Chapter 19 The Prevention and Management of Pain in Canine Patients 483studies did not use a validated acute pain clini-
cal measurement instrument, and in a recent
limited study acetaminophen did not increase
mechanical thresholds (KuKanich, 2016). While
the drug has somewhat lower bioavailability in
dogs than other species (Nierinckx et al., 2010),
interestingly dogs do not produce the N‐acetyl‐
p‐benzoquinoneimine (NAPQI) metabolite
responsible for hepatotoxicity in humans. Dogs
do, however, produce the para‐aminophenol
metabolite that can cause methemoglobinemia
and hemolysis (such as in cats, but without the
lack of glucoronidase that substantially exacer-
bates toxicity) (McConkey et al., 2009). There
are no toxicity data to suggest dogs have any
unusual level of adverse effects with judicious
use of acetaminophen. However, chronic use
cannot be advocated in dogs at this time, since
long‐term safety has not been established.
Tips for use
Acetaminophen can be alternated with NSAIDs,
but it is recommended not to exceed 325 mg
b.i.d., even for the largest dogs, or for extended
use. Acetaminophen can be contraindicated in
dogs exposed to methemoglobin‐inducing
drugs or toxins, and, more controversially, in
dogs with liver dysfunction or exposed to
hepatotoxic agents.
Opioids
Synthetic opioids are powerful tools to manage
pain because receptors for naturally occurring
opioids (endorphins, enkephalins) are distrib-
uted throughout the body and can be found in
both central and peripheral tissues. Several opi-
oid receptor types and subtypes have been iso-
lated, each with a variant effect. The reader is
guided to more comprehensive resources
regarding opioid neuropharmacology and prod-
ucts (e.g., Epstein, 2015) but a summary follows.
Activation of a mu‐opioid receptor inhibits
presynaptic release of and postsynaptic response
to excitatory neurotransmitters (especially in the
dorsal horn of the spinal cord), hyperpolarizing
second‐order neurons (Barkin et al., 2006).
Activation of kappa receptors promotes the
release of inhibitory neurotransmitters (predom-
inantly gamma‐aminobutyric acid (GABA)).
Pure mu agonists
Morphine remains the prototype opioid and in
widest use. It has no ceiling effect on analgesia
or respiratory depression, elicits histamine
release, and in nonpainful dogs (e.g., as a
premedicant) causes vomiting.
Oxymorphone (Numorphan®) and hydro-
morphone (Dilaudid®) do not elicit histamine
release, produce somewhat less nausea,
and have a shorter duration of action than
morphine.
Methadone may be a parenteral opioid alter-
native in animals, in part due to its additional
effect as an N‐methyl‐d‐aspartate (NMDA)
antagonist. Some veterinarians favor it as a pre-
medication due to its effectiveness, nice seda-
tion, and low ADE profile (minimal if any
nausea, no histamine release) (Ingvast‐Larsson
et al., 2010).
Fentanyl (Sublimaze®) is a potent short‐act-
ing opioid preparation most often used as an
intravenous constant rate infusion (CRI). A
transdermal patch (Duragesic®) has been used
in dogs though a number of studies have dem-
onstrated wide kinetic variability (Kyles et al.,
1996). The inherent liability of potential human
exposure (purposeful or accidental), especially
in children (deaths have occurred), must also be
considered.
Oral opioids experience a robust first‐pass
effect in dogs (KuKanich et al., 2005), but they
may not be without utility.
● Codeine: dogs do not convert codeine to
morphine as in humans, but do appear to
produce significant amounts of another bio-
active mu‐agonist metabolite, codeine‐6‐
glucuronide. However, oral codeine in this
limited study failed to raise mechanical
thresholds (KuKanich, 2016).
● Hydrocodone: data in dogs are conflicting,
with variable pharmacokinetics reported
(some possibly favorable although there
is poor conversion to hydromorphone)
(KuKanich & Spade, 2013; Benitez et al.,
2015a).
● Oxycodone: data are extremely limited in
dogs. Rectal suppository opioid formula-
tions may also be prescribed, but appear
to provide little advantage in bioavailabil-
ity over the oral route in dogs (Barnhart
et al., 2000).