A Textbook of Clinical Pharmacology and Therapeutics

156 ANALGESICS AND THE CONTROL OF PAIN

SITES OF ACTION OF ANALGESICS

Drugs can prevent pain:

• at the site of injury (e.g. NSAIDs);


• by blocking peripheral nerves (local anaesthetics);


• by closing the ‘gates’ in the dorsal horn and thalamus (one
  action of opioids and of tricyclic antidepressants that
  inhibit axonal re-uptake of 5HT and noradrenaline);


• by altering the central appreciation of pain (another effect
  of opioids).

aggregation. It has no irritant effect on the gastric mucosa and

can be used safely and effectively in most individuals who are

intolerant of aspirin. It is the standard analgesic/antipyretic

in paediatrics since, unlike aspirin, it has not been associated

with Reye’s syndrome and can be formulated as a stable sus-

pension. The usual adult dose is 0.5–1 g repeated at intervals

of four to six hours if needed.

Mechanism of action

Paracetamolinhibits prostaglandin biosynthesis under some

circumstances (e.g. fever), but not others. The difference from

other NSAIDs is still under investigation.

Adverse effects

The most important toxic effect is hepatic necrosis leading to

liver failure after overdose, but renal failure in the absence of

liver failure has also been reported after overdose. There is no

convincing evidence that paracetamolcauses chronic liver

disease when used regularly in therapeutic doses ( 4 g/24

hours).Paracetamolis structurally closely related to phenacetin

(now withdrawn because of its association with analgesic

nephropathy) raising the question of whether long-term abuse

ofparacetamolalso causes analgesic nephropathy, an issue

which is as yet unresolved.

Pharmacokinetics, metabolism and interactions

Absorption of paracetamolfollowing oral administration is

increased by metoclopramide, and there is a significant relation-

ship between gastric emptying and absorption. Paracetamolis

rapidly metabolized in the liver. The major sulphate and glu-

curonide conjugates (which account for approximately 95% of a

paracetamoldose) are excreted in the urine. When paracetamol

is taken in overdose (Chapter 54), the capacity of the conjugating

mechanisms is exceeded and a toxic metabolite, N-acetyl benzo-

quinone imine (NABQI), is formed via metabolism through the

CYP450 enzymes.

Cytokines

Spinal ganglion

(DRG)

Neurotrophins

Serotonin

Prostaglandins

Bradykinin

Histamine

ATPAdrenalineACh

trk 5-HT B H P2X Adren. M

GP130

VDCCs

Na+

TTX resistant

TTX sensitive K+

Cell body

Ca2+ H+ Ca2+

Capsaicin,

Heat,

Protons

Proteinases

PARs

Na+

Ca2+

K+

Mechanical

stimuli

Nociceptor

EP

TRPV1

NK1

CGRP

SST,etc.

Neuropeptides

Resiniferatoxin

Figure 25.2:Influence of inflammatory mediators on activity of a C-fibre nociceptor. DRG, dorsal root ganglion, TTX, tetrodotoxin;
GP130, glycoprotein 130; trk, tyrosine kinase; 5-HT, 5-hydroxytryptamine (serotonin) receptor; EP, prostaglandin EP receptor; B,
bradykinin receptor; H, histamine receptor; P2X, purinergic P2X receptor; Adren, adrenoceptor; M, muscarinic receptor; NKT,
neokyotorphine; CGRP, calcitonin gene-related peptide; SST, somatostatin; PARs protease activated receptors; TRPV1, transient receptor
potential vanilloid 1 receptor; VDCCs, voltage-dependent calcium channels.

DRUGS USED TO TREAT MILD OR

MODERATE PAIN

PARACETAMOL

Uses

Paracetamolis an antipyretic and mild analgesic with few, if
any, anti-inflammatory properties and no effect on platelet

Key points

Mechanisms of pain and actions of analgesic drugs

• Nociception and pain involve peripheral and central
  mechanisms; ‘gating’ mechanisms in the spinal cord and
  thalamus are key features.


• Pain differs from nociception because of central
  mechanisms, including an emotional component.


• Many mediators are implicated, including prostaglandins,
  various peptides that act on μ-receptors (including
  endorphins), 5HT, noradrenaline and anandamide.


• Analgesics inhibit, mimic or potentiate natural
  mediators (e.g. aspirin inhibits prostaglandin
  biosynthesis, morphine acts on μ-receptors, and tricyclic
  drugs block neuronal amine uptake).