Opioids

Opioid Analgesics—Morphine Type
Source of opioids. Morphine is an opium
alkaloid . Besides morphine,
opium contains alkaloids devoid of analgesic
activity, e.g., the spasmolytic papaverine,
that are also classified as opium
alkaloids. All semisynthetic derivatives
(hydromorphone) and fully synthetic
derivatives (pentazocine, pethidine
= meperidine, l-methadone, and
fentanyl) are collectively referred to as
opioids. The high analgesic effectiveness
of xenobiotic opioids derives from their
affinity for receptors normally acted
upon by endogenous opioids (enkephalins,
!-endorphin, dynorphins). Opioid
receptors occur in nerve cells. They
are found in various brain regions and
the spinal medulla, as well as in intramural
nerve plexuses that regulate the
motility of the alimentary and urogenital
tracts. There are several types of opioid
receptors, designated μ, ", #, that
mediate the various opioid effects; all
belong to the superfamily of G-proteincoupled
receptors.
Endogenous opioids are peptides
that are cleaved from the precursors
proenkephalin, pro-opiomelanocortin,
and prodynorphin. All contain the amino
acid sequence of the pentapeptides
[Met]- or [Leu]-enkephalin. The effects
of the opioids can be abolished by
antagonists (e.g., naloxone), with the
exception of buprenorphine.
Mode of action of opioids. Most
neurons react to opioids with hyperpolarization,
reflecting an increase in K+
conductance. Ca2+ influx into nerve terminals
during excitation is decreased,
leading to a decreased release of excitatory
transmitters and decreased synaptic
activity. Depending on the cell
population affected, this synaptic inhibition
translates into a depressant or excitant
effect.
Effects of opioids. The analgesic
effect results from actions at the level
of the spinal cord (inhibition of nociceptive
impulse transmission) and the
brain (attenuation of impulse spread,
inhibition of pain perception). Attention
and ability to concentrate are impaired.
There is a mood change, the direction
of which depends on the initial condition.
Aside from the relief associated
with the abatement of strong pain,
there is a feeling of detachment (floating
sensation) and sense of well-being
(euphoria), particularly after intravenous
injection and, hence, rapid buildup
of drug levels in the brain. The desire
to re-experience this state by renewed
administration of drug may become
overpowering: development of psychological
dependence. The atttempt to quit
repeated use of the drug results in withdrawal
signs of both a physical (cardiovascular
disturbances) and psychological
(restlessness, anxiety, depression)
nature. Opioids meet the criteria of “addictive”
agents, namely, psychological
and physiological dependence as well as
a compulsion to increase the dose. For
these reasons, prescription of opioids is
subject to special rules (Controlled Substances
Act, USA; Narcotic Control Act,
Canada; etc). Regulations specify,
among other things, maximum dosage
(permissible single dose, daily maximal
dose, maximal amount per single prescription).
Prescriptions need to be issued
on special forms the completion of
which is rigorously monitored. Certain
opioid analgesics, such as codeine and
tramadol, may be prescribed in the usual
manner, because of their lesser potential
for abuse and development of
dependence.

Differences between opioids regarding
efficacy and potential for dependence
probably reflect differing affinity
and intrinsic activity profiles for
the individual receptor subtypes. A given
sustance does not necessarily behave
as an agonist or antagonist at all receptor
subtypes, but may act as an agonist
at one subtype and as a partial agonist/
antagonist or as a pure antagonist
(p. 214) at another. The abuse potential
is also determined by kinetic properties,
because development of dependence is
favored by rapid build-up of brain concentrations.
With any of the high-efficacy
opioid analgesics, overdosage is likely
to result in respiratory paralysis (impaired
sensitivity of medullary chemoreceptors
to CO2). The maximally possible
extent of respiratory depression is
thought to be less in partial agonist/
antagonists at opioid receptors (pentazocine,
nalbuphine).
The cough-suppressant (antitussive)
effect produced by inhibition of the
cough reflex is independent of the effects
on nociception or respiration
(antitussives: codeine. noscapine).
Stimulation of chemoreceptors in
the area postrema results in
vomiting, particularly after first-time administration
or in the ambulant patient.
The emetic effect disappears with repeated
use because a direct inhibition of
the emetic center then predominates,
which overrides the stimulation of area
postrema chemoreceptors.
Opioids elicit pupillary narrowing
(miosis) by stimulating the parasympathetic
portion (Edinger-Westphal nucleus)
of the oculomotor nucleus.
Peripheral effects concern the motility
and tonus of gastrointestinal
smooth muscle; segmentation is enhanced,
but propulsive peristalsis is inhibited.
The tonus of sphincter muscles
is raised markedly. In this fashion, morphine
elicits the picture of spastic constipation.
The antidiarrheic effect is
used therapeutically (loperamide, p.
178). Gastric emptying is delayed (pyloric
spasm) and drainage of bile and
pancreatic juice is impeded, because the
sphincter of Oddi contracts. Likewise,
bladder function is affected; specifically
bladder emptying is impaired due to increased
tone of the vesicular sphincter.
Uses: The endogenous opioids
(metenkephalin, leuenkephalin, !-endorphin)
cannot be used therapeutically
because, due to their peptide nature,
they are either rapidly degraded or excluded
from passage through the bloodbrain
barrier, thus preventing access to
their sites of action even after parenteral
administration .
Morphine can be given orally or
parenterally, as well as epidurally or
intrathecally in the spinal cord. The opioids
heroin and fentanyl are highly lipophilic,
allowing rapid entry into the
CNS. Because of its high potency, fentanyl
is suitable for transdermal delivery.
In opiate abuse, “smack” (“junk,”
“jazz,” “stuff,” “China white;” mostly
heroin) is self administered by injection
(“mainlining”) so as to avoid first-pass
metabolism and to achieve a faster rise
in brain concentration. Evidently, psychic
effects (“kick,” “buzz,” “rush”) are
especially intense with this route of administration.
The user may also resort to
other more unusual routes: opium can
be smoked, and heroin can be taken as
snuff .
Metabolism . Like other opioids
bearing a hydroxyl group, morphine is
conjugated to glucuronic acid and eliminated
renally. Glucuronidation of the
OH-group at position 6, unlike that at
position 3, does not affect affinity. The
extent to which the 6-glucuronide contributes
to the analgesic action remains
uncertain at present. At any rate, the activity
of this polar metabolite needs to
be taken into account in renal insufficiency
(lower dosage or longer dosing
interval).
Tolerance. With repeated administration
of opioids, their CNS effects can
lose intensity (increased tolerance). In
the course of therapy, progressively
larger doses are needed to achieve the
same degree of pain relief. Development
of tolerance does not involve the peripheral
effects, so that persistent constipation
during prolonged use may
force a discontinuation of analgesic
therapy however urgently needed.
Therefore, dietetic and pharmacological
measures should be taken prophylactically
to prevent constipation, whenever
prolonged administration of opioid
drugs is indicated.
Morphine antagonists and partial
agonists. The effects of opioids can be
abolished by the antagonists naloxone
or naltrexone, irrespective of the receptor
type involved. Given by itself,
neither has any effect in normal subjects;
however, in opioid-dependent
subjects, both precipitate acute withdrawal
signs. Because of its rapid presystemic
elimination, naloxone is only
suitable for parenteral use. Naltrexone
is metabolically more stable and is given
orally. Naloxone is effective as antidote
in the treatment of opioid-induced
respiratory paralysis. Since it is more
rapidly eliminated than most opioids,
repeated doses may be needed. Naltrexone
may be used as an adjunct in withdrawal
therapy.
Buprenorphine behaves like a partial
agonist/antagonist at μ-receptors.
Pentazocine is an antagonist at μ-receptors
and an agonist at #-receptors.
Both are classified as “low-ceiling” opioids,
because neither is capable of
eliciting the maximal analgesic effect
obtained with morphine or meperidine.
The antagonist action of partial agonists
may result in an initial decrease in effect
of a full agonist during changeover to
the latter. Intoxication with buprenorphine
cannot be reversed with antagonists,
because the drug dissociates only
very slowly from the opioid receptors
and competitive occupancy of the receptors
cannot be achieved as fast as the
clinical situation demands.
Opioids in chronic pain: In the
management of chronic pain, opioid
plasma concentration must be kept continuously
in the effective range, because
a fall below the critical level would
cause the patient to experience pain.
Fear of this situation would prompt intake
of higher doses than necessary.
Strictly speaking, the aim is a prophylactic
analgesia.
Like other opioids (hydromorphone,
meperidine, pentazocine, codeine),
morphine is rapidly eliminated,
limiting its duration of action to approx.
4 h. To maintain a steady analgesic effect,
these drugs need to be given every
4 h. Frequent dosing, including at nighttime,
is a major inconvenience for
chronic pain patients. Raising the individual
dose would permit the dosing
interval to be lengthened; however, it
would also lead to transient peaks
above the therapeutically required plasma
level with the attending risk of unwanted
toxic effects and tolerance development.
Preferred alternatives include
the use of controlled-release
preparations of morphine, a fentanyl
adhesive patch, or a longer-acting opioid
such as l-methadone. The kinetic
properties of the latter, however, necessitate
adjustment of dosage in the
course of treatment, because low dosage
during the first days of treatment
fails to provide pain relief, whereas high
dosage of the drug, if continued, will
lead to accumulation into a toxic concentration
range.
When the oral route is unavailable
opioids may be administered by continuous
infusion (pump) and when appropriate
under control by the patient – advantage:
constant therapeutic plasma
level; disadvantage: indwelling catheter.
When constipation becomes intolerable
morphin can be applied near the
spinal cord permitting strong analgesic
effect at much lower total dosage.