adrenergic receptors. Medetomidine andexmedetomidine are the selective alpha-2 agonists currentlyvailable in North America. Medetomidine is supplied as aacemic mixture of 2 optical enantiomers. Dexmedetomidines the active enantiomer, whereas levomedetomidine has nopparent pharmacological activity. As a result, dexmedeto-idine is approximately twice as potent as medetomidine.he clinical effects of medetomidine and dexmedetomidinere comparable when equivalent sedative doses are adminis-ered to cats and dogs. Medetomidine has a rapid onset after
arenteral injection, and the drug has a duration of action of

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pproximately 1 hour in dogs. The alpha-2 to alpha-1 adren-rgic receptor selectively ratios for medetomidine and xyla-ine are 1620:1 and 160:1, respectively.20 Medetomidine andexmedetomidine are approved for use in dogs in Canadand the United States, and studies evaluating the use of theserugs in cats have been completed.21-24

Selective alpha-2 agonists induce reliable dose-dependentedation, analgesia, and muscle relaxation in cats andogs.25,26 The sedative and analgesic effects of selective al-ha-2 agonists are mediated by activation of alpha-2 adren-rgic receptors located in the pons (locus ceruleus) and theorsal horn of the spinal cord, respectively. In addition toroviding sedation and analgesia, preoperative administra-ion of medetomidine reduces the amount of intravenous andnhalation anesthetic required to induce and maintain anes-hesia.27-29 Perioperative administration of selective alpha-2gonists also blunts the neuroendocrine response and reducesatecholamine and cortisol levels.30,31 Blood pressure in-reases, and heart rate and cardiac output decrease after me-etomidine administration. Bradycardia and atrioventricularlockade are potential complications, and heart rate andhythm should be monitored closely. Medetomidine does notensitize the myocardium to catecholamines or facilitate de-elopment of ventricular arrhythmias in patients anes-hetized with isoflurane.32,33 Respiratory rate and minuteentilation are well maintained after administration ofedetomidine or dexmedetomidine in conscious and anes-

hetized dogs.34,35 Blood glucose and urine production in-rease significantly after administration of medetomidine.

Selective alpha-2 agonists are used perioperatively to se-ate and calm patients, provide muscle relaxation, and po-entiate the analgesic and anesthetic effects of other drugs.

edetomidine and dexmedetomidine are administered atelatively low doses, and the use of these drugs is usuallyimited to healthy, hemodynamically stable patients. Preop-ratively, selective alpha-2 agonists are often given in combi-ation with opioids. The preanesthetic intramuscular doseanges for medetomidine in healthy dogs and cats are 0.005o 0.01 mg/kg and 0.01 to 0.02 mg/kg, respectively. Ultra-ow doses of medetomidine can be given postoperatively torovide sedation. The postanesthetic intramuscular doseanges for medetomidine in healthy for healthy dogs and catsre 0.001 to 0.002 mg/kg and 0.002 to 0.004 mg/kg, respec-ively. Dexmedetomidine can be given at approximately halff the medetomidine dose. Atropine or glycopyrrolate can besed to manage bradycardia associated with administrationf low and ultra-low doses of selective alpha-2 agonists.

pioids

Endorphins, enkephalins, and dynorphins are the endoge-ous ligands for spinal and supraspinal opioid receptors.urrently, 3 major classes of opioid receptors have been

loned: OP1 (�), OP2 (�) and OP3 (�). OP1, OP2, and OP3eceptors modulate supraspinal and spinal analgesia, as wells sedation, bradycardia, respiratory depression, and gastro-
ntestinal motility. Receptor subtypes of each of these classes M
ave been identified, and expression of these subtypes variesmong tissues. There are also significant differences in thexpression of opioid receptors among species. Parenteral ad-inistration of opioids usually causes sedation in dogs,hereas administration of high doses of opioids can cause

xcitation and dysphoria in cats. Respiratory depression is aignificant side effect in human patients, but ventilation isetter maintained in cats and dogs. Butorphanol, morphine,ydromorphone, and fentanyl are the opioids used mostommonly in small animals. Buprenorphine and tramadolave also been used perioperatively to a limited extent.Opioid agonists are the safest and most effective class of

nalgesic drugs used for the management of perioperativeain in cats and dogs. Morphine, hydromorphone, and fen-anyl are the opioid agonists used most commonly in smallnimals. These analgesic drugs are agonists at all 3 types ofpioid receptors. Opioid agonists are equally efficacious inreating moderate to severe pain, but differ in potency anduration of action. Intraoperative administration of mor-hine, hydromorphone, or fentanyl reduces isoflurane re-uirements by 30% to 50% in cats and dogs.36-39 Significantespiratory depression can occur intraoperatively and post-peratively if the additive effects of opioid agonists and gen-ral anesthetics are not considered. Morphine and hydro-orphone are often administered as preanesthetics, and

omiting can occur with either drug. High doses of hydro-orphone (� 0.1 mg/kg) can also cause significant postop-

rative hyperthermia in cats.40-42 Morphine and hydromor-hone have an intermediate duration of action (2-4 hours)fter parenteral administration. The preanesthetic intramus-ular dose range for morphine in cats and dogs is 0.2 to 0.4g/kg. Hydromorphone is approximately 5 times more po-

ent than morphine, and the preanesthetic intramuscularose range for hydromorphone in cats and dogs is 0.05 to 0.1g/kg. Approximately half of the preanesthetic dose of mor-hine or hydromorphone can be given intraoperatively orostoperatively. Morphine can also be given epidurally aloner in combination with local anesthetics. The dose range forreoperative or postoperative epidural administration oforphine is 0.1-0.3 mg/kg. At this dose range, the onset time

s slow (1-2 h), but the duration of action in long (12-24 h).orphine can also be given postoperatively as an intrave-

ous constant-rate infusion at a dose range of 0.1 to 0.2g/kg/h. Morphine has a relatively long duration of action

nd the drug will accumulate over time. As a result, patientshould be monitored closely, and the infusion rate should beeduced as needed. Fentanyl can also be given intravenouslys a preanesthetic. The drug is approximately 100 times moreotent than morphine and has a relatively short duration ofction (0.5 hour). The preanesthetic intravenous dose rangeor fentanyl in cats and dogs is 0.001 to 0.005 mg/kg. Fent-nyl is less likely to accumulate over time, and the drug isften given intraoperatively to dogs as an intravenous con-tant rate infusion. The amount of inhalation anesthetic re-uired to maintain adequate anesthetic depth is reduced by0% to 50%, which improves cardiovascular function.
inute ventilation may decrease, and positive-pressure ven-

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ilation may be required to prevent significant hypoventila-ion (PaCO2 � 60 mm Hg). Intraoperatively, the dose rangeor fentanyl in dogs is 0.005 to 0.01 mg/kg/h. Fentanyl canlso be given postoperatively as an intravenous constant-ratenfusion at a dose range of 0.001 to 0.005 mg/kg/h. Objectivelinical data on the use of intraoperative and postoperativeentanyl infusions in cats are limited.

Fentanyl patches were designed to be applied to humankin. Even in healthy cats and dogs, systemic absorption ofentanyl from transdermal patches is erratic.43,44 In surgicalatients, altered body temperature, peripheral circulation,nd hydration can all compromise transdermal absorption ofentanyl. On the other hand, heating pads and forced-airarmers can dramatically increase fentanyl absorption intra-peratively and postoperatively. Consequently, preoperativend intraoperative use of fentanyl patches should be avoided.nce normal body temperature, peripheral circulation, andydration are restored, fentanyl patches can be used postop-ratively with reasonable efficacy. Onset time is very slow,nd there is a 12- to 24-hour lag before effective plasmaoncentrations are reached. If the patch stays properly ad-ered to on the patient, plasma fentanyl concentrations areaintained for 3 to 5 days. Transdermal fentanyl is dosed atrate of 0.003 to 0.005 mg/kg/h in cats and dogs.Opioid agonist-antagonists are also used to manage peri-

perative pain in cats and dogs. Butorphanol is the opioidgonist-antagonist used most commonly in small animals.utorphanol is an agonist at the OP2 (�) receptor and anntagonist or partial agonist at the OP3 (�) receptor. Thenalgesia produced by butorphanol is not as profound as thatroduced by opioid agonists, and its duration of action iselatively short (1-2 hours). However, side effects (vomiting,espiratory depression, bradycardia) are less likely to occurfter administration of butorphanol than after administra-ion of morphine, hydromorphone, or fentanyl. Intraopera-ive administration of butorphanol also reduces isofluraneequirements by 10% to 20% in cats and dogs.36,45 Butor-hanol can be used perioperatively to manage mild to mod-rate pain. The preanesthetic intramuscular dose range forutorphanol in cats and dogs is 0.2 to 0.4 mg/kg. Approxi-ately half of the preanesthetic dose can be given intraoper-

tively or postoperatively. Butorphanol can be given postop-ratively as an intravenous constant-rate infusion at a doseange of 0.1 to 0.2 mg/kg/h. Small intravenous doses of bu-orphanol (0.1 mg/kg) can also be given postoperatively toeverse sedation and respiratory depression caused by admin-stration of excessive doses of opioid agonists.

MDA Antagonists

Glutamate is the endogenous agonist for spinal and su-raspinal NMDA receptors. Blockade of NMDA receptors inhe dorsal horn of the spinal cord prevents windup and theevelopment of central sensitization. Ketamine is the mostidely used NMDA antagonist in veterinary medicine. Ket-mine is supplied as a racemic mixture of 2 optical enanti-
mers. S(�) ketamine has 4 times the affinity of L(�) ket- a
mine for the NMDA receptor and has a shorter duration ofction. The clinical analgesic potency of S(�) ketamine ispproximately twice that of the racemic mixture. Nonrace-ic mixtures of ketamine may be available for use in small

nimals in the near future.Ketamine can be used to manage pain throughout the peri-

perative period at anesthetic and subanesthetic doses.46 In-ravenous or intramuscular administration of anestheticoses produces “dissociative” anesthesia with poor muscleelaxation in both cats and dogs. Cardiovascular effects areimited, and ventilation is better maintained than with othernesthetic drugs. Dysphoria and seizures can also occur afterdministration of high doses of ketamine, but dysphoria isess severe or absent at low subanesthetic or analgesic doses.he anesthetic effects of ketamine last for approximately 30inutes, but motor effects can persist for several hours. In-

ravenous administration of ketamine at an infusion rate of.6 mg/kg/h decreases isoflurane requirements by 25%.37 In-raoperative and postoperative administration of ketaminelso reduces pain scores in dogs after forelimb amputation.47

ecause of the potential for dysphoria, opioid infusions are aetter choice for most patients than opioid-ketamine infu-ions or ketamine infusions alone. However, patients withignificant preexisting central sensitization or those undergo-ng major procedures with significant surgical trauma mayenefit from intraoperative and postoperative opioid-ket-mine infusions. Intraoperatively, the intravenous infusionose range for cats and dogs is 0.4 to 0.6 mg/kg/h. Postoper-tively, a lower intravenous infusion dose range of 0.2 to 0.3g/kg/h is used to avoid dysphoria and motor effects. An

ntravenous bolus of 0.5 to 1.0 mg/kg can be given as aoading dose or to provide short-term analgesia.

ocal Anesthetics

Local anesthetics have the unique ability to produce com-lete blockade of sensory nerve fibers and prevent the devel-pment of central sensitization. Consequently, peripheralnd central neural blockade are often used in combinationith other analgesic and anesthetic drugs to manage periop-

rative pain. Local anesthetics block the generation and con-uction of nerve impulses by inhibiting voltage-gated sodiumhannels in nerve fibers. Lidocaine is also given systemicallyo manage pain and to reduce ileus after abdominal surgery.he mechanism of action of systemic administration of lido-aine is unclear, but peripheral, central, and antiinflamma-ory mechanisms have been proposed.48

Lidocaine, mepivacaine, and bupivacaine are the local an-sthetics used most commonly in cats and dogs. Lidocaineas a fast onset (10 minutes) and a short duration of action1-2 hours) and is used for short diagnostic and surgicalrocedures. Mepivacaine is similar to lidocaine in potencynd onset, but has a longer duration of action (2-3 hours),auses less tissue irritation, and has a higher therapeutic in-ex. Bupivacaine is approximately 4 times the potency ofidocaine and mepivacaine, has a slow onset (20 minutes),
nd a long duration of action (4-6 hours) and is used for most

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urgical procedures. Aminoamide local anesthetics are highlyrotein-bound and are metabolized primarily by the liver.onsequently, anemic and hypoproteinemic patients areore susceptible to local anesthetic toxicity. In most patients,

he clearance of lidocaine is dependent on blood flow ratherhan hepatic metabolism. As a result, the clearance of lido-aine is significantly reduced in patients with low cardiacutput. Local anesthetics are relatively safe if they are usedorrectly. Administration of an excessive dose and accidentalntravenous administration are the most common causes ofystemic toxicity in small animals. As a general rule, the totalose of lidocaine or bupivacaine should not exceed 8 mg/kgr 2 mg/kg, respectively. Clinicians should always consider

ncluding peripheral or central neural blockade in their peri-perative pain management plans. These techniques reduce

nhalation anesthetic requirements, attenuate the neuroendo-rine response to surgical trauma, and improve outcome.ocal anesthetic techniques for cats and dogs are described inetail in several recent articles.4,49,50

Systemic administration of lidocaine can be used periop-ratively to reduce inhalation anesthetic requirements, torovide analgesia, to control ventricular arrhythmias, and toanage postoperative ileus. Intravenous administration of

idocaine at a rate of 3 mg/kg/h reduces isoflurane require-ents by 20% to 30%.37,51 Intravenous loading doses of 1 tomg/kg are appropriate for most dogs. Intraoperatively, the

ntravenous infusion dose range for dogs is 4 to 6 mg/kg/h.ostoperatively, a lower intravenous infusion dose range of 2o 3 mg/kg/h is used to provide analgesia and to improveastrointestinal motility. Objective clinical data on the use ofntraoperative and postoperative lidocaine infusions in catsre limited.

OX Inhibitors

Prostaglandins play a central role in inflammation and theevelopment of peripheral sensitization. Production of pros-aglandins in the dorsal horn of the spinal cord also contrib-tes to the development of central sensitization. Inhibition ofonstitutive (COX-1) and inducible (COX-2) cyclooxygen-se inhibits the conversion of arachadonic acid to prostaglan-ins and thromboxanes and produces a peripheral antiin-ammatory effect. In the dorsal horn, inhibition of COXroduces a central analgesic effect. COX inhibitors vary inheir selectivity for the different isoenzymes, as well as theirbility to produce central analgesic and antiinflammatoryffects.52,53

Several COX inhibitors are approved for perioperative usen cats and dogs. COX inhibitors are usually given postoper-tively alone or in combination with opioids. Parenteral for-ulations of ketoprofen, meloxicam, and carprofen are

vailable in Canada and the United States and are betteruited for perioperative administration. Ketoprofen has aapid onset (0.5 hour), a short half-life, and an intermediateuration of action (12 hours). The drug inhibits platelet func-ion but does not appear to prolong bleeding time in healthy
nimals undergoing elective surgery.54 Ketoprofen can be a
iven subcutaneously to cats and dogs immediately after sur-ery at a dose of 2 mg/kg. Therapy with ketoprofen can beontinued at a dose of 0.5 mg/kg twice daily for 3 to 5 days.eloxicam and carprofen have a slow onset time (1-2 hours)

nd a long duration of action (24 hours). These drugs do notppear to inhibit platelet function and do not prolong bleed-ng time in healthy animals. Meloxicam can be given subcu-aneously to dogs immediately after surgery at a dose of 0.2g/kg. Therapy with meloxicam can be continued at a dosef 0.1 mg/kg once daily for 3 to 5 days. Carprofen can beiven subcutaneously to dogs immediately after surgery at aose of 4 mg/kg. Therapy with carprofen can be continued atdose of 4 mg/kg once daily for 3 to 5 days. Deracoxib is also

abeled for perioperative use in dogs, but no parenteral for-ulation is available. Side effects are not usually a problem inealthy animals with normal platelet, gastrointestinal, andenal function. There is little benefit to preoperative admin-stration of COX inhibitors, and there is significant risk foratients with compromised platelet and renal function.

igure 2. Components of balanced anesthesia. General an-sthetics (propofol, isoflurane) are used to induce hypnosis orloss of consciousness, but these drugs have very low thera-eutic indices and produce significant cardiopulmonary de-ression at clinically relevant doses. Concurrent administra-ion of analgesic drugs not only attenuates autonomicesponses (increased heart rate and arterial pressure, in-reased respiratory rate) to surgical trauma, but reduces themount of intravenous and inhalation anesthetics required tonduce and maintain anesthesia. Administration of alpha-2gonists and local anesthetics can also improve muscle relax-
tion.

Table 3. Examples of Anesthetic and Pain Management Protocols for Healthy Cats*

Surgical Procedure Preoperative Management Intraoperative Management Postoperative Management Comments

Castration(Protocol 1)

PremedicationAcepromazine: 0.1-0.2mg/kg, IMButorphanol: 0.2-0.4mg/kg, IM

Induction and maintenanceKetamine: 10-15 mg/kg, IM

Ketoprofen: 2.0 mg/kg, SCimmediately after recovery fromanesthesia

Mild pain


PremedicationMedetomidine: 0.01-0.02mg/kg, IM†Butorphanol: 0.2-0.4mg/kg, IM

Induction and maintenanceKetamine: 5-10 mg/kg, IM


Mild pain

Ovariohysterectomy(Protocol 1)

PremedicationAcepromazine: 0.1-0.2mg/kg, IMHydromorphone: 0.05-0.1mg/kg, IM

InductionThiopental: 8-12 mg/kg, IV toeffectIsoflurane: 3%MaintenanceIsoflurane: 1.5%-2.5%

Ketoprofen: 2.0 mg/kg, SCimmediately after recovery fromanesthesiaKetoprofen: 1.0 mg/kg, POonce daily for 2-3 days

Moderate painSome patients may requireadditional hydromorphonepostoperatively.


PremedicationMedetomidine: 0.01-0.02mg/kg, IM†Hydromorphone: 0.05-0.1mg/kg, IM� Glycopyrrolate: 0.01 mg/kg, IM




Onychectomy(Protocol 1)

PremedicationAcepromazine: 0.1-0.2mg/kg, IMHydromorphone: 0.05-0.1mg/kg, IM

InductionPropofol: 4-6 mg/kg, IV toeffectIsoflurane: 3%MaintenanceIsoflurane: 1.5%-2.5%Digital nerve block0.5% bupivacaine:0.5-1.0 mLDo not exceed a total dose of2 mg/kg.


Moderate painDigital nerve block reducesanesthetic requirementsand improves analgesiapostoperatively.

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ultimodal analgesia is not a difficult concept to understand,or is it a difficult concept to put into practice. In the perioper-tive setting, a multimodal analgesic protocol is simply a bal-nced anesthetic and pain management protocol (Fig 2). At firstlance, the notion that analgesic drugs should be given to anes-hetized patients that are unable to consciously perceive paineems irrational. However, most intravenous (propofol) andnhalation (isoflurane, sevoflurane) anesthetics simply producenconsciousness and do not substantially alter nociceptive pro-essing. In fact, autonomic responses (sudden changes in respi-atory rate, heart rate, and blood pressure) that occur duringurgery as a result of noxious stimulation usually reflect inade-uate analgesia rather than insufficient anesthetic depth. Theafest approach for most patients is to limit the amount of in-alation anesthetic required by providing supplemental intra-perative analgesic therapy with opioids and local anestheticechniques.

After initial assessment of analgesic requirements anddentification of major anesthetic risk factors, drugs are se-ected to minimize risk and to provide optimal anesthetic andain management throughout the perioperative period. Pa-ient monitoring and supportive care are also selected to op-imize cardiopulmonary function and to minimize anestheticisk. Hypoventilation (PaCO2 � 60 mm Hg), hypotensionmean arterial pressure � 60 mm Hg), and bradycardia areommon perioperative complications. Care should be takeno avoid or reduce doses of anesthetic and analgesic drugshat have similar side effects. Opioids and inhalation anes-hetics can induce significant respiratory depression. Ace-romazine, inhalation anesthetics, and epidural anesthesiaan cause significant hypotension. Alpha-2 agonists and opi-ids can cause bradycardia and enhance oculovagal and vis-erovagal reflexes triggered by surgical manipulation. Givenhe potential for significant intraoperative complications,here is no substitute for diligent patient monitoring by aualified, experienced anesthetist.The type of surgery (invasive vs minimally invasive) and

he surgical site (somatic vs visceral) should also be consid-red when developing anesthetic and pain managementlans. Pain must be managed aggressively throughout theerioperative period in patients scheduled for invasive surgi-al procedures, whereas postoperative administration ofOX inhibitors may be appropriate for patients scheduled

or minimally invasive procedures. Peripheral or central neu-al blockade is appropriate for most patients scheduled forurgical procedures of the front or hind limbs and for thosecheduled for dental procedures. Conversely, completelockade of nociceptive input from somatic and visceral af-erents may be impossible to achieve in patients scheduled forhoracic or abdominal surgical procedures.

Perioperative use of analgesic drugs and techniques re-uces the doses of intravenous and inhalation anestheticsequired to induce and maintain anesthesia, improves cardio-ulmonary function during surgery, and promotes a smooth

recovery from anesthesia after surgery. These analgesic drugs

T Su O (P A *S †

Table 4. Examples of Anesthetic and Pain Management Protocols for Healthy Dogs*

Surgical Procedure Preoperative Management Intraoperative Management Postoperative Management Comments


PremedicationAcepromazine: 0.05-0.1 mg/kg,IMButorphanol: 0.2-0.4 mg/kg,IM

InductionPropofol: 4-6 mg/kg, IV to effectIsoflurane: 3%MaintenanceIsoflurane: 1.5%-2.5%


Mild pain


PremedicationMedetomidine: 0.005-0.01 mg/kg, IM†Butorphanol: 0.2-0.4 mg/kg,IM� Glycopyrrolate: 0.005-0.01mg/kg, IM

InductionPropofol: 2-3 mg/kg, IV to effectIsoflurane: 3%Maintenance:Isoflurane: 1.0%-2.0%


Mild pain


PremedicationAcepromazine: 0.05-0.1 mg/kg,IMHydromorphone: 0.05-0.1 mg/kg, IM


Meloxicam: 0.2 mg/kg, SCimmediately after recovery fromanesthesiaMeloxicam: 0.1 mg/kg, POonce daily for 2-3 days



PremedicationMedetomidine: 0.005-0.01 mg/kg, IM†Hydromorphone: 0.05-0.1 mg/kg, IM �Glycopyrrolate: 0.005-0.01mg/kg, IM

InductionThiopental: 4-6 mg/kg, IV toeffectIsoflurane: 3%Isoflurane: 3%MaintenanceIsoflurane: 1.0%-2.0%

Meloxicam: 0.2 mg/kg, SCimmediately after recovery fromanesthesiaMeloxicam: 0.1 mg/kg, POonce daily for 2-3 days


Dentistry with anupper canineextraction

PremedicationMidazolam: 0.1-0.2 mg/kg, IMHydromorphone: 0.05-0.1 mg/kg, IM

InductionPropofol: 4-6 mg/kg, IV to effectIsoflurane: 3%MaintenanceIsoflurane: 1.0%-2.0%Infraorbital nerve block0.5% Bupivacaine: 0.5-1.0 mL


Moderate painInfraorbital nerve blockreduces anestheticrequirements and improvesanalgesia postoperatively.

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nd techniques also have the potential to reduce major com-lications and improve outcome. In a busy practice setting,imple, straightforward anesthetic and pain managementrotocols are the best choice for most patients. Pain can beanaged safely and effectively in the vast majority of surgicalatients with opioids, COX inhibitors, and peripheral orentral neural blockade. Alpha-2 agonists, NMDA antago-ists, and other adjunctive drugs are helpful in patients withignificant short-term or long-term central sensitization. Andast, atraumatic surgical technique is the first, and most im-ortant, step in the prevention of peripheral and central sen-itization and the development of pathological pain. Exam-les of balanced anesthetic and pain management protocolsor routine surgical procedures in healthy cats and dogs areutlined in Tables 3 and 4, respectively.

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tic implications. J Am Vet Med Assoc 219:1346-1356, 20012. Lemke KA: Understanding the pathophysiology of periopera-

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Analgesia for Anesthetized Patients · analgesic drugs and techniques. Surgical trauma and inﬂam- ... NMDA antagonists (ketamine) can be used throughout the perioperative period