Peri-Operative Analgesia: Prepare, Pre-empt, and Prevent

Karen Kerr BA, BVSc (Hons), MANZCVS (Anesthesia & Analgesia)

Amanda M. Shelby BSc, RVT, VTS (Anesthesia & Analgesia)
Elizabeth A. Martinez DVM, DACVAA

A variety of drugs are available to manage acute, procedure-related pain in dogs and cats. This article provides a brief overview of
common medications that contribute to perioperative multimodal analgesia for painful procedures, including where they act on the
nociceptive pathway, as described in Think Anesthesia: Pain and its Recognition (see Figure 1). These medications include primary
analgesics and adjunctive medications that assist in reducing pain signaling and can be used in different combinations to prevent
peripheral and central sensitization and their ongoing negative sequelae (see Table 1). Pain is not purely sensory. Pain has an emotional
component that can dramatically impact a patient’s experience, therefore; anxiolytic and antiemetic drugs are also part of an overall
multimodal analgesic plan despite not specifically reducing nociception itself.[1]

Figure 1. Nociceptive Pathway with Analgesic Medications Effective at Respective Sites

Drug Class
Analgesia Effects
+/- subclassification

µ-agonists moderate to
severe
analgesia ± sedation
Opioids Partial mild to
µ-agonist moderate
Agonist- mild sedation ± analgesia
antagonist
Alpha2-agonists mild to sedation and analgesia
moderate
NSAIDs mild to analgesia and anti-inflammatory
moderate
NK1-receptor antagonist maropitant none anti-emesis
Anticonvulsant gabapentin +/- mild; anxiolysis
chronic pain
Atypical Antidepressant trazodone none mild to moderate sedation
Phenothiazine acepromazine none mild to moderate sedation
Benzodiazepines diazepam none +/- sedation or excitement
midazolam Muscle relaxation
Table 1: Common Premedicants in Dogs and Cats

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Before starting a medical procedure, it is important to consider the expected level of pain the procedure will produce and make an
analgesic plan appropriate to prevent or treat that level of pain. Attention is given to the timing of medications as it benefits the patient
when formulating the analgesic plan (see Figure 2).

Pre-hospital & Pre-induction Pre-operatively

Pre-emptive analgesia Pre-emptive analgesia (bolus doses or CRIs)
Adjunctive anxiolysis and antiemesis Sensory blockade (local and regional analgesia)
Intra-operatively Post-operatively
Redosing of short acting analgesics Redosing of analgesics
Continuation of CRIs Continuation and/or tapering of CRIs
Additional analgesia if required Additional analgesia if required
Figure 2: Benefits of Analgesia within Time Points of the Peri-anesthetic Period

OPIOIDS
Opioids have long been a cornerstone of pain management in both veterinary and human medicine. Indeed, the analgesic properties
of Papaverum somniferum, the opium poppy, had been known for millennia before morphine was isolated in 1806.[2] In humans, opioids’
addictive properties and their devastating individual and societal consequences have led to tight regulation and an unreliable supply
for veterinary use in the USA. Opioids are generally the first line of pain relief for severe acute pain, and thus a core component of
pre-emptive analgesia. However, the optimal effects of opioids are achieved when they are part of a multimodal analgesic plan and
appropriate analgesia is possible to achieve in their absence.

Opioid receptors are ubiquitous in the central nervous system (CNS) with high concentrations in areas involved in nociceptive signaling
between the spinal cord and the cerebral cortex including the
rostral ventral medulla and dorsal horn of the spinal cord. Opioid
receptors are also found in peripheral nervous and non-nervous
tissues. All commonly administered opioids bind to μ (mu)-opioid
receptors, which are responsible for the greatest magnitude of pain
relief, although the remaining three opioid receptors, κ (kappa), δ
(delta) and the nociception receptor also contribute to analgesia. [3]
Keynote:
• Agonists – elicit a dose-dependent maximal response from
a receptor
• Partial agonists – elicit a dose-dependent response that
plateaus at submaximal magnitude
• Antagonists – elicit no response but competitively bind the
receptor preventing other opioids from binding
• Agonist-antagonists – act as agonists at one receptor and
antagonists at another

Mu-opioid receptor agonist drugs provide analgesia by indirectly stimulating descending inhibition of pain signals from the brain to
the spinal cord and directly stimulating pain inhibition within the spinal cord and peripheral nerves. This decreases the transmission of
nociceptive signals from the periphery to the CNS, modulates the signal within the CNS, and decreases the perception of pain upon
recovery of consciousness. See Table 2 for specific characteristics of commonly used opioids in veterinary medicine.

Most opioids have rapid absorption and high bioavailability when administered intramuscularly (IM) or subcutaneously (SC), meaning
that a large proportion of administered drug enters the bloodstream and can exert a clinical effect. Oral (PO) bioavailability, however, is
low in dogs and cats despite effective initial absorption from the gastrointestinal tract, due to metabolism in the liver prior to entering
the circulation (i.e., first pass effect). A novel approach to providing perioperative opioid analgesia PO is the combination of methadone
with fluconazole; fluconazole acts as a suicide inhibitor preventing metabolism of methadone, and naltrexone, an opioid antagonist
to reduce the risk of human use, shows promise but is not yet available for clinical use. A trial formulation of this combination
administered PO twice daily provided equivalent analgesia to dogs undergoing ovariohysterectomy to SC methadone dosed every four
hours.[4]

2
 Route of Dose Dosing
Action Drug Comments
administration (mg/kg) Interval*
IV / IM / SC 0.1 – 0.5 2–4h Administer slowly IV
LD: 0.3 – 0.5 IM or due to potential for
Morphine CRI slowly IV to effect histamine release.
0.05 – 0.4 mg/kg/h Vomiting may occur.
EPI 0.1 24 h
IV / IM / SC 0.1 – 0.5 4–6h
Methadone also
Methadone LD: 0.1 – 0.3 IM or has NMDA-receptor
CRI slowly IV to effect antagonist effects.
0.12 mg/kg/h
mu-agonist
IV / IM / SC 0.05 – 0.1 2–4h
LD: 0.03 – 0.1 IM or Vomiting may occur,
Hydromorphone
CRI slowly IV to effect especially IM.
0.02 – 0.03 mg/kg/h
LD: 0.001 – 0.01 IM or
slowly IV to effect Duration of action is
Up to 0.04 mg/kg/h brief after individual
intra-operatively with dosing and epidural
Fentanyl CRI respiratory monitoring administration,
and support. so infusion is
Post-operatively: 0.002 recommended.
– 0.006 mg/kg/h
IV / IM / SC 0.01 – 0.02 4 – 12 h IV / IM route is
Cats: 0.02 preferred in the
OTM 4–8h perioperative setting.
– 0.05
Partial mu-agonist Buprenorphine SC (Simbadol™; May be repeated daily
Cats: 0.24 24 h
Zoetis) for 3 days.
Transdermal Administered 1 – 2 h
2.7 – 6.7 4 days
(Zorbium™ Elanco) prior to procedure
Agonist- Poor sole analgesic,
antagonist Butorphanol IV / IM / SC 0.2 – 0.4 1–2h antitussive
Table 2: Opioid Drugs Commonly Administered in Dogs and Cats
Notes: IV = intravenous; IM = intramuscular; SC = subcutaneous; CRI = continuous rate (IV) infusion; LD = loading dose, to be administered IM or slowly IV
over several minutes; OTM = oral transmucosal; EPI = epidural. *Duration of action of each drug by route of administration is variable, and assessment of
patient pain should guide re-administration rather than time since previous dose.

Buprenorphine has high bioavailability following oral transmucosal (OTM) administration in cats, which bypasses first pass metabolism,
although resultant analgesia is highly variable.[5] Buprenorphine may also be administered perineurally as an adjunct to local anesthesia,
while other opioids used in this manner provide less consistent results.[6]

Metabolism of opioids occurs primarily in the liver in mammals and the metabolites are excreted in the urine and bile. Remifentanil has
a very short half-life due to its metabolism via blood and tissue nonspecific esterases. [7] The duration of action varies between opioids,
and shorter-acting medications such as fentanyl and its derivatives are usually administered by IV continuous rate infusion (CRI). Other
opioids may also be administered as CRIs to prevent periods of insufficient analgesia between dosing intervals.

Mu-agonist drugs elicit dose-dependent receptor activation without a ceiling effect in clinically recommended dose ranges; therefore,
they have the greatest potential for adverse effects at high doses, although cardiorespiratory depression and other side effects can
occur with any opioid. Opioid-induced bradycardia and respiratory depression are not usually clinically significant in conscious

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animals but may become more severe in anesthetized patients where physiological responses are obtunded, and multiple depressant
medications are concurrently administered. An opioid antagonist such as naloxone may be administered to reverse opioid effects or,
alternatively, butorphanol may be administered to reverse µ-agonist effects while still providing some analgesia via activity at the kappa
receptor.[8]

Other adverse effects include gastrointestinal stasis, dysphoria, vomiting (with morphine and hydromorphone), panting, and urine
retention (most common with epidural administration of µ-agonists). Effects on pupil diameter are species-specific, with dogs showing
miosis (contracted pupils) and cats mydriasis (dilated pupils). Hyperthermia may occur in cats after opioid administration. with
hydromorphone being the most common opioid to produce hyperthermia. However, hyperthermia in cats but has been reported
with all commonly administered opioids. Depressant effects (i.e., CNS and cardiorespiratory) of opioids are dose-dependent, and, at
clinical doses, this class of drugs is considered low risk and appropriate for a wide range of patients, with appropriate monitoring and
physiological support.

NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs)

NSAIDs have both anti-inflammatory and analgesic properties and veterinary approved NSAIDs are used to control inflammation and
pain from osteoarthritis in dogs and horses. Specific NSAIDs are also approved to control postoperative pain in dogs and cats and are
commonly included in a multimodal pain management plan.
NSAIDs minimize inflammation and pain by reducing the production of specific soluble mediators of inflammation called
prostaglandins (PGs), at the site of injury (transduction) and within the dorsal horn of
Keynote: NSAIDs reduce pain and inflammation at the spinal cord (modulation). They achieve this by inhibiting the activity of the
the site of painful stimulation, reducing transduction enzyme cyclooxygenase (COX), which converts arachidonic acid into PGs. There are
and nociceptor sensitization. They also reduce
central sensitization by reducing pro-inflammatory two commonly recognized isoforms of the COX enzyme: COX-1 and COX-2, that
prostaglandin production in the spinal cord. contribute to both physiological and inflammatory processes. Simplistically, COX-1 is
primarily constitutive, with roles in physiological “housekeeping” activities, such as
preserving blood flow to the kidneys and gastrointestinal tract, and maintaining platelet function.[9, 10] COX-2 is upregulated in
inflammatory and injured tissue and produces PGs that contribute to further inflammation, although its upregulation also provides
protective effects during insult or stress to the gastrointestinal mucosa or kidney.[11-13] Common side effects associated with NSAIDs
result from the inhibition of constitutive prostaglandin effects in various tissues and are described in Table 3.

System Adverse Effects COX Involved Prevention

Consider administering gastric ulcer
prevention or treatment
Avoid NSAID use in:
Ulceration, vomiting, diarrhea, COX-1 constitutive
Gastrointestinal tract - Patients with gastrointestinal
anorexia, abdominal pain COX-2 induced
erosions or ulceration
- Patients also receiving corticosteroid
medications
Only administer prior to anesthesia in
healthy, well-hydrated patients with
blood pressure monitoring and fluid
support
Avoid NSAID use in:
Acute ischemic renal failure
Kidneys COX-1 and COX-2 - Dehydrated, hypotensive, or
Renal papillary necrosis
hypovolemic patients (may administer
once stabilized)
- Patients with impaired renal function
- Procedures with high risk of
hemorrhage
Do not use non-selective COX
Platelet dysfunction
Platelets COX-1 constitutive inhibitors perioperatively, discontinue
Prolonged bleeding
current use 10-14 days prior to surgery
Table 3: Adverse effects of NSAID administration by body system and COX enzyme, with approaches to their prevention.

NSAIDs can be categorized by their selectivity for COX receptors, as newer drugs are developed to inhibit COX-2 with greater selectivity

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than COX-1 (see Table 4). Drugs with greater selectivity for the COX-2 enzyme may be safer during chronic therapy especially with
respect to gastrointestinal and renal toxicity, although the evidence to support this improved safety is limited.[14]

NSAID Classification Examples Comments

Preferential or selective
COX-1 inhibitors
Nonspecific COX
inhibitors
Preferential and
moderately selective
COX-2 inhibitors
Highly selective COX-2
inhibitors
Table 4: NSAIDs Selectivity
(Source: https://www.jurox.com/us/developments-in-veterinary-anesthesia/nsaids)
aspirin, carprofen, ketoprofen,
vedaprofen, tepoxalin
carprofen, flunixin, ketoprofen,
meloxicam, phenylbutazone,
tolfenamic acid, vedaprofen
Carprofen, deracoxib, etodolac,
meloxicam, tolfenamic acid,
mavacoxib
firocoxib, robenacoxib
COX-1 inhibitor potency at least 5X greater
than COX-2 inhibition
No significant biological or clinical difference
in drug concentrations producing COX-1 or
COX-2 inhibition
COX-2 inhibition potency at least 5-100X COX-
1 inhibition

ALPHA2-ADRENERGIC AGONIST DRUGS

The benefits of alpha2-agonist drugs include reliable, dose-dependent sedation, muscle relaxation, anxiolysis, analgesia, and
significant anesthetic-sparing effects. These attributes make them popular pre-anesthetic medications and components of preventive
and adjunctive analgesia. Alpha2-agonists provide spinal (modulation and prevention of central sensitization) and supraspinal
(modulation and inhibition of perception) analgesia by interaction with alpha2-adrenergic receptors in the CNS and inhibiting pain
signal transmission. Sedative and anxiolytic effects are centrally mediated and minimize the emotional component of pain. Effects are
reversible with alpha2-receptor antagonists such as atipamezole. Antagonist medications reverse the sedative and analgesic effects
of alpha2-agonists within 5 – 10 minutes of IM administration. Antisedan® (atipamezole hydrochloride 5 mg/mL for dogs, Zoetis Inc.)
is approved for reversal of the sedative and analgesic effects of dexmedetomidine and medetomidine in dogs and its off-label use is
common in cats. Atipamezole returns the patient’s systemic vascular resistance and cardiac output to pre-sedation levels, but the heart
rate is not reliably increased and marked hypotension may occur, especially in anesthetized patients.[15]

Excitement, rigidity, and agitation may occur with high doses of alpha2-agonists, due to binding of alpha1-receptors. The ratio of affinity
for alpha2- to alpha1-receptors is tenfold higher for dexmedetomidine and medetomidine (1620:1) than their predecessor xylazine
(160:1).[16] Xylazine is not commonly administered nor recommended for sedation or analgesia in small animal practice anymore due
to its lack of specificity and more prominent side effects, although it remains the drug of choice for inducing emesis in cats. Older,
published studies have identified xylazine administration as a risk factor for peri-anesthetic fatalities in dogs and cats; however, this
same risk was not found in a large study which included the drugs medetomidine and dexmedetomidine.[17, 18]

Dexmedetomidine / Medetomidine:
Medetomidine is an alpha2-agonist consisting of two optical enantiomers: dexmedetomidine, considered to be primarily responsible
for clinical effects, and levomedetomidine, with no apparent significant effects at clinically recommended dose rates.[19] Clinical
differences between the racemic (combined) medetomidine and the isolated dexmedetomidine are minimal, and equipotent dosing of
dexmedetomidine is approximately half that of medetomidine.[20, 21] Injectable formulations of dexmedetomidine are most commonly
used in the peri-anesthetic setting. These include Dexdomitor® (dexmedetomidine injection 0.5 mg/mL or 0.1 mg/mL, Zoetis Inc.)
which is indicated for use as a sedative and analgesic in dogs and cats to facilitate clinical examinations, clinical procedures, minor
surgical procedures, and minor dental procedures, and for use as a preanesthetic to general anesthesia in dogs and cats.[22] Sileo®
(dexmedetomidine oromucosal gel 0.1 mg/mL, Zoetis Inc.) is an oral transmucosal dexmedetomidine indicated for the treatment of
noise aversion in dogs; however, it does not have the same indications as Dexdomitor®.[23]

Drug combinations of an opioid and alpha2-agonist are commonly used in anesthetic premedication for their synergistic effects
of reliable sedation and pre-emptive analgesia, allowing lower doses of each drug to be used and minimizing dose-dependent
side effects. In dogs undergoing ovariohysterectomy, morphine (0.3 mg/kg) and dexmedetomidine (0.01 mg/kg) administered
intramuscularly 30 minutes before surgery yielded lower post-operative pain scores than morphine (0.6 mg/kg) alone, despite halving
the opioid dose administered when combined.[24] Dexmedetomidine alone provides inadequate analgesia for invasive or painful
procedures, and is best used as an adjunct analgesic medication, combined with other analgesics in a multimodal approach. For
example, following ovariohysterectomy, medetomidine provided poorer pain relief than butorphanol in cats[25] and a dexmedetomidine

5
infusion in dogs provided poorer pain relief than fentanyl or combined morphine, lidocaine, and dexmedetomidine infusions.[26]

Analgesic effects of dexmedetomidine are present at low doses and appear to be of a shorter duration than sedative effects, although
this may be a confounding effect of sedation itself.[27] Administering dexmedetomidine as a low-dose intravenous infusion can provide
consistent antinociception and anesthetic dose-sparing with less side effects than administering higher doses intermittently. Dose-
dependent cardiovascular changes may still be observed, but are minimal at the low end of the common dose range in anesthetized
dogs and cats[28, 29], and post-operative infusion of dexmedetomidine provided analgesia without clinically significant side effects
in critically ill dogs.[30] In humans, dexmedetomidine infusions are associated with shorter ICU stays and duration of mechanical
ventilation of critical care patients compared with midazolam sedation, although bradycardia and hypotension are more common with
dexmedetomidine..[31]

Dexmedetomidine increases the duration of regional anesthetic blocks when administered systemically or perineurally. In studies
assessing analgesia for hindlimb orthopedic procedures in dogs, a dexmedetomidine CRI significantly prolonged the time to rescue
analgesia provided by spinal anesthesia and perineural dexmedetomidine administered in femoral and sciatic blocks with lidocaine
prolonged block duration, and with bupivacaine provided analgesia equivalent to epidural bupivacaine and buprenorphine.[32-34] The
mechanism of action of perineural dexmedetomidine administration is likely the delay of systemic absorption of local anesthetics
through local vasoconstriction and direct prolongation of the hyperpolarization of the nerve. When administered epidurally with a local
anesthetic, dexmedetomidine may decrease the risk of urine retention associated with opioids but the motor blockade and return to
normal ambulation may be prolonged.[35]

LOCAL ANESTHETICS
Local anesthetic drugs are sodium channel blockers which hyperpolarize peripheral nerves and completely prevent pain transmission
for their duration of action, making local and regional nerve blocks one of the most effective anti-nociceptive and anesthetic-sparing
strategies available. Local anesthetic drugs are the only true analgesics (i.e., they can completely prevent pain transmission). When
administered epidurally or intrathecally, local anesthetics can also affect modulation in the spinal cord to decrease central sensitization.
The efficacy of local anesthetics at preventing pain means that regional or local techniques should be a primary consideration for every
painful procedure.

Local and regional anesthetic options range from the simple and effective testicular blocks, linear incisional blocks, and intraperitoneal
administration to more specialized techniques, some of which require the use of nerve stimulators or ultrasound guidance to perform.
A variety of local anesthetic drugs are available, each with their own characteristics, including recommended maximum doses for each
species, time to onset, and duration of analgesia (see Table 5). The most recent innovation in veterinary-approved local anesthesia
is bupivacaine formulated in a liposome-encapsulated injectable suspension (Nocita™, Elanco Animal Health) which provides local
anesthesia up to 72 hours after administration. It is FDA-approved for local infiltration in cranial cruciate ligament surgery in dogs and as
a peripheral nerve block for onychectomies in cats.[36]

Maximum Suggested Duration of

Local Anesthetic Clinical Dose Rate Onset time* action**
Dogs 5 mg/kg
Lidocaine 3-5 minutes 60-120 minutes
Cats 2-5 mg/kg
Dogs 5 mg/kg
Mepivacaine 5-10 minutes 90-180 minutes
Cats 2 mg/kg
Dogs 3 mg/kg
Bupivacaine 20-30 minutes 180-480 minutes
Cats 2 mg/kg
Liposomal
Encapsulated Dogs: 5.3 mg/kg 30 minutes Up to 72 hours
Bupivacaine Cats: 5.3 mg/kg/forelimb
(Nocita™, Elanco)
Dogs 3 mg/kg 10 minutes (0.75%)
Ropivacaine 180-480 minutes
Cats 2 mg/kg 20-30 minutes (0.25-0.5%)
Table 5: Clinical Characteristics of Local Anesthetics Commonly Administered to Dogs and Cats
Notes: *high concentrations provide faster onset, longer durations**larger injected volumes are associated with faster onset, longer durations

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Lidocaine is unique among local anesthetics in that it can also be administered intravenously where it demonstrates a wide range of
effects. Single lidocaine boluses are most used to manage tachyarrhythmias and lidocaine CRIs may be administered for analgesic,
anesthetic-sparing, and anti-inflammatory effects. Lidocaine CRIs are best reserved for dogs versus cats as their therapeutic index is
lower in cats, increasing the risk of adverse effects. For ocular procedures, lidocaine may offer equivalent analgesia to morphine.[37]
Lidocaine may also be administered intravenously to reduce coughing on intubation, which is especially useful in patients where the
increase in intracranial pressure associated with coughing would have significant negative effects.[38]

Adverse effects associated with local anesthetics occur at high plasma concentrations, which may be due to inadvertent IV
administration during local or regional injection; therefore, aspiration prior to injection is essential to ensure appropriate (extravascular)
needle placement. The total administered dose of local anesthetics should be monitored throughout a procedure to prevent toxicity.
Toxicity affects the CNS and cardiovascular systems in a fairly predictable order, with neurological signs occurring at lower doses and
cardiac toxicity occurring at higher dose rates for most local anesthetic drugs. Bupivacaine is an exception and cardiotoxic effects may
occur at similar plasma concentrations to CNS toxicity.[39]

N-METHYL-D-ASPARTATE (NMDA)-RECEPTOR ANTAGONISTS

The existence of NMDA-receptors located in the dorsal horn of the spinal cord is an important element in pain signaling because
these receptors are important in transmitting nociceptive information from the periphery to the brain. Because NMDA receptors are
located in the ascending pain pathways, they are believed to play a key role in wind-up and central sensitization.[40] NMDA receptor
antagonists have been shown to modulate pain and central sensitization; therefore, these drugs play a key role in pharmacological pain
management. Clinically available NMDA receptor antagonists include ketamine, tiletamine, and amantadine. The opioid methadone
also has NMDA antagonist effects, which may add to its efficacy in preventing central sensitization.

Ketamine (CIII)
Ketamine is a dissociative anesthetic that acts as a noncompetitive antagonist at NMDA receptors. Ketamine has been administered
at sub-anesthetic doses for anti-nociception, often as a constant rate infusion during and beyond painful procedures in dogs and cats.
Subcutaneous administration has been reported in human patients and anecdotally in dogs and cats. [23, 41-44]

As a component of a balanced anesthesia technique, plasma ketamine concentration of 2 to 3 µg/mL provided the most benefits with
minimal adverse effects in isoflurane-anesthetized dogs.[45] Ketamine infusions can be administered concurrently with opioids and/or
lidocaine to reduce inhalant anesthetic requirements and facilitate a multimodal pain management plan.[46]

Tiletamine (CIII)
Tiletamine is another dissociative anesthetic, which is only available in formulations with the benzodiazepine zolazepam. These
products are indicated for restraint, along with performance of minor procedures in dogs and anesthesia in cats. Tiletamine’s analgesic
effects are not well described as it is not accessible as a sole medication.

Amantadine
Amantadine is an orally administered NMDA receptor antagonist that was first recognized as an antiviral drug and used in the treatment
of Parkinson’s disease in human patients. Amantadine was shown to be useful, in combination with NSAIDSs for management
of chronic osteoarthritis pain in dogs.[47] In a study evaluating the effect of amantadine on oxymorphone-induced thermal
antinociception in cats, the authors concluded that amantadine may decrease the oxymorphone dose needed for antinociception in
some, but not all, cats.[48] Pharmacokinetic studies in cats and greyhounds suggest that twice daily dosing may be more appropriate
than once daily.[48, 49] Amantadine is not an effective analgesic when used alone, but is added to multidrug and multimodal therapy
analgesic protocols.[50]

OTHER ANALGESIC and ADJUVANT DRUGS

Oral Opioid and Neurotransmitter Reuptake Inhibitor
Tramadol is a CIV scheduled drug used in dogs and cats. In the USA, it is not approved for use in veterinary medicine. Injectable
products are available outside the USA. Tramadol is often described as an “atypical opioid” as its analgesic effects occur through
interaction with opioid receptors and reuptake of serotonin and norepinephrine. The efficacy of tramadol as a peri-operative analgesic
is unreliable and traditional µ-opioids are preferred for painful procedures. Tramadol is a racemic combination of two enantiomers 1)
(+)-tramadol, which has weak affinity and agonist effects for µ-opioid receptors and inhibits reuptake of serotonin in the CNS, and 2)
(–)-tramadol, which inhibits reuptake of norepinephrine in the CNS. Optimal analgesic effects occur when tramadol is metabolized
to (+)-O-desmethyl tramadol (M1), which has much higher affinity for the µ-receptor than tramadol itself.[51] Drugs that require

7
metabolism to yield clinical effects are referred to as pro-drugs.

In dogs, more tramadol is metabolized to the inactive metabolite N-desmethyltramadol (M2) than M1 compared to humans and
cats. The M1 that is produced in the canine liver is rapidly and further metabolized to inactive metabolites. This results in low levels of
circulating active M1 often below the concentration where analgesic efficacy occurs in humans.[52] There is also metabolic variability
between individuals and breeds, reminiscent of the subset of humans known as “poor metabolizers” who produce low amounts of
M1 and experience poor analgesia with tramadol.[51, 52] Accordingly, analgesia provided by tramadol in dogs is underwhelming and
less reliable than other common analgesics, such as coxib NSAIDs in tibial plateau leveling osteotomies (TPLOs).[53] Pain scores with
tramadol were similar to that of oral hydrocodone (another pro-drug that shows poor metabolism in dogs) and acetaminophen, each
of which resulted in an unacceptable number of treatment failures.[54, 55]

Cats are more extensive metabolizers of tramadol to the M1 tramadol metabolite and M1 has a longer elimination half-life in cats
than in dogs due to their limited glucuronidation ability, resulting in greater magnitude and duration of analgesic effects. In healthy
cats undergoing ovariohysterectomy, pre-operative tramadol (oral, intravenous, or intramuscular) provided adequate pain relief for at
least six hours postoperatively and cats administered tramadol had a lower requirement for rescue analgesia compared to pethidine.
[56-58]
Perhaps the greatest limitation in the use of tramadol in cats is the bitter taste of oral formulations and lack of injectable product
availability in the USA. Compounded transdermal tramadol formulations are available but there is no good data demonstrating
bioavailability. One study found that plasma tramadol concentrations following a single dose of the transdermal compounded
formulation were undetectable or significantly lower than the commercial available an oral dosing formulation.[59]

Administering tramadol with other serotonergic drugs presents a risk of serotonin syndrome, a rare but potentially severe condition
causing autonomic and neuromuscular hyperactivity and an altered mental status. Common drugs that increase serotonin activity
include most antidepressants (fluoxetine, sertraline, trazodone, amitriptyline, clomipramine, duloxetine, venlafaxine), monoamine
oxidase inhibitors (selegiline, amitraz), and atypical antipsychotics (bupropion, risperidone, olanzapine).[60]

Acetaminophen
Acetaminophen (also known as paracetamol) is a commonly used analgesic in humans, including in those with underlying conditions
that preclude the use of NSAIDs. Acetaminophen has also been administered as an
analgesic in dogs. Acetaminophen’s mechanism of action is not well understood, but Keynote: Acetaminophen should NOT be
its effects appear to be central in origin, involving COX inhibition in the cerebral cortex, administered to cats.
a metabolite of acetaminophen involved in modulating pain in the dorsal horn of the
spinal cord, along with postulated activity in the opioid, serotonergic, and cannabinoid systems.[61, 62] Clinical effects of acetaminophen
are analgesia and antipyresis, without significant anti-inflammatory effects.

Limited literature exists on the efficacy of acetaminophen in dogs and among recently published studies there are conflicting results.
For instance, in dogs premedicated with meperidine and acepromazine for ovariohysterectomy, there was no difference in analgesia
between post-operative IV acetaminophen and saline groups.[63] Conversely, when acetaminophen was administered IV prior to, and
then orally every 8 hours for 48 hours following ovariohysterectomy in dogs that were administered a fentanyl infusion throughout
surgery, the analgesic effect of acetaminophen was similar to clinically effective doses of carprofen or meloxicam, based on pain scores.
[64]
A combination of acetaminophen and codeine was less effective than carprofen at reducing lameness in dogs with experimentally-
induced synovitis.[65] Neither tramadol nor a combination of hydromorphone and acetaminophen provided adequate analgesia
following TPLO.[54]

Acetaminophen is not FDA-approved for use in veterinary medicine by the FDA and its use is contraindicated cats as their
glucuronidation ability is limited and toxicity occurs at low doses and may include severe methemoglobinemia, oxidative red blood
cell damage, Heinz body anemia, and death.[66] In dogs, acetaminophen has minimal side effects when administered at recommended
clinical doses of 10 – 15 mg/kg, orally or intravenously, for a short period. Orally, 100 mg/kg acetaminophen administered to dogs
does not result in toxicity, but at 128 mg/kg hepatopathy developed and worsening signs of methemoglobinemia and nephrotoxicity
occurred at 200 mg/kg.[67], A mild increase in alanine transaminase (ALT) was observed in dogs when acetaminophen was administered
prior to ovariohysterectomy and for 48 hours afterwards, with no other clinical or laboratory side effects. In the same study, a similar
increase in ALT was observed in dogs administered carprofen at equipotent doses.[64]

Maropitant
Maropitant (Cerenia®, Zoetis) is a neurokinin-1 (NK1) receptor antagonist approved as an antiemetic in dogs and cats that also has

8
MAC-sparing and suspected visceral analgesic effects. NK1 receptors are specific for substance P, a tachykinin neurotransmitter
involved in a multitude of bodily events, including emesis, inflammation, anxiety, and pain processing.[68] Maropitant prevents vomiting
by competitively binding NK1 receptors in regions of the brainstem associated with vomiting, preventing substance P, which acts
as an emetogen, from binding.[69] Post-operative nausea and vomiting is a common cause of perioperative anxiety and morbidity
and may contribute to the affective component of the pain experience. Vomiting due to emetic premedicants such as morphine,
hydromorphone, or dexmedetomidine can be prevented by injecting maropitant at least 1 hour or giving orally 2 to 18 hours prior to
premedication.[69, 70]

Substance P is also released from a variety of tissues in response to injury and inflammation, including peripheral sensory nerve endings
and the dorsal horn of the spinal cord, where it contributes to the nociceptive signal. By inhibiting the binding of substance P to NK1
receptors in the central and peripheral nervous systems maropitant may decrease pain signal transduction peripherally and spinal
modulation: however, this has not been consistently demonstrated in clinical studies. One possible explanation for this is that substance
P often functions as a “co-transmitter” in the CNS, working to enhance the effects of other substances involved in pain processing rather
than being critical, as in the case of emesis.[71] Another suggestion is that there is heterogeneity of NK1-receptor subtypes between
location and species, affecting the specificity and efficacy of antagonists between different types of pain and species of animal.[72, 73]

In an ovarian ligament stimulation model of visceral pain, maropitant provided 15% reduction of MAC for sevoflurane in cats at the
recommended dose of 1 mg/kg[74] and 24% MAC reduction in dogs at the same dose followed by a 30 µmcg/kg/h infusion.[75] In cats
undergoing ovariohysterectomy, post-operative pain scores and rescue analgesia requirements were lower when a maropitant infusion
(1 mg/kg followed by 100 µg/kg/h) was added to a protocol including morphine and meloxicam, but no significant differences were
demonstrated in dogs when maropitant was administered as a single dose in otherwise similar protocols.[24, 44, 76] In a multimodal
protocol for radical mastectomies, dogs administered ketamine and lidocaine infusions after morphine premedication had lower
pain scores and analgesic requirements when maropitant (1.5 mg/kg then 100 µg/kg/h) was added.[77] These studies suggest that
maropitant may provide adjunctive analgesia as part of a multimodal protocol.

Adverse effects of Cerenia® include pain on subcutaneous injection and a decrease in arterial blood pressure following rapid
intravenous administration.[78, 79]

Gabapentin
Gabapentin is an anticonvulsant and is FDA-approved in human patients for the treatment of seizures and postherpetic neuralgia.[80]
Structurally similar to the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), gabapentin is not a GABA receptor agonist.
The primary mechanism of action of gabapentin is decreased release of excitatory neurotransmitters through presynaptic inhibition of
calcium channels. Gabapentin has been administered, off-label, in veterinary species for the treatment of chronic pain, especially when
there is a neuropathic component and pain is not controlled with NSAIDs, opioids, and/or other drug classes.

Results of preclinical studies showed that intravenous gabapentin did not lower the minimum alveolar concentration (MAC) of
isoflurane and oral gabapentin did not affect thermal antinociception in cats.[81, 82] In dogs, the MAC of isoflurane was decreased by oral
gabapentin administration, however it is unclear if the decrease was associated with analgesia.[83] While published case reports in dogs
and cats have suggested some analgesic benefit, there is a lack of controlled clinical studies in dogs and cats evaluating the efficacy of
gabapentin as an analgesic drug.[84-87]

The terminal half-life of gabapentin is short in dogs and cats, therefore oral dosing at least every 8 hours is recommended.[88] Potential
adverse effects include sedation and ataxia, which are more likely to occur when higher doses are administered. Abrupt withdrawal of
chronic administration may result in seizures; therefore, it is recommended to taper the dose over the course of one week.

SUMMARY
When possible, practice multimodal pain management, utilizing both pharmacological and nonpharmacologic treatment modalities.
The 2022 AAHA Pain Management Guidelines for Dogs and Cats describes a tiered approach to managing pain in dogs and cats in their
Decision Tree for Prioritizing Pain Management Therapies.[89] Remember that early intervention in response to either acute or chronic
pain will aid in making pain easier to control. Like anesthesia, pain management is a continuum of care that should include assessment
and treatment of pain, reevaluation on a regular basis and, if required, modification of the pain management plan.

9
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