Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 14 OPIOID ANALGESICS
inflammatory and ‘nociceptive’ mediators released following
tissue injury. This causes afferent neurones to
fire more frequently. It also allows low-intensity signals
to stimulate spinal cord neurones. Central sensitization
occurs due to changes within the spinal cord. Nerve
fibers in the dorsal horn of the spinal cord increase their
excitability and afferent information is ‘overinterpreted’
by the spinal afferent system. The clinical significance
of these mechanisms is that any pain perceived by the
animal is more severe once tissue damage has occurred,
and analgesics may be less effective.
This has given rise to the concept of pre-emptive
analgesia: giving analgesics before tissue damage occurs.
Postoperative pain may be more easily controlled when
it is pre-empted by administration of analgesic therapy
instituted before the patient is exposed to noxious
stimuli, whether or not the patient is conscious. The
reasons for this are not entirely understood but appear
to be related to the fact that the organization and function
of the nervous system change following painful
stimuli. The significance of this hypersensitivity remains
controversial in humans but it is important in several
species of experimental animals. It may therefore be
much easier to prevent pain produced by surgery than
to suppress it once it is already present. In human
patients, it has been clearly shown that fixed-interval
administration of analgesics (a regular dose at a regular
time) is more effective in achieving pain relief and
requires lower overall doses of opioids than dosing on
demand. It is therefore more effective (and humane) and
safer to administer opioids to control pain likely to
result from a procedure than attempt to reduce pain
after severe signs have emerged.
Drugs
EXAMPLES
Morphine and its analogs (e.g. oxymorphone), pethidine
(meperidine), methadone, codeine, fentanyl and its analogs
(alfentanil and remifentanil), buprenorphine, butorphanol,
pentazocine and tramadol.
The opioid analgesics remain the most potent and efficacious
analgesic drugs in veterinary medicine. The prototype
drug is morphine, named after the Greek god of
dreams, Morpheus. It is derived from the dry residue of
the exudate from the unripe seed capsule of the poppy
Papaver somniferum. This residue is opium, which contains
a mixture of alkaloids, of which there are two
main types. These are the phenanthrene alkaloids, which
include morphine and codeine, and the benzylisoquinoline
alkaloids, of which papaverine is the main example,
which have smooth muscle relaxant effects but no analgesic
properties.
Drugs derived directly from the opium poppy are
known as opiates while any substances that interact
specifically with opioid receptors (see below), including
endogenous peptides and opiates, are known as
opioids.
Clinical applications
Opioids are effective for treatment of moderate-tosevere
pain, particularly acute pain due to trauma and
surgical procedures. Although these drugs can have significant
side effects, these are significantly reduced in the
face of pre-existing pain and for most animals are
usually not of sufficient concern to prevent use of opioid
drugs at clinical dose rates.
Chemical structure
Morphine has a five-ring structure that is the core for
many of the semisynthetic opioids, including heroin
(diacetyl morphine), oxymorphone, pentazocine, butorphanol,
buprenorphine and naloxone.
Synthetic opioids have fewer rings and form either
piperidines such as pethidine (meperidine) or the phenylpiperidines,
which include fentanyl, sufentanil and
alfentanil.
Remifentanil is also a phenylpiperidine, but as a 4-
anilidopiperidine derivative of fentanyl, has an ester
linkage in the piperidine ring, making it susceptible to
metabolism by plasma esterases.
Methadone has a structure very different from that
of morphine but retains the active moieties of morphine.
Opioid antagonists, including naloxone, naltrexone and
nalbuphine, structurally resemble agonists but generally
have bulky unsaturated N-linked substitutions.
Opioid receptors and drug/effector
mechanisms
Classes of opioid receptor
The opioid receptors are pharmacologically distinct,
closely related membrane proteins that share common
characteristics because they have evolved from a
common ancestral G protein-coupled receptor. Three
types of opioid receptor have been identified in mammals.
These are termed mu (µ, the Greek letter m, for ‘morphine
receptor’, also MOP using standard nomenclature),
kappa (κ, the Greek letter k, for ketocyclazocine,
the first class of drug used to define the receptor functionally,
also KOP using standard nomenclature) and
delta (δ, the Greek letter d for deferens, because the
mouse vas deferens was the first tissue used to define
the receptor functionally, also DOP using standard
nomenclature). Each of the three receptor proteins is
encoded by an independent gene. A fourth closely
related gene encodes an opioid-like receptor (NOP using
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