Clinical Pharmacology and Therapeutics

160 ANALGESICS AND THE CONTROL OF PAIN
that it is caused by liberation of endogenous opioids. Pain
relief by acupuncture may also be mediated by encephalin
release, because it is antagonized by naloxone.
Narcotic analgesics exert their effects by binding to opioid
receptors. The resulting pattern of pharmacological activity
depends on their affinity for the various receptors and
whether they are full or partial agonists. The affinity of narcotic
analgesics for μ-receptors parallels their analgesic potency.
In addition to their involvement in brain function, the opioid
peptides play a neuroendocrine role. Administration in humans
suppresses the pituitary–gonadal and pituitary–adrenal axis
and stimulates the release of prolactin, thyroid-stimulating
hormone (TSH) and growth hormone. High concentrations of
opioid peptides are also present in sympathetic ganglia and
the adrenal medulla. Their function at these sites has not been
elucidated, but they may play an inhibitory role in the sympathetic
system.
Following repeated administration of an exogenous opioid,
the sensitivity of the receptors decreases, necessitating an
increased dose to produce the same effect (‘tolerance’). On
withdrawal of the drug, endogenous opioids are not sufficient
to stimulate the insensitive receptors, resulting in a withdrawal
state characterized by autonomic disturbances, e.g. pallor,
sweating and piloerection (‘cold turkey’) and abdominal pain.
MORPHINE
Use
• The most important use of morphine is for pain relief. The
effective dose is highly variable. Previous analgesic
requirements (if known) should be taken into account
when selecting a dose.
• Morphine may be given as an intravenous bolus if rapid
relief is required (e.g. during myocardial infarction).
• Alternatively, morphine can be given continuously by an
infusion pump (e.g. post-operatively), either
intravenously or subcutaneously.
• Morphine is effective orally, although larger doses are
needed due to presystemic metabolism. Morphine is
given by mouth initially every four hours, giving
additional doses as needed between the regular doses as a
‘top-up’, the daily dose being reviewed and titrated. Once
the dose requirement is established, sustained-release
morphine (12-hourly) is substituted, which should still be
supplemented by immediate release morphine, for
breakthrough pain.
• Spinal (epidural or intrathecal) administration of
morphine is effective at much lower doses than when
given by other routes and causes fewer systemic side
effects. It is useful in those few patients with opioidresponsive
pain who experience intolerable side effects
when morphine is administered by other routes.
• Continuous subcutaneous infusions by pump are useful
in the terminally ill. There is an advantage in using
diamorphine rather than morphine for this purpose, since
its greater solubility permits smaller volumes of more
concentrated solution to be used.
• Morphine is effective in the relief of acute left ventricular
failure, via dilatation of the pulmonary vasculature and
the great veins.
• Morphine inhibits cough, but codeine is preferred for this
indication.
• Morphine relieves diarrhoea, but codeine is preferred for
this indication.
Mechanism of action
Morphine relieves both the perception of pain and the emotional
response to it.
Adverse effects
Certain patients are particularly sensitive to the pharmacological
actions of morphine. These include the very young, the
elderly and those with chronic lung disease, untreated
hypothyroidism, chronic liver disease and chronic renal failure.
Overdose leads to coma. Morphine depresses the sensitivity
of the respiratory centre to carbon dioxide, thus causing a progressively
decreased respiratory rate. Patients with decreased
respiratory reserve due to asthma, bronchitis, emphysema or
hypoxaemia of any cause are more sensitive to the respiratory
depressant effect of opioids. Bronchoconstriction occurs via
histamine release, but is usually mild and clinically important
only in asthmatics, in whom morphine should be used with
care and only for severe pain. Morphine causes vomiting in
20–30% of patients by stimulation of the chemoreceptor trigger
zone. Dopamine receptors are important and opioidinduced
emesis is responsive to dopamine-receptor antagonists
(e.g. prochlorperazine). Morphine increases smooth muscle
tone throughout the gastro-intestinal tract, which is combined
with decreased peristalsis. The result is constipation with hard
dry stool. The increase in muscle tone also involves the
sphincter of Oddi and morphine increases intrabiliary pressure.
Dependence (both physical and psychological) is particularly
likely to occur if morphine is used for the pleasurable
feeling it produces, rather than in a therapeutic context. In
common with most other opioids it causes pupillary constriction.
This provides a useful diagnostic sign in narcotic overdosage
or chronic abuse. Patients with prostatic hypertrophy
may suffer acute retention of urine, as morphine increases the
tone in the sphincter of the bladder neck.
Pharmacokinetics
Morphine can be given orally or by subcutaneous, intramuscular
or intravenous injection. Morphine is metabolized by
combination with glucuronic acid and also by N-dealkylation
and oxidation, about 10% being excreted in the urine as morphine
and 60–70% as a mixture of glucuronides. Metabolism
occurs in the liver and gut wall, with extensive presystemic
metabolism. The dose–plasma concentration relationships for
morphine and its main metabolite are linear over a wide
range of oral dosage. Morphine-6-glucuronide has analgesic
properties and contributes substantially to the analgesic
action of morphine. Only low concentrations of this active
metabolite appear in the blood after a single oral dose. With
repeated dosing the concentration of morphine-6-glucuronide