14

Opioid analgesics
Richard Hammond, Macdonald Christie and Anthony Nicholson

INTRODUCTION administration of the analgesic confirming and treating

the presence of pain.
Pain It is also important to recognize that pain is only one
Recognition of pain in animals and its of many internal and environmental stressors placed on
management critically ill or postsurgical animals. Fear and anxiety
Most clinicians now accept that ‘beneficial’ effects of can intensify the distress associated with pain. There-
pain are limited (minimizing the extent of an injury, fore, sedation is often desirable in these patients and
encouraging rest, learning of avoidance behavior). In the combination of analgesics and anxiolytics (e.g.
animals under direct veterinary care, these responses are acepromazine, midazolam, medetomidine) may be very
maladaptive and deleterious. Ongoing or severe pain beneficial. Much can also be done to provide relief from
confers no useful function in the clinical setting and is pain and distress other than using drugs. Other strate-
associated with a well-established, evidence-based list of gies include:
negative aspects. These include: the shift to a catabolic ● wound care: careful dressing and stabilization will

state, reduced voluntary food intake, impaired respira- limit movement and self-trauma; dressings/splints
tory function and delayed recovery from anesthesia, ● nutrition: important in wound healing and a useful

delayed wound healing, central/peripheral hypersensiti- diversionary activity

zation and chronic hyperalgesic states, and an increased ● physiotherapy: assists early mobilization and

development of metastatic disease following tumor reduces inflammation

removal. These aspects are in addition to the ethical ● environment: providing comfort and padding.

considerations of alleviating suffering of patients under

our care. The importance of pre-emptive analgesia
Despite this acceptance, many clinicians are unwilling A painful stimulus associated with tissue damage is
to provide the plane of analgesia adequate for the pre- detected by tissue nociceptors. The stimulus is transmit-
existing level of pain or the proposed surgical interven- ted via primary afferent neurones to the spinal cord or
tion. Common (but not excusable) reasons for neglect cranial nerve nuclei. Two main types of neurones are
of analgesia in small animals primarily are based upon involved: C-fibers (slow, dull pain) and Aδ fibers (fast,
misconceptions as to opioid safety or unwanted effects sharp pain). These fibers enter the spinal cord via the
and inability to adequately recognize pain. Indeed, it has dorsal horn and interact with other spinal nociceptive
been hypothesized that evolutionary processes have neurones and neurotransmitters to achieve perception
contributed to making recognition of pain in animals of the stimulus in the higher centers in the brain. This
difficult. Animals showing weakness, distress or pain system is highly malleable and can change over time
become targets for predators. Therefore, the laws of according to input.
survival require that abnormal behavior be avoided at Both types of clinically important pain (inflammatory
all costs. Thus, just because an animal does not exhibit and neuropathic) are associated with a generalized
what the clinician thinks are typical signs of pain (e.g. increase in sensitivity of the whole nociceptive process-
vocalizing) does not mean that it is not in pain. ing system. This leads to nonpainful stimuli being per-
The indicators of pain in animals are often nonspe- ceived as painful (allodynia) and an exaggeration of
cific and may be confused with disease (anorexia), hypo- pain responses (hyperalgesia). The latter can occur at
volemia (tachycardia), pulmonary disease (tachypnea) the site of injury (primary) or at distant tissues (second-
or reaction to being in a strange environment (altered ary). Such sensitization is initiated almost immediately
behavior). In most cases there are few contraindications following a painful stimulus, both centrally within the
for giving the animal ‘the benefit of the doubt’ and using nervous system as well as in the peripheral tissues.
the administration of an analgesic as both diagnostic Peripheral sensitization occurs largely because of an
and therapeutic tool, an improvement of the animal on increase in sensitivity of peripheral nociceptors to

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 CHAPTER 14 OPIOID ANALGESICS

inflammatory and ‘nociceptive’ mediators released fol- Drugs derived directly from the opium poppy are
lowing tissue injury. This causes afferent neurones to known as opiates while any substances that interact
fire more frequently. It also allows low-intensity signals specifically with opioid receptors (see below), including
to stimulate spinal cord neurones. Central sensitization endogenous peptides and opiates, are known as
occurs due to changes within the spinal cord. Nerve opioids.
fibers in the dorsal horn of the spinal cord increase their
excitability and afferent information is ‘overinterpreted’ Clinical applications
by the spinal afferent system. The clinical significance
of these mechanisms is that any pain perceived by the Opioids are effective for treatment of moderate-to-
animal is more severe once tissue damage has occurred, severe pain, particularly acute pain due to trauma and
and analgesics may be less effective. surgical procedures. Although these drugs can have sig-
This has given rise to the concept of pre-emptive nificant side effects, these are significantly reduced in the
analgesia: giving analgesics before tissue damage occurs. face of pre-existing pain and for most animals are
Postoperative pain may be more easily controlled when usually not of sufficient concern to prevent use of opioid
it is pre-empted by administration of analgesic therapy drugs at clinical dose rates.
instituted before the patient is exposed to noxious
stimuli, whether or not the patient is conscious. The Chemical structure
reasons for this are not entirely understood but appear Morphine has a five-ring structure that is the core for
to be related to the fact that the organization and func- many of the semisynthetic opioids, including heroin
tion of the nervous system change following painful (diacetyl morphine), oxymorphone, pentazocine, butor-
stimuli. The significance of this hypersensitivity remains phanol, buprenorphine and naloxone.
controversial in humans but it is important in several Synthetic opioids have fewer rings and form either
species of experimental animals. It may therefore be piperidines such as pethidine (meperidine) or the phenyl-
much easier to prevent pain produced by surgery than piperidines, which include fentanyl, sufentanil and
to suppress it once it is already present. In human alfentanil.
patients, it has been clearly shown that fixed-interval Remifentanil is also a phenylpiperidine, but as a 4-
administration of analgesics (a regular dose at a regular anilidopiperidine derivative of fentanyl, has an ester
time) is more effective in achieving pain relief and linkage in the piperidine ring, making it susceptible to
requires lower overall doses of opioids than dosing on metabolism by plasma esterases.
demand. It is therefore more effective (and humane) and Methadone has a structure very different from that
safer to administer opioids to control pain likely to of morphine but retains the active moieties of morphine.
result from a procedure than attempt to reduce pain Opioid antagonists, including naloxone, naltrexone and
after severe signs have emerged. nalbuphine, structurally resemble agonists but generally
have bulky unsaturated N-linked substitutions.
Drugs
EXAMPLES Opioid receptors and drug/effector
mechanisms
Morphine and its analogs (e.g. oxymorphone), pethidine
(meperidine), methadone, codeine, fentanyl and its analogs Classes of opioid receptor
(alfentanil and remifentanil), buprenorphine, butorphanol, The opioid receptors are pharmacologically distinct,
pentazocine and tramadol. closely related membrane proteins that share common
characteristics because they have evolved from a
common ancestral G protein-coupled receptor. Three
The opioid analgesics remain the most potent and effica- types of opioid receptor have been identified in mammals.
cious analgesic drugs in veterinary medicine. The pro- These are termed mu (µ, the Greek letter m, for ‘mor-
totype drug is morphine, named after the Greek god of phine receptor’, also MOP using standard nomencla-
dreams, Morpheus. It is derived from the dry residue of ture), kappa (κ, the Greek letter k, for ketocyclazocine,
the exudate from the unripe seed capsule of the poppy the first class of drug used to define the receptor func-
Papaver somniferum. This residue is opium, which con- tionally, also KOP using standard nomenclature) and
tains a mixture of alkaloids, of which there are two delta (δ, the Greek letter d for deferens, because the
main types. These are the phenanthrene alkaloids, which mouse vas deferens was the first tissue used to define
include morphine and codeine, and the benzylisoquino- the receptor functionally, also DOP using standard
line alkaloids, of which papaverine is the main example, nomenclature). Each of the three receptor proteins is
which have smooth muscle relaxant effects but no anal- encoded by an independent gene. A fourth closely
gesic properties. related gene encodes an opioid-like receptor (NOP using

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 INTRODUCTION

standard nomenclature, also known as ORL-1) that nisms, e.g. they can all activate inwardly rectifying
interacts with some opioid-like peptides orphanin-FQ potassium conductance and inhibit voltage-operated
or nociceptin but not the classic opioid drugs. The calcium conductances in cell membranes to produce
potential role of this receptor in pain control is still inhibition of excitability. However, different responses
being investigated. can be evoked in different cell types in response to acti-
Other types and subtypes of opioid receptor have vation of different opioid receptors. These are likely
been suggested on the basis of indirect pharmacological to reflect changes in the expression of G proteins and
evidence but their existence has either been ruled out or effector systems between cell types rather than any
they have not yet been clearly established. The sigma inherent differences in the properties of the receptors
(σ) receptor is no longer considered to be an opioid themselves.
receptor. Opioid receptor activation produces a wide array of
The epsilon (ε) receptor is not a distinct opioid recep- cellular responses, the net result of which depends upon
tor, being best explained by the presence of a very low the location of each receptor type in the nervous system
density of µ receptors in some tissues. The suggestion and on the specific biochemical cascades activated in
that a subtype of µ-receptor is the target of the different types of cell. For example, µ-opioid receptors
major active metabolite of morphine, morphine-6- are located throughout neural systems responsible for
glucuronide, has little or no experimental support. pain sensation, from the spinal cord to the brain. The
Further receptor subclassifications such as µ1 and µ2, inhibition of pain transmission produced by µ-opioid
δ1 and δ2 and κ1 and κ2 are controversial. It remains agonists is highly selective and other sensory modalities
possible but not established that some subtypes arise are not disrupted. µ-Receptors also occur on nerve cells
from alternatively spliced mRNA products of transcripts responsible for generating respiratory rhythms in the
of the three major receptors, or from hetero-oligomer- brainstem and thus depress respiration when stimulated.
ization among the three major receptor types. The κ3 Receptor selectivity, distribution and pharmacological
subtype is no longer accepted. responses produced by opioid agonists are summarized
in Table 14.1.
Effector mechanisms All opioid receptors appear to function primarily by
Opioid drugs mimic the actions of endogenous opioids exerting inhibitory modulation of synaptic transmission
(endorphins), which are peptides produced in the in both the CNS and various peripheral nerve cells,
nervous and endocrine systems that stimulate opioid including the myenteric plexus. Receptors are often
receptors. A number of opioid peptides ranging in size found on presynaptic nerve terminals, where their action
from five to over 30 amino acids are synthesized from results in decreased release of neurotransmitters, or on
the three large precursors: pro-opioimelanocortin, pro- nerve cell bodies, where they inhibit the generation of
enkephalin and prodynorphin. Endogenous opioid action potentials. In some parts of the nervous system
systems appear to usually have only weak tonic activity opioid receptors inhibit excitatory neurotransmission
but become highly active under certain environmental and in others release of inhibitory neurotransmitters is
conditions, e.g. during extreme stress and pain. The impaired, leading to disinhibition or a net excitatory
analgesic activity of some opioid drugs (e.g. tramadol) effect.
is due to interaction with opioid receptors as well as
other neurotransmitter systems. Known drug interactions with opioid receptors
Different opioid drugs bind to distinct opioid recep- Some opioids act with high efficacy and potency at one
tors with varying degrees of affinity and have differing receptor type and with much lower potency and lower
durations of action, which result in different pharmaco- efficacy at other receptors; these are called full agonists,
logical profiles. To complicate matters, a given opioid e.g. morphine at µ-receptors. Some opioids are partial
drug may act as an agonist, a partial agonist or an agonists at one receptor type, e.g. buprenorphine is a
antagonist at each type of receptor (Fig. 14.1). Selection partial µ-receptor agonist with little activity at other
of an opioid for a particular use depends on these types. Others are mixed agonist-antagonists, having
properties as well as its absorption, distribution agonist actions at one receptor type and antagonist
and metabolism. activity at others (e.g. nalbuphine is a µ-antagonist as
All the cloned opioid receptor types belong to the well as a κ-agonist).
Gi/Go-coupled superfamily of receptors. Under normal Endogenous opioid peptides display some selectivity
circumstances opioid receptors do not couple directly for different receptor types. Enkephalins and β-
with Gs or Gq and none of the cloned receptors forms endorphin interact selectively with both µ- and δ-
a ligand-gated ion channel. All three classic receptor receptors. Dynorphins are selective for κ-receptors and
types (µ, δ and κ) and the NOP-receptor couple through endomorphins are selective for µ-receptors; however,
Gi/Go proteins generally share common effector mecha- the existence of endomorphins will remain tentative

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 A B
Agonist opioid Partial agonist opioid Agonist
(morphine) (buprenorphine) opioid

µ µ µ µ
κ Agonist κ κ κ
Both receptors Partial
activated activation
opioid actions of µ receptor

increase
increase

Agonist

Partial

Analgesia
Agonist +
Analgesia

agonist partial
agonist

Log dose increase Log dose increase

C D
Opioid antagonist Agonist Partial agonist opioid Agonist
(naloxone) opioid (buprenorphine) opioid

µ µ µ µ
κ Antagonist κ κ κ
No activation
Activation of κ receptor
of receptors
but occupation without
action at the µ receptor

Agonist
increase

Agonist
increase

Agonist + Agonist + agonist–

antagonist antagonist
Analgesia
Analgesia

Agonist–
(blocking action
antagonist
at µ receptor)
(κ interaction)

Log dose increase Log dose increase

Fig. 14.1 Opioid receptor interactions. A lock-and-key analogy is used to illustrate different drug interactions at mu
(m) and kappa (k) receptors, below which is a relative dose–response curve for analgesic potency. (A) An opioid
agonist stimulates both receptor types, which results in increased analgesic effect with increased dose. (B) A partial
agonist weakly stimulates the m-receptor to achieve a reduced maximum analgesic effect compared with a full
agonist. A large dose of a partial agonist will block the receptor actions of the full agonist and so move its dose–
response curve to the right and depress the maximal analgesic response. Buprenorphine, a commonly used partial
agonist, has very strong receptor binding so that even with very large doses of an agonist, the limited analgesic
effect of buprenorphine predominates. (C) Complete opioid antagonists possess no intrinsic activity but block the
m- and k-receptors. Because of the competitive nature of the binding at the receptors, more agonist is required in
the presence of antagonist to produce its full analgesic effect. (D) Agonist-antagonists have mixed activity at the
two receptor types. Most, such as nalbuphine, have agonist activity at k-receptors and antagonist activity at m-
receptors. In the presence of a full m-agonist, these opioids tend to act as antagonists and increase the dose of full
agonist required to achieve maximum analgesic effect.

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 INTRODUCTION

Table 14.1 Features of different opioid receptor types

Receptor type Mu (m) Kappa (k) Delta (d)

Some selective drugs Fentanyl Butorphanol (also a partial None available but some
used clinically Morphine µ-agonist) are in development
Methadone Pentazocine (also a partial
Oxycodone µ-agonist)
Pethidine (and most other opioid analgesics in Nalbuphine (also a weak partial
use) µ-agonist)
Location of receptors Brain: Brain: Brain:
relevant for clinical All pain sensation and modulation pathways Basal ganglia Basal ganglia
effects Chemoreceptor trigger zone Limbic centers Cortex and thalamus
Respiratory centers Cortex and thalamus Spinal cord: dorsal horn
Baroreflex centers Spinal cord: dorsal horn
Basal ganglia (motor effects) Kidney
Limbic centers (emotional responses) Myenteric plexus (gut motility)
Cortex and thalamus (sensory processing)
Spinal cord: dorsal horn (pain sensation)
Myenteric plexus (gut motility)
Selective actions Analgesia (strong) Analgesia (moderate from Analgesia (mild–moderate
Cough suppression spinal cord) from spinal cord)
Constipation Diuresis Motor excitation
Hypotension Sedation
Sedation Dysphoria
Motor excitation (some species) Hallucinosis
Respiratory depression – cause of overdose
death
Tolerance and dependence
Vomiting

until an endogenous mechanism for their synthesis is inflammation. This forms the rationale for direct intra-
found. Most of the analgesic actions as well as side articular instillation of opioids during joint surgery.
effects of the opioids used clinically are due to their
interactions with µ-receptors and, to a lesser extent, κ- Adverse effects in relation to receptor class
receptors in the CNS. The major effects of concern are respiratory depression,
Most of the analgesic actions as well as unwanted hypotension and bradycardia. These effects usually
effects of opioids have been ascribed to interactions result from the CNS location of opioid receptors. Respi-
with opioid receptors in the CNS. Opioid receptors are ratory depression occurs primarily because µ-opioid
expressed preferentially on the CNS terminations of receptor stimulation inhibits the activity of neurones in
nociceptive primary afferent neurones and thence the ventral medulla that respond to hypercapnia (ele-
throughout ascending systems involved in the sensation vated PaCO2). Nausea and vomiting, motor excitation
and emotional appreciation of pain. Opioid receptors and bradycardia are also mediated by the actions of
are also expressed on descending pain modulation opioids on CNS opioid receptors. Some effects, such as
systems. Throughout these neural pathways µ-opioid reduced gastrointestinal motility, are due to the pres-
receptors dominate but κ- and δ-receptors are also ence of opioid receptors throughout the myenteric
present in some places, e.g. the dorsal horn of the spinal plexus that control the tone and peristaltic rhythms of
cord. the gastrointestinal tract and its sphincters. Histamine
More recently, interest has developed in the modifica- release presumably results from an opioid receptor-
tion of peripheral opioid receptors. Opioid receptors are independent action of some opioids on circulating mast
also present on peripheral terminations of nociceptive cells.
nerve fibers. The cell bodies of these neurones in dorsal
root ganglia express mRNAs for all three classic recep-
tor types and receptor proteins. Opioid receptors are
Pharmacokinetics
intra-axonally transported into the neuronal processes, Absorption
where opioids are thought to inhibit nerve cell activity Most opioids are absorbed well from oral, intramuscu-
and produce pain relief only in circumstances where lar, subcutaneous and intravenous routes. Unwanted
sensory nerves are sensitized to all stimuli, e.g. during effects such as histamine release during intravenous

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 CHAPTER 14 OPIOID ANALGESICS

administration of some agents (primarily pethidine) can partial µ-agonists such as buprenorphine and mixed
make the intravenous route unsuitable. agonist-antagonists with weak partial µ-receptor activ-
While most opioids are readily absorbed after oral ity, e.g. pentazocine and butorphanol, reach a ceiling
administration, extensive first-pass metabolism makes effect beyond which no further respiratory depression
this route unsuitable in many cases. Rectal administra- can be produced despite increased analgesic effects
tion, e.g. suppositories, may sometimes partly overcome from increasing doses. These opioids are therefore safer
this limitation. Special routes of administration, such as than full agonists which may be beneficial in some
intrathecal, can be used under some circumstances to circumstances. However, it should be noted that
achieve a high concentration of opioids at a principal partial µ-receptor agonists can produce severe respira-
site of analgesic action, the dorsal horn of the spinal tory depression when used in combination with seda-
cord, while minimizing side effects arising from sites tives that also depress respiration. It should also be
higher in the neuraxis (see below). noted that there is a ceiling effect associated with use of
partial µ-agonists for pain relief, particularly after con-
Distribution and protein binding tinuous administration for several days (see Tolerance
Distribution and protein binding of different opioids and physical dependence). Opioids with some agonist
vary greatly and are discussed under individual activity at κ-receptors, such as butorphanol, also tend
subheadings. to produce less respiratory depression than pure
µ-receptor agonists.
Metabolism and elimination
Rates of metabolism and routes of elimination also vary Nausea and vomiting
among opioids and are discussed under individual Nausea and vomiting are due to direct actions on opioid
subheadings. Active metabolites are important in some receptors located on dorsal medullary neurones in and
circumstances. For example, the active metabolite of around the area postrema. This brain region, which
morphine, morphine-6-glucuronide, is approximately lacks a fully developed blood–brain barrier, is also
five times as potent as morphine. In most species this is known as the chemoreceptor trigger zone. While some
a minor metabolite of little consequence but in patients opioids, such as morphine and oxymorphone, may
with renal failure, it accumulates to significantly enhance induce more vomiting than others, all can potentially
therapeutic actions as well as side effects. do so.

Bradycardia
Adverse effects Opioids may produce a dose-related bradycardia,
Most opioids that act on µ-receptors produce a similar although this tends to be more pronounced with fen-
spectrum of unwanted effects, although there are tanyl and its analogs. This action is caused by depres-
individual differences as discussed for specific agents sion of brainstem cardiovascular control centers,
below. resulting in an increased parasympathetic nervous tone.
In all cases, this may be prevented or treated by use of
Respiratory depression a parasympatholytic such as atropine or glycopyrrolate.
Respiratory depression is the most serious unwanted Pethidine has a structure similar to atropine and as a
effect of opioid agonists and is the primary cause of result does not reduce heart rate at normal clinical
mortality due to overdose All aspects of respiratory doses.
activity are depressed but responsiveness to hypercapnia Myocardial contractility and vascular tone are well
is most affected. Respiratory depression occurs as a preserved when opioids are administered at clinical
result of actions on respiratory control nerve networks doses. As a result, the bradycardia produced by the
located in the ventral medulla. Respiratory reflexes, clinical use of an opioid, especially in the presence of
including the cough reflex, are also profoundly depressed pre-existing pain, does not normally result in significant
and many weak opioid agonists (especially butorpha- hypotension. Indeed, the dose-sparing effect of an opioid
nol) are useful cough suppressants. If PaCO2 is allowed when used concurrently with an anesthetic often results
to increase after opioid agonist administration then in more favorable cardiovascular parameters.
cerebral vasodilation may result in increased intracra-
nial pressure. This may be detrimental in cases of closed Constipation
head injury. In ventilated patients, however, where nor- The use of opium for relief of diarrhea and dysentery
mocapnia is maintained, opioids will reduce intracranial predates its use for pain therapy. Synthetic opioids,
pressure and cerebral metabolic oxygen demand. particularly those that poorly penetrate the CNS (e.g.
Partial µ-receptor agonists tend to produce less respi- loperamide), are currently used to manage diarrhea (see
ratory depression than full agonists. In many species Chapter 19). Constipation is not usually of concern

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 INTRODUCTION

during short-term opioid use for acute pain relief but dose to produce the same effect, and physical depen-
management using stool softeners and other adjuncts dence characterized by a withdrawal syndrome on ces-
may prove necessary during prolonged opioid therapy. sation of use.
Constipation results primarily from inhibitory actions Tolerance can usually be overcome by increasing the
of opioids on neurones of the myenteric plexus, although dose of opioid used but this carries the risk of increasing
the CNS is also involved to a minor extent. Both µ- and physical dependence. The maximum analgesic effect
κ-opioid agonists (relative actions depend on species) achievable may be blunted in tolerant patients for partial
markedly inhibit the propulsive contractions of peristal- agonists such as buprenorphine, pentazocine and butor-
sis, slowing gastrointestinal transit and thereby increas- phanol, regardless of dose. Tolerance and dependence
ing water resorption. Biliary and pancreatic secretion is do not develop appreciably after a single opioid dose
inhibited and sphincter tone is increased, contributing but are of concern if therapy is continued for more than
to constipation. several days. Both phenomena are dose related and
develop in parallel. Therefore, if there is need to escalate
Urinary retention doses of opioids over a period of days to produce ade-
Urinary retention is a minor and variable side effect of quate control of pain then the likelihood increases that
opioids in most species, resulting from increased sphinc- a withdrawal syndrome will be manifested on cessation
ter tone. Where high concentrations are administered of use.
intrathecally or into the extradural space, retention may Opioid withdrawal is intensely dysphoric if severe
be significant, for a period of some hours, and regular and can be minimized by use of gradually diminishing
monitoring of urinary bladder tone should be per- opioid doses. The syndrome differs somewhat among
formed. Opioids with agonist activity at κ-receptors species but can include agitation, violent escape attempts,
produce diuresis, thus increasing urine flow. ptosis, yawning, lacrimation, rhinorrhea, diarrhea, uri-
nation, ejaculation and piloerection.
Histamine release
Opioids are secretagogues and histamine release results
from a nonopioid receptor-mediated action on circulat-
Indications and techniques of opioid
ing mast cells. Pethidine and to a lesser extent morphine
use in small animals
may produce significant histamine release on intravenous Animals presenting in pain
administration of clinical doses. Intravenous use of pethi- Veterinary surgeons may be presented with an animal
dine should be avoided. In contrast, fentanyl produces in pain, most frequently following trauma. In these
little or no histamine release. Pruritus is a relatively cases moderate-to-high doses of opioid, often in combi-
common sequel to extradural administration of mor- nation with sedation and a second mode of analgesia
phine (pethidine is not used via this route) and has been (multimodal analgesia), are needed to overcome the pre-
reported in many species including man, the horse and existing nociception. However, the most frequent indi-
the dog. This is a receptor-mediated action (it is reversed cation for opioid administration in veterinary practice
by opioid antagonists such as naloxone) but has a poorly is perioperatively. This may be preoperative, intraopera-
understood mechanism (it may be treated by subanes- tive, postoperative or a combination of any or all of
thetic concentrations of the sedative-anesthetic propofol, these.
a drug with no known opioid receptor antagonism).
Preoperative analgesia
Excitatory motor effects Preoperative opioids regularly form part of the premedi-
Motor excitation, muscular rigidity and explosive motor cation protocol, usually in combination with a sedative
behavior can occur with µ-opioid receptor agonists at or tranquilizer. Premedicants commonly used in com-
high doses in some species. These actions are dose panion animal practice include acepromazine (ACP),
related and mediated by the CNS. They are thought to medetomidine and the benzodiazepines diazepam and
arise from disinhibition of basal ganglia neural systems midazolam. All three agents have a synergistic effect
and possibly midbrain emotional motor systems. Cats, with most opioids in current usage. With α2-agonists
horses, pigs and ruminants are particularly susceptible this may be explained by a co-localization of receptor
to excitatory motor effects. Opioids are routinely and activity. Analgesic effects of medetomidine are princi-
effectively used in these species and these effects are not pally (but not exclusively) due to spinal antinociception
normally seen at even high-end clinical doses. via binding to nonnoradrenergic receptors located on
the dorsal horn. There is also some evidence of supra-
Tolerance and physical dependence spinal analgesic mechanisms in the locus ceruleus.
Repeated or continuous use of opioids results in devel- In severely compromised animals in whom only low-
opment of tolerance, or a need to administer an increased level sedation is required, a low dose of an opioid alone

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 CHAPTER 14 OPIOID ANALGESICS

may achieve the desired effect, although in general the inhaled, and at the same time provide analgesia; this
level of sedation produced by standard clinical doses is combination of drugs is often referred to as ‘balanced
poor for most opioids when used as the sole agent. Apart anesthesia’.
from providing increased sedation when used in combi- There are two commonly used approaches to the
nation with a sedative or tranquilizer, opioids as part of delivery of intraoperative opioids: intermittent bolus
a premedication protocol can act in a pre-emptive and continuous infusion.
fashion, reducing both the intraoperative and postopera-
tive analgesic requirements. Controlling surgical pain in Intermittent boluses
animals before they fully recover from general anesthesia All µ-agonists, with the exception of the ultra-short
is easier and requires less total drug to be administered acting agent remifentanil, can be administered by inter-
than waiting for the animals to show obvious signs of mittent intravenous bolus, the important difference
pain and then administering an analgesic. between them being the dosing intervals, which need to
be greater for the longer-acting drugs. If such adminis-
tration is continued for a long surgical procedure, then
Opioids and anesthesia induction
the dosing interval will often need to be increased as the
Another preoperative application for some of the full
case progresses to avoid accumulation, which may only
opioid agonists is as a component of the protocol for
become apparent during recovery. Signs of accumula-
induction of anesthesia. Selected opioid agents have
tion observed during recovery include prolongation of
been used for anesthetic induction in a number of situ-
recovery, in particular delayed extubation, respiratory
ations because of the marked cardiovascular stability
depression and possibly excitatory behavior, including
they provide, aside from bradycardia. This technique is
thrashing and vocalization, which can be difficult to
most often reserved for very ill and moribund animals,
distinguish from insufficient analgesia and an extreme
the very elderly or those with a pronounced degree of
response to pain.
cardiovascular compromise. In such cases, higher doses
of ultra-fast acting pure agonist µ-receptor opioids (fen-
Continuous infusion
tanyl, alfentanil) may be administered as part of a
Shorter-acting µ-agonists are well suited to this tech-
coinduction (immediately prior to the induction agent).
nique and more recently have been developed for this
As a result, the dose of induction agent will be signifi-
purpose. As well as acting as supplements to inhala-
cantly reduced but other unwanted effects such as ven-
tional anesthesia, these drugs may also be used as part
tilatory depression are minimized or, where seen, can
of a total intravenous anesthesia (TIVA) protocol in
be quickly managed in the anesthetized patient with a
conjunction with a hypnotic agent such as propofol and
controlled airway. It is also recommended that where
muscle relaxants. In some instances, all three classes of
possible, without stressing the patient, animals be pre-
drug may be administered as continuous infusions. By
oxygenated via facemask or oxygen chamber, prior to
selection of the appropriate agents and infusion rates,
induction of anesthesia.
this technique can provide precise control of anesthetic
The onset of anesthesia during an opioid induction is
depth and hence reduce recovery times. Fentanyl has
much slower than that achieved with other intravenous
traditionally been the agent of choice for this indication
agents such as thiopental and propofol. Delay in onset
in veterinary anesthetic practice. The cumulative nature
during induction relates to those factors that influence
of fentanyl when infused for more than 90 min and
the transfer across the blood–brain barrier: lipid solubil-
the introduction of remifentanil means that fentanyl
ity, ionization and protein binding. Some opioids, fen-
is no longer the infusion opioid of choice in most
tanyl in particular, make animals hyperresponsive to
circumstances.
sudden, loud sounds, which should therefore be avoided
during induction.
Extradural and intrathecal
administration of opioids
Intraoperative use of opioids Other techniques for opioid administration periopera-
Many studies have demonstrated a reduced requirement tively are extradural (epidural) and intrathecal (sub-
for inhalant anesthetic agents (reduction in the minimum arachnoid, spinal) placement of opioids alone or in
alveolar concentration – MAC) in animals that have combination with local anesthetic agents. These tech-
received opioid analgesics. This effect is dose dependent; niques can be used to supplement general anesthesia or
however, even at extremely high dose rates the MAC heavy sedation and provide highly effective analgesia
reduction is still not 100%, which further indicates the with MAC reduction of 30–60% and good cardiovas-
inability of opioids to act as true anesthetic agents. cular stability. Patient and procedure selection are very
Therefore opioid analgesics can be used to supplement important if these techniques are to be used without
the main anesthetic agent, whether it be infused or general anesthesia but they can be extremely successful

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 INTRODUCTION

in the right circumstances, such as a tail amputation in motor neurones, thus providing further analgesia and
well-sedated dogs. muscle relaxation, which is particularly useful for ortho-
In conjunction analgesia lasts 12–24 h following a pedic procedures of the hindlimbs. However, sympa-
single dose of morphine with an onset time of 30– thetic blockade may also occur, causing peripheral
60 min, especially when used in combination with a vasodilation and consequent hypotension and hypother-
local analgesic. mia, which in part can be ameliorated by ensuring an
When administered into the extradural space or adequate hydration status and appropriate intravenous
directly into the cerebrospinal fluid (subarachnoid fluid administration during the procedure. Lidocaine
space), opioids provide very profound analgesia by (lignocaine) is frequently used for its rapid onset of
acting on the µ-receptors within the substantia gelati- action to provide early surgical analgesia while bupiva-
nosa of the spinal cord. The lower lipid solubility, and caine, ropivacaine and levo-bupivacaine tend to be used
hence slower uptake into the cord, of morphine increases for their longer duration of action and relative selectiv-
spread of the drug within the extradural space. This ity for sensory over motor blockade.
increases the number of dermatomes over which Analgesia provided by neuraxial placement of opioids
analgesia is produced and is considered beneficial in is useful for procedures of the hindlimbs particularly
veterinary species. In humans the cranial spread of mor- and also for forelimb procedures, thoracotomies and
phine is associated with a biphasic and often delayed major intra-abdominal surgery.
respiratory depression. It is for this reason that mor-
phine is rarely used for human extradural or spinal Alternative routes of therapy
anesthesia. Highly lipid-soluble opioids such as fentanyl Other routes that have been used more recently for
and butorphanol are best delivered via an epidural cath- postoperative analgesia include intra-articular instilla-
eter so that repeated doses may be administered. This tion of an opioid prior to joint closure, instillation into
particular technique is not often used in veterinary med- the interpleural space following intrathoracic surgery,
icine because of the technical skill involved in catheter and transdermal delivery of fentanyl.
placement and the subsequent patient monitoring
required to avoid complications or inadvertent catheter
removal. Intra-articular
In cats and dogs a spinal needle is usually inserted at Intra-articular morphine has been shown to be an effec-
the lumbosacral space, which especially in the dog gen- tive means of providing analgesia in multiple species
erally ensures epidural rather than spinal drug delivery. including the horse and dog, especially where a joint is
Several recommendations have been made as regards inflamed. Analgesia has been successfully provided to
these techniques to avoid complications. First, in large dogs following median sternotomy by the instillation of
dogs it is recommended by some that no more than morphine into the interpleural space, a technique previ-
6 mL of drug and diluent be injected into the epidural ously reserved for local anesthetics, bupivacaine in
space of any size of animal and if cerebrospinal fluid particular.
flows back through the needle, indicating spinal place-
ment, then only 25% of the calculated volume should Fentanyl patches
be administered. It is also important to use sterile and Fentanyl patches have been developed for use in humans,
preservative-free drugs to avoid problems with neuro- as a means of providing analgesia for prolonged periods.
toxicity, which may be more apparent with spinal Although formulated to provide appropriate fentanyl
administration than epidural. release rates for absorption through human skin, it has
Delayed respiratory depression is the most common been shown that effective plasma levels can also be
and significant side effect of epidural or spinal opioid attained in dogs and cats.
administration observed in small animals. Others It is important to note that in animals, the plasma
observed in humans but not well documented in small concentrations of fentanyl vary considerably between
animals include urinary retention, pruritus, nausea and individuals and in some animals it is unlikely that sig-
vomiting. Animals may become sedated after epidural nificant analgesia will be produced. It is therefore par-
morphine due to its cephalad spread in the cerebrospi- ticularly important to carry out regular assessments of
nal fluid, but in general the sedation is no more than the adequacy of pain relief in animals treated with
that seen with other routes of administration. patches and to be prepared to provide additional anal-
In many situations opioids are not the sole agent gesia when required.
delivered by these techniques but are combined with Onset of analgesia is slow (up to 12 h) but the
other drugs, most commonly a local anesthetic but also patches can provide effective pain relief for up to 72 h.
analgesics of a different modality such as ketamine. All regulations relating to controlled substances still
Local anesthetic agents act at both the sensory and apply.

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 CHAPTER 14 OPIOID ANALGESICS

Small dogs and cats may be dosed with half a patch, CLINICAL PHARMACOLOGY OF
but the patch should not be cut in half. Cover half the INDIVIDUAL OPIOID AGONISTS
gel membrane with tape. ‘Half-patch dosing’ is sug-
gested for pediatric, geriatric and systemically ill cats Choice of the most appropriate opioid analgesic, as well
and small dogs. as its dose and route of administration in a given clinical
The patch may be placed either on the dorsal situation, is dictated by the pharmacodynamic and
or lateral cervical area or the lateral thorax. If the neck pharmacokinetic factors discussed above. Table 14.2
is used, collars/leashes cannot be placed over the patch. summarizes important pharmacodynamic features of
The thorax is easily used and contact maximized the available opioids discussed below and Table 14.3
(especially in cats), but can be difficult to bandage. The lists appropriate doses and routes of administration in
site must be clean and dry at the time of application. different species.
The patch should not be placed where a heating
pad may come into contact as this may increase release
Morphine
of drug from the patch. All patients wearing patches
should have heart and respiratory rates monitored Morphine is the opioid analgesic against which others
regularly. are compared.

Table 14.2 Relative activities of opioid agonists and antagonists at µ- and κ-receptors

Drug Receptor activity Mu (m) Kappa (k) Analgesic efficacy

Morphine Agonist ++ 0 Strong
Pethidine (meperidine) Agonist + + Moderate-strong
Methadone Agonist ++ 0 Strong
Oxymorphone Agonist ++ 0 Very strong
Fentanyl Agonist ++ + Very strong
Alfentanil Agonist ++ + Very strong
Codeine* Agonist + 0 Weak
Tramadol** Agonist + 0 Moderate
Buprenorphine Partial agonist P+ P+? Moderate
Butorphanol Agonist–antagonist P+ + Moderate-weak
Pentazocine Agonist–antagonist P+ ++ Moderate-weak
Nalbuphine Agonist–antagonist P+? + Moderate-weak
Naloxone Antagonist – - N/A
Nalorphine Antagonist – P+ N/A
Nalmefene Antagonist – - N/A

++, Strong agonist activity; +, agonist activity; P+, partial agonist activity; 0, no activity; -, weak antagonist activity; – –, strong antagonist activity;
N/A, not applicable,?, the action is very weak or absent.
* Opioid actions of codeine are due exclusively to its slow metabolic conversion to morphine.
** Tramadol is moderately analgesic because it is a dual µ-receptor agonist (its metabolites are more potent) and monoamine (noradrenaline
and serotonin) transport inhibitor.

Table 14.3 Opioid dosages and duration of action

Drug Route of administration Dose rate (mg/kg)† Duration of analgesic

action (h)¶
‡
Dog Cat
Agonists
Morphine Intravenous 0.05–0.1 0.05 1–4§
Intraoperative bolus 0.1 0.05
Intramuscular or subcutaneous 0.1–0.5 0.1–0.3 4–6
Extradural 0.1–0.2 0.1–0.2 12–24
Interpleural 0.5–1.0 8–12
Intra-articular 0.1–1.0 8–12
Oral 0.1–3.0 0.1–1.0 4–8
Sustained release 1.5–3.0 N/A 8–12

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 CLINICAL PHARMACOLOGY OF INDIVIDUAL OPIOID AGONISTS

Table 14.3 Opioid dosages and duration of action (continued)

Drug Route of administration Dose rate (mg/kg)† Duration of analgesic

action (h)¶
‡
Dog Cat
Pethidine Intravenous Contraindicated in small
(meperidine) animals
Intramuscular or subcutaneous 2–10 2–10 1–2
Methadone Intravenous 0.05–0.1 0.05–0.1 4–6§
Intramuscular or subcutaneous 0.1–1.0 0.1–1.0 4–6
Oxymorphone Intravenous 0.02–0.2 0.02–0.1 2–4§
Intraoperative bolus 0.1 0.05
Intramuscular or subcutaneous 0.02–0.2 0.02–0.1 4–6
Epidural 0.02–0.1 0.02–0.1 8–12
Fentanyl Intraoperative IV bolus 0.002–0.005 0.001–0.005 0.3–0.5
Constant rate IV infusion:
Loading dose 0.01 0.005
Infusion rate 0.0025–0.010 mg/kg/h 0.0025–0.005 mg/kg/h
Anesthetic induction IV 0.01 N/A
+ diazepam (0.5 mg/kg) or
midazolam (0.2 mg/kg)
Transdermal: 2–4 µg/kg/h 2–4 µg/kg/h ≥72
Patch sizes: 25, 50, 75 and 100 mg/h
Intravenous induction 0.04 mL/kg Contraindicated
Intramuscular or subcutaneous 0.02–0.04 mL/kg 0.5–1.0
Alfentanil Intravenous 0.01–0.025
Remifentanil* Intravenous 0.1–0.6 µg/kg/min 0.05–0.3 µg/kg/min Half-life approximately
4 min irrespective of
infusion duration
Codeine Oral 0.5–2.0 0.5–2.0 4–6
With paracetamol (acetaminophen) 0.5–2.0 Contraindicated 6–8
Subcutaneous 0.5–2.0 0.5–2.0
Buprenorphine Intravenous 0.005–0.02 0.005–0.01 3–4
Intramuscular or subcutaneous 0.005–0.04 0.005–0.04 4–12
Epidural 0.005–0.02 0.005–0.01 12–18
Butorphanol Intravenous 0.2–0.4 0.2–0.4 1–3 (dog)
4 (cat)
Intramuscular or subcutaneous 0.2–0.4 0.2–0.4 2–6
Antitussive dose 0.05–0.1 6–12
Oral 0.2–1.0 0.2–1.0 6–8
Pentazocine Intravenous 1–3 0.75–1.5 1–3
Intramuscular or subcutaneous 1–3 0.75–1.5 2–3
Oral 2–10 4–6
Antagonists
Naloxone Intravenous 0.01–0.04 20 min (0.3)
Intramuscular or subcutaneous
Nalorphine Intravenous 10–20 2–3
Intramuscular or subcutaneous 10–20 2–3
Nalbuphine Intravenous 0.5–1.5 1–6
Intramuscular or subcutaneous 0.5–2.0 4–8
Nalmefene Intravenous 0.03 ≥4
†
Dose selected will depend on desired effect, whether for sedation and/or analgesia, and other drugs concurrently administered.
‡
Where no dose rate is given for cats there are generally no recommendations available in the literature, rather than that drug being
contraindicated for use in cats. A similar or lower dose may be used with caution.
¶
Duration of action will be affected by concurrent drug administration, desired effect and type of procedure performed and therefore act as a
guide only. These variables will influence the repeat dosing schedule and hence each animal should be assessed for evidence of pain and
response to therapy.
§
Intravenous boluses can be ‘titrated’ to effect by administering a bolus from the lower end of the dose range and repeating every 5–10 min
until the desired effect is achieved. At the same time, it is important not to overdose the patient.
* IPPV or support ventilation is mandatory at all but lower doses.

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 CHAPTER 14 OPIOID ANALGESICS

Clinical applications Doses from the lower end of the range should be used
Morphine is effective for treatment of visceral pain as in cats. When used preoperatively in cats, coadministra-
well as somatic pain, unlike nonopioid analgesics. Mor- tion of a sedative/anxiolytic reduces the likelihood of
phine is appropriate in most situations where medium- excitement. Interpleural and intra-articular routes have
to long-term analgesia is required. It is commonly used not been described in cats. A common postoperative
for trauma patients and perioperatively and is the most protocol for morphine involves an initial dose at 0.1 mg/
commonly used opioid for epidural administration. kg administered slowly IV then waiting 5–10 min before
Clinical studies have shown the analgesic effective- administering a second dose if considered necessary.
ness of morphine, IV or IM, for arthrotomy, lateral Further doses may be required at 30–60 min intervals
thoracotomy and median sternotomy. It has also been to maintain adequate analgesia. Low-dose ACP can be
demonstrated to be effective intra-articularly following a very useful adjunct in these situations.
arthrotomy and interpleurally after sternotomy.
Morphine is suitable for use as a premedicant, gener- Pharmacokinetics
ally in combination with a sedative. It is generally given Although morphine is well absorbed when administered
intramuscularly or subcutaneously. Dogs will often sali- orally, extensive first-pass metabolism occurs, as with
vate, vomit, defecate and pant, while cats may salivate most other opioids. It is therefore usually administered
and appear nauseous. These effects are markedly reduced parenterally (SC, IM, IV). Peak analgesic action is seen
by combination with acepromazine. Cats may not about 10 min after IV injection and 45 min after SC
appear to be sedated by morphine but generally they injection. Analgesia may only last for 1–2 h after IV
become more tractable, so venous access is easier to administration. However, the duration of analgesia is
achieve. In humans a relatively high dose of morphine increased to up to 6 h following SC or IM administra-
at the time of induction has been shown to significantly tion. Extradurally administered morphine may provide
reduce the postoperative morphine requirements com- analgesia for 24 h after an onset time to peak analgesia
pared with patients who first received morphine at the of 30–60 min.
end of surgery. Following IV administration, plasma morphine con-
Extradural morphine may be delivered prior to centrations correlate poorly with pharmacological activ-
surgery after anesthetic induction or at the end of the ity, in part because of delayed entry into the cerebrospinal
surgical procedure. Prior administration will provide fluid through the blood–brain barrier. Similarly, the
some intraoperative analgesia, depending on the dura- analgesia and other effects continue despite decreasing
tion of the procedure, as well as lowering the require- plasma concentrations. It has been estimated that less
ment for volatile anesthetic, which may have the added than 0.1% of an intravenously administered dose of
benefit of a shorter recovery period. Other routes for morphine has reached the central nervous system at the
postoperative use of morphine include intra-articular time of peak plasma concentration. This is because of
and interpleural. More commonly, local anesthetics will low lipid solubility, a high degree of ionization at physi-
be instilled in preference to morphine, although a com- ological pH (about 75%), protein binding (30–35%)
bination may prove to be most efficacious. and rapid conjugation to glucuronic acid.
Morphine is predominantly metabolized in the liver
Mechanism of action and kidney by conjugation with glucuronic acid to form
Morphine is a µ-receptor selective opioid agonist, with morphine-3-glucuronide (75–85%) and morphine-6-
very low affinity at κ-receptors and virtually no activity glucuronide (5–10%). These metabolites are predomi-
at δ-receptors. It produces profound analgesia and seda- nantly excreted in urine and so may accumulate in
tion in the dog. patients with renal failure. Morphine-6-glucuronide
acts at µ-receptors to produce analgesia and respiratory
depression while morphine-3-glucuronide has no
pharmacological action. The actions of morphine-6-
glucuronide may account for a significant part of the
Formulations and dose rates clinical efficacy of morphine. It may also be for this
reason that morphine appears to be a less effective anal-
DOGS AND CATS gesic in cats who, as a species, are less able to perform
• IV: 0.05–0.1 mg/kg conjugation.
• IM, SC: 0.1–0.5 mg/kg
• Extradural: 0.1–0.2 mg/kg
• Interpleural: 0.5 mg/kg
Adverse effects
• Intra-articular: 1.0 mg/kg Central nervous system
• PO: 0.1–1.0 mg/kg, 1.5–3.0 mg/kg sustained release (dog) CNS depression in the form of sedation and drowsiness
is common following morphine administration in dogs,

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 CLINICAL PHARMACOLOGY OF INDIVIDUAL OPIOID AGONISTS

humans and nonhuman primates. In some circumstances usually be managed by treatment with atropine.
this CNS depression may be viewed as a benefit rather Although bradycardia is more profound in anesthetized
than a side effect. Other species, cats, horses and swine human patients compared with conscious ones, slow IV
in particular, display CNS stimulation, which manifests administration to anesthetized small animal patients
as motor excitement and mania. It may be that in these will generally ameliorate this effect.
species the doses administered are in excess of those
required to produce effective analgesia. Another Nausea and vomiting
unwanted effect associated with the administration of Opioids directly stimulate the chemoreceptor trigger
morphine is dysphoria (disquieted state accompanied by zone in the fourth ventricle of the brain, which in turn
restlessness and a feeling of malaise), particularly when initiates the vomiting reflex. Dogs are more susceptible
administered intravenously too quickly. to this than cats, although both species will salivate and
Stimulation of the Edinger–Westphal nucleus of show signs of nausea. Dogs are more likely to vomit if
the third cranial nerve results in miosis in dogs, rats, their stomach is not properly emptied following at least
rabbits and humans. However, in the cat, horse, 6 h fasting prior to anesthesia. In humans, vomiting is
sheep and monkey the pupils dilate after morphine more likely to occur in ambulatory patients than those
administration. lying down, suggesting a vestibular component, which
may in part explain its greater frequency in dogs. It is
Respiratory system not uncommon for dogs also to defecate following vom-
Dose-related respiratory depression is common to all iting. Morphine is more likely than other commonly
pure µ-agonists. The principal effect is a reduction in used opioids to induce nausea, vomition and salivation
the sensitivity of the respiratory center to carbon dioxide, in healthy animals when used as a premedicant. Signs
which is associated with increased irregularity in breath- of nausea and vomiting are rarely observed in anesthe-
ing pattern. Although dose-related respiratory depres- tized animals or in those recovering from surgery.
sion is the most life-threatening side effect of morphine,
most postoperative patients can tolerate the mild-to-
Gastrointestinal system
moderate depression that occurs with therapeutic doses.
Opioids increase smooth muscle tone along the whole
Clinically significant hypoventilation is rarely a problem
gastrointestinal tract, together with a decrease in pro-
unless high doses (>1 mg/kg) are used. In many cases of
pulsive peristalsis. These effects cause a delay in gastric
animals with pre-existing pain, morphine may improve
emptying and constipation. There is also an increase of
ventilatory parameters by slowing ventilation and
muscle tone in the biliary tract, with a decrease in bile
increasing tidal volume. In stressed, painful animals,
formation and flow. Normal clinical use of morphine
tachypnea and hypopnea are not infrequent.
infrequently results in significant clinical signs attribut-
In conscious dogs, following morphine administra-
able to these effects.
tion, there is an initial rise in body temperature, which
stimulates the respiratory center and results in panting.
With time the body temperature declines and CNS Musculoskeletal system
depression ensues, leading to the more common respira- Muscle rigidity has been observed in humans given large
tory depression. doses of µ-agonist opioids rapidly IV during induction
of anesthesia. This particularly affects the muscles of
Histamine release the chest wall and so limits ventilatory efforts. This
Intravenous administration can cause histamine release phenomenon has not been reported to occur in
if the drug is given too rapidly. Histamine release causes small animals.
systemic hypotension, which can worsen circulatory
shock, and IV morphine administration should there- Epidural-specific side effects
fore be avoided or used with great caution in such Delayed respiratory depression, pruritus, urinary reten-
patients. tion, nausea and vomiting are well recognized in humans
given extra or subdural opioids. Respiratory depression
Cardiovascular system is also the most common to occur in small animals,
Morphine has no, or very little, direct effect on the although its prevalence is low. If suspected, respiratory
heart, causing no direct myocardial depression or pre- depression should be treated initially with buprenor-
disposition to arrhythmias. However, bradycardia may phine or low-dose naloxone intravenously where there
occur with all opioids except pethidine (meperidine) and is need for an immediate reversal. The other unwanted
is commonly observed in anesthetized animals. This effects are not generally seen in small animals, although
results from increased vagal activity due to medullary urinary retention may occur, in which case expression
stimulation. Serious bradycardia is uncommon and can of the bladder may be required.

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Contraindications and precautions Pharmacokinetics

● Caution should be exercised when administering Pethidine is moderately lipid soluble and has an onset
morphine to animals with head trauma. It is impor- of action shorter than that of morphine following IM
tant to ensure that ventilation is adequate to avoid injection. About 70% is protein bound to albumin,
problems associated with increased arterial CO2. lipoprotein and α1-acid glycoprotein.
● Rapid intravenous administration of large doses Most pethidine is metabolized in the liver to norpethi-
should be avoided in hypovolemic animals because dine, pethidinic acid and norpethidinic acid, which are
of the risk of histamine release and a further decrease then excreted via the kidneys. Norpethidine can accu-
in arterial blood pressure. mulate in renal failure and has about half the analgesic
● Epidural administration of any drug is best avoided potency of pethidine. Norpethidine also causes CNS
during sepsis and in the presence of clotting abnor- stimulation and may result in myoclonus and seizures,
malities or localized skin infections. a situation more common with prolonged administra-
tion in the presence of renal impairment.
Known drug interactions
● As with other opioids, morphine has a synergistic
action with ACP, the most commonly used sedative in Adverse effects
small animal practice. Because of the additive effect of ● In equianalgesic doses, pethidine’s respiratory depres-
this and similar combinations, caution would suggest sant effects are comparable to morphine.
that the individual dose of each drug be reduced from ● Pethidine should not be given IV as it significantly
that given alone. This will of course be tempered by depresses myocardial contractility and causes hista-
the animal’s temperament and the desired effect. Of mine release.
particular concern when using such combinations is ● Vomiting is rarely seen after administration and it
the exacerbation of ventilatory depression. does not cause excitement in cats or horses.
● Similarly, morphine has at least additive actions on ● Bradycardia is rarely seen due to pethidine’s atro-
respiratory depression when used with other seda- pine-like structure which may cause tachycardia.
tives such as benzodiazepines and barbiturates. ● Large doses of pethidine, greater than 20 mg/kg, will
● Verapamil augments the analgesia produced by induce excitement and seizures in cats.
morphine.

Pethidine (meperidine) Known drug interactions

Pethidine should be used cautiously in conjunction with
Clinical applications monoamine oxidase inhibitors such as selegiline (see
Pethidine has only very mild sedative effects when given Chapter 7). Use with monoamine oxidase inhibitors
alone to healthy animals but is unlikely to induce bra- leads to excessive metabolism to norpethidine, with
dycardia, unlike other opioids. Because of its short greatly increased risk of myoclonus and seizures.
duration of action (1–2 h at the most), pethidine is of
more practical use as a preanesthetic medication than
as a postoperative analgesic. Vomiting is less common Methadone
than with morphine when used as a premedicant. Methadone is a synthetic opioid with a pharmacological
profile similar to morphine.
Mechanism of action
Pethidine has a similar receptor selectivity profile to
morphine, is slightly less efficacious and has lower Clinical applications
potency. It has an extremely fast onset, even when given Similar use to morphine, although not for epidural use
by the subcutaneous route (less than 5 min). as it is not available in preservative-free formulation.

Formulations and dose rates

Mechanism of action
DOGS AND CATS The potency and efficacy of methadone are similar to
• 2–10 mg/kg IM, SC morphine and it is more selective for µ-receptors.
Although absorption of pethidine can be variable after IM Its analgesic efficacy is similar to morphine after a
administration, this route is preferred to SC because of the single dose but is several times greater after repeated
local irritation and pain that may be produced. Pethidine is administration. This may result from its very long
not to be administered IV in small animals because of plasma half-life, which in humans is on average 24 h;
marked histamine release. however, this does not appear to be the case in
animals.

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Formulations and dose rates Oxymorphone

Mechanism of action
DOGS Oxymorphone is not available in Europe or Australasia.
• 0.05–0.1 mg/kg IV
It is a µ-agonist with approximately 10 times the potency
• 0.1–1.0 mg/kg IM, SC
of morphine.
CATS
As with morphine, lower dose rates are recommended for Clinical applications
use in cats, as is the concurrent use of a sedative/ Oxymorphone is probably the opioid most widely used
tranquilizer to avoid excitement. in veterinary practice in North America, where its indi-
cations are similar to those for morphine. Oxymor-
phone is useful at all perioperative stages, as well as for
cases of trauma. It is much more effective as a premedi-
Pharmacokinetics cant when used in combination with a tranquilizer or
The duration of action of methadone in dogs is 3–5 h. sedative such as ACP or an α2-agonist.
It has a more rapid onset of action than morphine, 15–
20 min following IM or SC administration and 5–10 min Formulations and dose rates
after IV administration. Unlike morphine, methadone
has a very high bioavailability following oral adminis- DOGS
tration in humans (80–85%) but this may not be the • 0.02–0.2 mg/kg IM, SC, IV or epidural
case in dogs and cats. CATS
Methadone has a long elimination half-life (24–35 h) • 0.02–0.1 mg/kg IM, SC or IV
in humans but the duration of action of a single dose is
comparable to that of morphine. Similarly, in animals,
the duration of action appears to be similar to
Pharmacokinetics
morphine.
The duration of action of oxymorphone is 2-6 h with
shorter times resulting from IV administration.
Adverse effects
Adverse effects
● Methadone is less likely to cause nausea and vomit-
● Oxymorphone tends to have the same side effects
ing than morphine when used as a premedicant.
as morphine, although there is less respiratory
● Sedation and dysphoria are less common following
depression and nausea and vomiting.
methadone administration, although cats may display
● It causes pronounced auditory hypersensitivity.
excitement, as occurs with morphine. In one study,
● Panting occurs because of lowering of the
premedicant doses up to 0.5 mg/kg IM in cats did
temperature equilibrium point of the hypothalamic
not produce any excitation or mania. Therefore,
thermoregulatory center.
despite literature to the contrary, methadone would
● Oxymorphone delivered intravenously does not
appear to be as safe and reliable an opioid to use in
induce histamine release, in contrast to morphine.
cats as morphine.
● Respiratory depression, bradycardia and cough sup-
Contraindications and precautions
pression are associated with methadone administra-
As for morphine.
tion, as occurs with morphine.
● Histamine release following IV administration would
Known drug interactions
appear to be minimal, based on studies in which
As for morphine.
cardiovascular stability was maintained during
administration of induction doses.
Fentanyl
Clinical applications
Contraindications and precautions Because of its relatively short duration of action
As for morphine. (30–60 min), fentanyl is often used as a continuous-rate
infusion to maintain general anesthesia, in combination
with other drugs, or as part of an induction protocol
Known drug interactions for seriously ill patients. Intraoperatively it may be used
As for morphine, although analgesia is not enhanced by as an intermittent bolus prior to a noxious stimulus to
verapamil. provide analgesia and to blunt the hemodynamic

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 CHAPTER 14 OPIOID ANALGESICS

response to the stimulus. Fentanyl has been demon-

Transdermal patches
strated to be effective at reducing the MAC of inhaled • 2–4 µg/kg/h
volatile anesthetic agents, both clinically and in the
CATS
laboratory. However, caution must be exercised in
regard to maintenance of both adequate ventilation to Intraoperative IV bolus
prevent hypercapnia and an adequate heart rate to mini- • 1–5 µg/kg
mize or eliminate hypotension. Constant rate infusion – IV
Fentanyl is also available in combination with a • Loading dose: 5 µg/kg
number of butyrophenone tranquilizers, e.g. droperidol • Infusion rate: 0.0025–0.005 µg/kg/min
(Leptan® or Innovar-Vet®) and fluanisone (Hypnorm®), Transdermal patches
in which combinations it is used to produce profound • 2–4 µg/kg/h
neuroleptanalgesia. These combination premixes are
highly popular despite the fixed concentrations of the
two drugs and the pharmacokinetic mismatch between
Pharmacokinetics
the durations of the different agents.
Fentanyl is highly protein bound and lipid soluble, with
Fentanyl is the opioid most often used as part of the
wide redistribution to peripheral tissues.
protocol for induction of anesthesia in veterinary
patients. This may then be followed by either short-term
fentanyl infusion as part of balanced anesthesia or use Adverse effects
of one of the fentanyl analogs with shorter elimination ● Apart from being a potent analgesic, fentanyl causes
times. Fentanyl has also been administered to small profound sedation and respiratory depression.
animals via transdermal patches (see above). This prop- ● Auditory sensitization and altered thermoregulation
erty is by virtue of the very high lipid solubility of fen- (resulting in panting) may occur.
tanyl which increases absorption into dermal lipid. ● Large intravenous doses will cause bradycardia, par-
Fentanyl can be administered into the epidural space ticularly when administered rapidly. This effect
with a very rapid onset of action but an equally short appears to be more profound during general
duration of action because of its high lipid solubility. anesthesia.
For best effect it should be administered as intermittent
boluses through an epidural catheter. This is not a tech- Contraindications and precautions
nique often attempted in veterinary practice. The effec- High doses of fentanyl during anesthesia may cause
tiveness of epidural fentanyl is enhanced by combining short-term ventilatory depression requiring assisted
it with a local anesthetic, particularly longer acting ventilation. This is rarely seen on anesthesia induction,
agents such as ropivacaine or bupivacaine. Combina- with lower doses during anesthesia or on repeat
tions of these two drugs are available commercially for bolusing.
this use in humans.
Known drug interactions
Mechanism of action ● When combined with other central-depressant
Fentanyl is a potent selective µ-opioid agonist with an drugs, the side effects associated with fentanyl tend
affinity at µ-receptors approximately 50–100 times that to be more pronounced.
of morphine. It is highly effective and short acting. ● α2-Agonists increase the degree of bradycardia
while all central depressants tend to worsen
Formulations and dose rates
respiratory depression.
Fentanyl is available as an injectable solution and in transdermal
patches. Patch sizes available deliver 25, 50, 75 and 100 mg/h. Special considerations
Care must be taken when using transdermal patches to
DOGS prevent ingestion by animals or young children. As fen-
Intraoperative IV bolus tanyl is a controlled substance, close monitoring of
• 2–5 µg/kg patch use and disposal is legally important.
Constant rate infusion – IV
• Loading dose: 10 µg/kg Alfentanil, sufentanil
• Infusion rate: 0.0025–0.010 µg/kg/min
Anesthetic induction These short-acting opioid agents were developed as
• 10 µg/kg fentanyl with diazepam (0.5 mg/kg) or midazolam analogs of fentanyl in an attempt to produce a shorter
(0.2 mg/kg) IV acting, less cumulative alternative. As such, they have
been largely replaced by remifentanil. At the time of

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 CLINICAL PHARMACOLOGY OF INDIVIDUAL OPIOID AGONISTS

writing they do, however, retain some clinical use and

they retain the advantage over fentanyl of a shorter
Formulations and dose rates
duration of action, particularly following a prolonged Remifentanil is marketed as a sterile lyophilised powder for reconsti-
continuous infusion. Studies, both clinical and experi- tution with sterile water.
mental, have been undertaken using alfentanil in dogs
and cats. The results of these indicate that the actions DOGS AND CATS
and side effects of alfentanil in these species are very Constant rate infusion – IV
similar to those of fentanyl, in particular good analge- • Loading dose: not needed
sia, MAC reduction of inhaled agents, bradycardia and • Infusion rate: 0.05–0.6 µg/kg/min
respiratory depression. Alfentanil is less potent than
fentanyl while sufentanil is 5–10 times more potent.
Both are full µ-agonists and more lipid soluble than
Pharmacokinetics
Remifentanil has a rapid onset of action (<1 min) and a
fentanyl.
rapid offset of action following discontinuation (<3–
10 min). The time to offset of action is not prolonged to
a clinically significant extent by renal impairment or pro-
Remifentanil longed infusion, i.e. it has no context-sensitive half-life.
Clinical applications Remifentanil is rapidly distributed throughout the body
Remifentanil is a 4-anilidopiperidine derivative of fen- and undergoes widespread vascular and extravascular
tanyl containing an ester linkage to propanoic acid, metabolism, via nonspecific blood and tissue esterases, to
making it susceptible to esterase metabolism. The remifentanil acid. The rapid, complete metabolism results
primary metabolite, remifentanil acid, has negligible in zero accumulation of the drug and therefore infusion
activity compared with remifentanil. It is ultra-short rates remain constant. There is no need for adjustment of
acting and displays analgesic effects, consistent with its targeting to maintain plasma concentrations.
agonist activity at the µ-receptor. The effect of remifen-
tanil on hemodynamics is typical of opioids (e.g.
Adverse effects
● Remifentanil causes profound sedation and
decreased blood pressure and heart rate). The reduced
respiratory depression.
blood pressure is by virtue of the bradycardia and may
● Bradycardia is marked with clinical doses and may
be prevented or reversed by use of an anticholinergic.
require anticholinergic intervention.
Remifentanil is proving to be a highly effective analgesic
when used as part of balanced anesthesia in the dog. Contraindications and precautions
Infusion rates of between 0.05 and 0.6 µg/kg/min Remifentanil is formulated with glycine and should not
produce profound analgesia and MAC sparing effects. therefore be instilled into the extradural space or admin-
Where heart rate is supported, blood pressure is well istered intrathecally.
maintained due to the reduction of inhaled volatile
agent. Codeine
Remifentanil has also been shown to be effective
Codeine (methylmorphine) occurs naturally in the
alongside infused propofol as part of a total intravenous
opium poppy. It has similar actions to morphine but
anesthetic technique. Because metabolism is indepen-
with only a quarter of its efficacy.
dent of hepatic function, remifentanil is useful as part
of anesthetic protocol for dogs with reduced hepatic Clinical applications
function. There are two main unwanted effects. Unlike Used for mild-to-moderate pain in humans and dogs,
in humans, in whom ventilation is often well main- commonly in combination with paracetamol (acetamin-
tained, dogs require assisted ventilation even at low ophen), or alone as a cough suppressant.
doses of infused remifentanil. Second, without the use
of an anticholinergic, bradycardia may be profound. Mechanism of action
This is rapidly reversed on termination of the infusion. The analgesic activity of codeine is probably due to slow
In addition, it should be recognized that as the analgesic metabolic conversion (demethylation) to morphine.
effects wear off rapidly, analgesia should be pre-
emptively provided by a different opioid (e.g. morphine) Formulations and dose rates
before terminating the remifentanil.
DOGS AND CATS
• 0.5–2.0 mg/kg PO, SC q.12 h
Dosage is similar when combined with paracetamol (acetaminophen)
Mechanism of action but this combination is contraindicated in cats.
Remifentanil is a potent selective µ-opioid agonist.

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 CHAPTER 14 OPIOID ANALGESICS

Adverse effects by cats). No studies have been performed on transmu-

● Respiratory depression is less pronounced with cosal usage in dogs, though the pH of their saliva is
moderate doses of codeine. closer to that of humans, where bioavailability after
● It does not usually cause vomiting. mucosal administration is only 30%.
● Constipation may occur with prolonged Recent studies of the clinical use of buprenorphine
administration. patches in companion animals have found them to be
entirely ineffective.

PARTIAL AGONISTS Mechanism of action

Buprenorphine is a potent synthetic opioid with partial
Buprenorphine
agonist activity at and very high affinity for
Clinical applications µ-receptors.
Buprenorphine is the prototypical drug in this class; it
is relatively safe, producing few side effects and minimal Formulations and dose rates
sedation. Buprenorphine has a high affinity for the µ-
receptors and will competitively inhibit pure µ-agonists DOGS
from binding. This property makes it useful for ‘revers- • 5–40 µg/kg IM, SC, IV or epidural prn or q.8 h
ing’ the effects of morphine or fentanyl if adverse con- CATS
sequences arise, while still maintaining a level of • 5–40 µg/kg IM, SC, IV or epidural prn or q.8 h
analgesia. Buprenorphine’s analgesic properties in
animals were first described in 1977 and it has been
used extensively in laboratory species as a means of Pharmacokinetics
managing acute postoperative pain. It also was used Buprenorphine has a long duration of action (8–12 h)
extensively for pain management in clinical practice, due to its slow dissociation from µ-receptors. Onset of
although the lack of veterinary product licensing analgesia is about 45 min after subcutaneous adminis-
restricted this. This analgesic is now licensed for use in tration. If more rapid onset is required, half the dose
dogs in some markets. can be given slowly intravenously.
Although it is widely used, misconceptions arising
from misinterpretation of early animal studies have Adverse effects
hampered its use in clinical pain management. Early ● Respiratory depression is less than with morphine
studies indicated that it exhibited a ‘bell-shaped’ dose– (probably because it is a partial agonist).
response curve, with high dose rates producing a para- ● Vomiting and gastrointestinal side effects do not
doxical reduction in analgesic efficacy. These initial occur to any great extent.
results in laboratory animals were uncritically trans-
lated into clinical opinion, that additional doses of Known drug interactions
buprenorphine would reduce the agent’s analgesic There is an augmentation of sedation and bradycardia
effects. Although repeated dosing with buprenorphine when administered in conjunction with other central
may eventually reach a plateau in terms of analgesic depressant drugs.
efficacy, inspection of the available animal data shows
that dose rates far in excess of those used clinically are
required for ‘self-reversal’. This ceiling effect makes AGONISTS–ANTAGONISTS
buprenorphine less useful for severe pain and inade-
Butorphanol
quate analgesia may be seen following moderate-to-
major bone trauma and surgery. Doses of 30 µg/kg will Clinical applications
provide relatively long periods (8–10 h) of analgesia and Butorphanol provides poor-to-moderate pain relief that
40 µg/kg may produce as much as 12 h of pain control. is more effective for visceral than somatic pain. As a sole
The onset of action is slow (30 min when given IV). agent, butorphanol provides mild sedation in dogs and
Buprenorphine is not available as an oral preparation next to none in cats. For this reason it is best adminis-
(significant first-pass effect renders it inactive), but its tered with a sedative or tranquilizer if it is to be used
lipophilic nature lends itself to absorption across skin as a premedicant. Because butorphanol is a partial
or mucous membranes. The alkaline salivary pH of cats agonist at µ-receptors, the analgesic efficacy of mor-
allows for excellent transmucosal absorption when the phine or other full agonists at µ-receptors can be reduced
injectable drug is given in the mouth (it should not be if butorphanol is given concurrently.
mixed with flavored syrups, as swallowing will inacti- Mixed partial agonists like butorphanol are not
vate it; the injectable form is tasteless and well tolerated considered useful in the management of chronic pain.

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 AGONISTS–ANTAGONISTS

First-pass effect destroys some of the drug and the Mechanism of action
analgesia is considered to be relatively short-lived (1– Pentazocine is a synthetic opioid that is a partial agonist
2 h). Because these drugs are κ-agonists and µ- at µ-receptors as well as being a κ-agonist. Its analgesic
antagonists, the pain relief is often less than optimal for efficacy is 25–50% that of morphine.
chronic discomfort. However, visceral nociception is
considered to be more responsive to κ-agonism, leading Formulations and dose rates
some urologists to advocate butorphanol’s use in chronic
bladder pain. DOGS
Butorphanol is a potent antitussive. It may also be • 1–3 mg/kg IM, SC or IV
used to antagonize pure µ-agonists with residual anal- • 2–10 mg/kg PO repeated q.3–4 h prn
gesia and reduction in side effects. CATS
• 0.75–1.5 mg/kg IM, SC or IV
Mechanism of action • 2–10 mg/kg PO
Butorphanol is a synthetic opioid that is a partial agonist
at µ-receptors as well as being a κ-agonist.
Pharmacokinetics
Analgesia occurs 20 min after SC administration and
Formulations and dose rates lasts for 2–4 h. Duration of analgesia is dose related,
lasting 20–120 min in cats after 0.75 and 1.5 mg/kg,
DOGS AND CATS respectively.
• 0.2–0.4 mg/kg IM, SC or IV prn or q.6–12 h
• 0.2–1.0 mg/kg PO q.6–12 h Adverse effects
● Pentazocine produces less respiratory depression
than morphine.
Pharmacokinetics ● Intravenous administration may cause a transient
Analgesia occurs 20 min after SC administration and decrease in arterial blood pressure.
lasts for about 4 h. Duration of analgesia appears to be ● Ataxia, inco-ordination and disorientation may
longer (2–6 h) in cats than in dogs (1–2 h). Visceral occur in dogs.
analgesia is achieved at lower doses (0.1 mg/kg) than ● Pentazocine causes dysphoria in cats. Alternative
somatic analgesia in cats (up to 0.8 mg/kg). analgesics are recommended.

Adverse effects Tramadol

● Butorphanol produces less respiratory depression
Clinical applications
than morphine because of its ‘ceiling effect’.
Tramadol provides moderate pain relief. Because of its
● At normal clinical doses, butorphanol produces
dual actions as a µ-agonist and monoamine transport
mild, transient depression of the cardiovascular
inhibitor, it produces less respiratory depression for a
system, which is more profound when combined
given analgesic effect.
with other central depressant drugs.
Mechanism of action
Known drug interactions
Tramadol is a synthetic opioid that is a weak agonist at
Cardiopulmonary side effects are more pronounced in
µ-receptors. Its major metabolites are more potent ago-
the presence of α2-agonists and inhalational anesthetic
nists at µ-receptors. Tramadol also inhibits monoamine
agents.
transporters (principally noradrenaline and serotonin)
which is thought to produce analgesia synergistically
Special considerations
with µ-agonism.
In many but not all countries, butorphanol is not a
controlled substance, unlike most of the other opioids,
as there is little potential for human abuse of the
Formulations and dose rates
drug. DOGS
• 1–5 mg/kg PO q.8–12 h
Pentazocine CATS
Clinical applications • 1–2 mg/kg PO q.12 h
Pentazocine provides moderate pain relief and is most
appropriately used as part of a premedication protocol Pharmacokinetics
for anesthesia. Duration of analgesia is dose related, lasting 4–8 h.

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 CHAPTER 14 OPIOID ANALGESICS

Adverse effects the agonist being reversed, further doses may be

● Tramadol produces less respiratory depression than required. In dogs treated with oxymorphone, naloxone
morphine. administered intravenously and intramuscularly reversed
● Sedation. the cardiopulmonary and sedative effects for about 30
● May decrease seizure threshold. and 60 min respectively.

Known drug interactions Adverse effects

Tramadol is contraindicated in patients treated with ● Observed side effects of naloxone administration
monoamine oxidase inhibitors (MAOIs) or monoamine generally result from sympathetic stimulation due to
transport inhibitors including noradrenaline uptake reversal of analgesia and sedation and include cate-
inhibitors, specific serotonin reuptake inhibitors, cholamine release, arrhythmias, hypertension and
deprenyl. death.
● The most pronounced effect of its administration is
the reversal of analgesia. For this reason, if it is to
OPIOID ANTAGONISTS be used in an animal that has respiratory depression
from narcotic overdose, it is recommended that the
There are infrequent indications for antagonists of naloxone be diluted and given slowly to titrate to the
opioid agonists in veterinary medicine; the most common desired effect.
use is to reverse an absolute or relative opioid agonist ● There are reports in the human literature of pulmo-
overdose. However, a partial agonist such as buprenor- nary edema and sudden death in response to nalox-
phine or an agonist-antagonist (butorphanol) may be a one administration.
better choice, as analgesia can be maintained while
reversing the unwanted side effects such as respiratory Known drug interactions
depression or excitement and agitation. Naloxone may have difficulty reversing the effects of
When using opioid antagonists, care must be taken buprenorphine because of a similar binding affinity of
not to overtreat, thereby exposing the animal to the full the two drugs for the µ-receptor.
pain of the procedure it has just undergone. If this
happens, the animal may become agitated and excitable, Nalorphine
from which point adequate pain control will be more Nalorphine was the first antagonist identified and used
difficult to achieve. clinically, but has now fallen into disfavor because of
its dysphoric effects and the existence of superior
Naloxone alternatives.
Clinical applications
Indications for use of naloxone are rare because of its Nalbuphine
ability to nonselectively antagonize all the effects of the Clinical applications
µ-agonists, both good and bad. It is used occasionally Nalbuphine is primarily used to reverse the undesired
in the management of behavior disorders such as tail effects of pure µ-agonists while tending to maintain
chasing (see Chapter 7). some analgesia. It can also be solely used for its agonist
analgesic effect.
Mechanism of action
Naloxone is a pure antagonist at all opioid receptors Mechanism of action
but has greatest affinity for µ-receptors. Nalbuphine is a µ-receptor antagonist (some studies
suggest it is a weak partial µ-agonist) and a κ-agonist.
Formulations and dose rates
DOGS AND CATS Formulations and dose rates
• 0.01–0.04 mg/kg IM, SC or IV
DOGS AND CATS
• 0.5–1.5 mg/kg IM, SC or IV
Pharmacokinetics
The onset of action is very rapid following intravenous
administration and its duration of action is correspond- Pharmacokinetics
ingly short. For this reason a similar dose may also be In humans the duration of action of nalbuphine is 2–6 h.
given intramuscularly or subcutaneously to prolong its It is thought to have a similar duration in small
action. Depending on the reason for administration and animals.

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 OPIOID ANTAGONISTS

Adverse effects duration is reported to be dependent on the dose admin-

● Respiratory depression is minimal with nalbuphine, istered. In one laboratory study in dogs, nalmefene
with no clinical effect upon the cardiovascular (0.03 mg/kg IV) was found to still be effective against
system. oxymorphone (4.5 mg IV) at 4 h. It has been demon-
● It will produce some sedation. strated to be effective for up to 8 h in humans.

Nalmefene
Nalmefene is a newer pure opioid antagonist that has a
longer duration of action than naloxone. The effective

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