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 nar-
cotic 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 sympa-
thetic 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 morphineis for pain relief. The
effective dose is highly variable. Previous analgesic
requirements (if known) should be taken into account
when selecting a dose. - Morphinemay be given as an intravenous bolus if rapid
relief is required (e.g. during myocardial infarction). - Alternatively, morphinecan be given continuously by an
infusion pump (e.g. post-operatively), either
intravenously or subcutaneously. - Morphineis effective orally, although larger doses are
needed due to presystemic metabolism. Morphineis
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
morphineis 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 opioid-
responsive 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
diamorphinerather than morphinefor this purpose, since
its greater solubility permits smaller volumes of more
concentrated solution to be used.- Morphineis effective in the relief of acute left ventricular
failure, via dilatation of the pulmonary vasculature and
the great veins. - Morphineinhibits cough, but codeineis preferred for this
indication. - Morphinerelieves diarrhoea, but codeineis preferred for
this indication.
- Morphineis effective in the relief of acute left ventricular
Mechanism of action
Morphinerelieves both the perception of pain and the emo-
tional response to it.Adverse effects
Certain patients are particularly sensitive to the pharmacolog-
ical 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. Morphinedepresses the sensitivity
of the respiratory centre to carbon dioxide, thus causing a pro-
gressively 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 morphineshould be used with
care and only for severe pain. Morphinecauses vomiting in
20–30% of patients by stimulation of the chemoreceptor trig-
ger zone. Dopamine receptors are important and opioid-
induced emesis is responsive to dopamine-receptor antagonists
(e.g.prochlorperazine).Morphineincreases 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 morphineincreases intrabiliary pres-
sure. Dependence (both physical and psychological) is particu-
larly likely to occur if morphineis used for the pleasurable
feeling it produces, rather than in a therapeutic context. In
common with most other opioids it causes pupillary constric-
tion. This provides a useful diagnostic sign in narcotic over-
dosage or chronic abuse. Patients with prostatic hypertrophy
may suffer acute retention of urine, as morphineincreases the
tone in the sphincter of the bladder neck.Pharmacokinetics
Morphinecan be given orally or by subcutaneous, intramus-
cular or intravenous injection. Morphineis metabolized by
combination with glucuronic acid and also by N-dealkylation
and oxidation, about 10% being excreted in the urine as mor-
phine 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
morphineand 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