A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition

OPIOIDS 159
Key points
Drugs for mild pain
• The main drugs for mild pain are paracetamol, aspirin
and ibuprofen.
• These work by inhibiting prostaglandin synthesis, and
are available over the counter.
• Paracetamol:
– is analgesic;
– is antipyretic but not anti-inflammatory;
– lacks gastric toxicity, and can be used safely in
children;
– does not cause bleeding;
– is dangerous in overdose because of production of a
toxic metabolite (N-acetyl-p-benzoquinone imine,
NABQI).
• Aspirin:
– is anti-inflammatory, analgesic and antipyretic;
– is uniquely useful for its antiplatelet effect (see
Chapters 29 and 30);
– is a common cause of indigestion and severe gastrointestinal
bleeding – especially in the elderly;
– is associated with Reye’s syndrome in children and
should not be prescribed for children 12 years of age;
– is dangerous in overdose (salicylate toxicity).
• Ibuprofen:
– is similar as an analgesic to aspirin, but is preferred
by some patients (e.g. for dysmenorrhoea);
– is not proven to have a clinically useful antiplatelet
effect.
• Topical NSAIDs (e.g. piroxicam gel):
– have modest efficacy (at best);
– have low toxicity.
OPIOIDS
Opium is derived from the dried milky juice exuded by
incised seed capsules of a species of poppy, Papaver somniferum,
that is grown in Turkey, India and South-East Asia.
Homer refers to it in the Odyssey as ‘nepenthes’, a drug given
to Odysseus and his followers ‘to banish grief or trouble of the
mind’. Osler referred to it as ‘God’s own medicine’. A number
of notably discreditable events, including the Opium Wars,
ensued from the commercial, social, moral and political interests
involved in its world-wide trade and use. Opium is a
complex mixture of alkaloids, the principal components being
morphine, codeine and papaverine. The main analgesic
action of opium is due to morphine. Papaverine is a vasodilator
without analgesic actions.
Until 1868, opium could be purchased without prescription
from grocers’ shops in the UK. Much work has gone into
synthesizing morphine analogues in the hope of producing a
drug with the therapeutic actions of morphine, but without its
disadvantages. Morphine was introduced as a ‘non-addictive’
alternative to opium and this in turn was superseded by
diamorphine, which was also believed to be non-addicting!
Synthetic drugs such as pethidine, dextropropoxyphene and
pentazocine were originally incorrectly thought to lack potential
for abuse.
Morphine is active when given by mouth and a more rapid
effect can be obtained if it is administered intravenously, but
the potential for abuse is also greatly increased. Some anaesthetists
give synthetic high potency opioids, such as fentanyl,
either intravenously or epidurally, for obstetric surgery (e.g.
Caesarean section).+
OPIOID RECEPTORS
Stereospecific receptors with a high affinity for opioid analgesics
are present in neuronal membranes. They are found in high concentrations
in the PAG, the limbic system, the thalamus, the
hypothalamus, medulla oblongata and the substantia gelatinosa
of the spinal cord. Several endogenous peptides with analgesic
properties are widely distributed throughout the nervous system.
They can be divided into the following three groups:
1. encephalins (leu-encephalin and met-encephalin) are
pentapeptides;
2. dynorphins are extended forms of encephalins;
3. endorphins (e.g. β-endorphin).
These peptides are derived from larger precursors (proopiomelanocortin,
pro-encephalin and pro-dynorphin) and
act as neurotransmitters or neuromodulators (neurotransmitters
convey information from an axon terminal to a related nerve
cell, whereas neuromodulators influence the responsiveness of
one or more neurons to other mediators, see Figure 25.6).
There are three types of opioid receptor, named μ, δ and κ.
All belong to the G-protein coupled receptor family, and μ is the
most important. A fourth category, σ, is now not classified as an
opioid receptor because they bind non-opioid psychotomimetic
drugs of abuse, such as phencyclidine and the only opioids
that bind appreciably to them are drugs like pentazocine that
have psychotomimetic adverse effects.
Blocking opioid receptors with naloxone (see below) has little
effect in normal individuals, but in patients suffering from
chronic pain it produces hyperalgesia. Electrical stimulation of
areas of the brain that are rich in encephalins and opioid receptors
elicits analgesia which is abolished by naloxone, implying
NT release
Neuromodulator
NT Molecule
NT responsiveness
NT Receptor
Figure 25.6: Role of neurotransmitter and neuromodulator at
synapse. --->, Stimulatory or inhibitory action; NT, neurotransmitter.