Pain Relief Notes

20.2.2 Pain Relief

Clinical pain syndromes:

a)Nociceptive pain

Cause: Noxious stimuli

Function: Protective, high threshold

Treatment: Analgesics, General/ Local Anaesthetics

b) Inflammatory pain

Cause: Inflammation, peripheral pathology

Function: Repair/pathologic, low threshold

Treatment: Anti-inflammatory and amplification reducing agents

c) Neuropathic pain

-Neurological disease affecting sensory pathway can produce chronic pain unrelated to any peripheral tissue injury

-Occurs with CNS disorders such as stroke, MS or peripheral nerve damage- mechanical inury, diabetic neuropathy or herpes zoster infection (shingles)

-Spontaneous activity in damaged sensory neurons- overexpression of voltage gated sodium channelss

Cause: Neuronal damage PNS/ CNS

Function: Pathological, low threshold

Treatment: Amplification reducing agents

d) Dysfunctional Pain

Cause: No noxious stimulus, no inflammation, no neuronal damage, no peripheral pathology- could be some structural changes in the brain?

Function: Pathologcial, low threshold

Treatment: Amplification reducing agents

Extension: transmitters in the pain pathway; NK1 antagonists

-Glutamate is the neurotransmitter released from the first-order neurons at synapses in the dorsal horn. It acts on AMPA receptors, leading to fast EPSPs in the second-order neurons.

-It can also act on NMDA receptors, which leads to a slower response. It is important in wind-up in central sensitisation.

-Many of these neurons (mainly C fibres) also release substance P, which is important in wind-up in central sensitisation and may also contribute to normal excitatory transmission.

-Antagonists of NK1 receptors, which are responsive to substance P were shown to be effective analgesics in animal models but were less effective in clinical trials.

-GABA is released from the inhibitory interneurons in the dorsal horn, which are important in gate control.

-Inhibitory neurons running from the nucleus raphe magnus to the dorsal horn release 5-HT.

-Inhibitory neurons from the locus coeruleus to the dorsal horn release noradrenaline.

Endogenous opioids also appear to be important in many of the descending pain control pathways.

Core: analgesic drugs and techniques: peripherally-acting analgesics: aspirin and other NSAIDS

Non-steroidal anti-inflammatory drugs- NSAID

i) Analgesic- CNS and peripheral effect – reduction of certain types of pain- may involve non-PG related effects

ii) Antipyretic (CNS effect)- lowering of body temperature- PG inhibition, IL-1 beta mediated

iii) Anti- inflammatory (except paracetamol) due mainly to PG inhibition- modification of the inflammatory reaction

-Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cycloxygenase, an enzyme that catalyses the formation of eicosinoids such as prostaglandins and thromboxanes from arachidonic acid.

-Ibuprofen mainly blocks COX-2, Aspirin more COX-1 than COX-2

-That aspirin inhibits COX was shown by the Nobel laureate John Vane et al in 1971 using cell free homogenates of guinea pig lungs: they showed a linear relationship between PGF_2a-like activity generation and the log concentration of the drug added.

-The isoform of COX that is expressed during inflammation is COX-2.

-Prostaglandins sensitise nociceptors to the actions of mediators such as bradykinins, which trigger nociceptive firing. By decreasing levels of prostaglandins, NSAIDs therefore limit the ability of other inflammatory mediators to produce nociceptor firing.

-They may also have central actions, as prostaglandins in the spinal cord are thought to facilitate transmission from first-order nociceptive neurons in the dorsal horn.

-They are therefore useful in mild to moderate pain in which prostaglandin synthesis plays a role, notably tissue damage and inflammation.

-Paracetamol is generally not considered to be an NSAID-rapidly metabolised to NAPQI, BQ; it is an analgesic and anti-pyretic but not an anti-inflammatory. This may be due to it having effects on central rather than peripheral prostaglandin production.

-It has also been shown to selectively inhibit COX-3, which is found only in the CNS, although whether this enzyme isotype is important in humans is uncertain.

-Side effects of NSAIDs are thought to be mainly related to inhibition of COX-1, which is constitutively expressed and has important roles in normal tissue homeostasis.

Side effects

-One of the main problems is ulceration and bleeding in the GI tract, which occurs because there is constitutive production of prostaglandins that inhibit acid secretion and protect the mucosa.

-Effect on renal blood flow

-Tendencey to prlong bleeding through inhibition of platelet function

-These side effects are much less common in COX-2 specific NSAIDs, such as celecoxib and etoricoxib. These are licensed in the UK but restricted to use in patients with a very high risk of serious GI side effects.

Core: local anaesthetics

• Lidocaine

• Procaine

• Amethocaine

• Bupivacaine

• Prilocaine

• Benzococaine

-They are typically tertiary amines, with the amine linked to a hydrophobic group by either an ester or an amide link.

-The type of linkage affects how they are metabolised: ester linkage = by esterases in the plasma; amide link = in the liver.

-Lidococaine has an amide link.

-They are weak bases and tend to exist mainly in an ionised form at physiological pH, although some remains in non-ionised form.

Mechanism of action

-Local anaesthetics are a division of a large group of drugs that affect action potentials, by altering one of the various stages.

-LAs block the initiation of APs by blocking voltage gated Na⁺ channels, preventing depolarisation of the membrane.

-They act on the same site as TTX but are much less potent.

-By blocking APs, LAs prevent the conduction of impulses by both sensory and effector neurons.

-They block the channels by physically plugging the central pore and are thought to cause additional electrostatic repulsion of Na⁺ ions.

The non-ionised form can cross the cell...

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