A Textbook of Clinical Pharmacology and Therapeutics

OPIOIDS 159

OPIOIDS

Opium is derived from the dried milky juice exuded by
incised seed capsules of a species of poppy, Papaver som-
niferum, that is grown in Turkey, India and South-East Asia.
Homer refers to it in the Odysseyas ‘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 inter-
ests 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 opiumis due to morphine.Papaverineis a vasodila-
tor without analgesic actions.
Until 1868, opiumcould be purchased without prescrip-
tion from grocers’ shops in the UK. Much work has gone into
synthesizingmorphineanalogues in the hope of producing a
drug with the therapeutic actions of morphine, but without its
disadvantages.Morphinewas introduced as a ‘non-addictive’
alternative to opiumand this in turn was superseded by
diamorphine, which was also believed to be non-addicting!
Synthetic drugs such as pethidine,dextropropoxypheneand
pentazocinewere originally incorrectly thought to lack poten-
tial for abuse.

Morphineis 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 anaes-

thetists 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 con-

centrations 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 sys-

tem. 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 (pro-
   opiomelanocortin, pro-encephalin and pro-dynorphin) and
   act as neurotransmitters or neuromodulators (neurotransmit-
   ters 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,δandκ.
   All belong to the G-protein coupled receptor family, and μis 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 phencyclidineand the only opioids
   that bind appreciably to them are drugs like pentazocinethat
   have psychotomimetic adverse effects.
   Blocking opioid receptors with naloxone(see below) has lit-
   tle 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 recep-
   tors elicits analgesia which is abolished by naloxone, implying

Neuromodulator

NT release NT responsiveness

NT Molecule NT Receptor

Figure 25.6:Role of neurotransmitter and neuromodulator at

synapse. --->, Stimulatory or inhibitory action; NT, neurotransmitter.

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 gastro-
    intestinal 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.