#14112 - Pain Relief - Neuroscience 1

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 membrane and can directly enter the pore from the membrane (hydrophobic pathway).

-The ionised form can only enter the channels from when they are open. This is called the hydrophilic pathway and is use-dependent.

-Use-dependent = the extent of the block increases with the frequency of APs because more APs more open channels.

pH will alter how effective LAs are. They will be more effective in basic conditions because more will exist in non-ionised form and less effective in acidic conditions because more will be in ionised form. They typically have a pKa of 8-9 which means that at biological pH they are almost entirely ionised resulting in slow penetration of nerves.

Sequence of blockade

-The smaller the diameter of the neuron, the more sensitive it will be to the block by an LA.

-Unmyelinated C type and myelinated Aδ fibres involved in pain sensation are the most sensitive so are affected first. Loss of pain is therefore the first effect.

-Other sensory neurons are the next up in size so are next affected, altering sensation of touch, temperature etc.

-Motor neurons are the largest so are relatively resistant to the effects of LAs and are affected last.

Duration of action

-The type of linkage affects how they are metabolised: ester linkage = rapidly metabolised by esterases in the plasma (half-lives of less than an hour); amide link = tend to be more stable and less easily broken down – broken down in the liver (half-life of about 2 hours)

-LAs will also have a short half life if they are rapidly lost from the site of action in the bloodstream. Local vasoconstrictors such as adrenaline or felypressin are therefore often administered alongside an LA to minimise loss from the site of action and increase the duration of effect.

-More hydrophobic, lipid soluble LAs are more able to use the hydrophobic pathway so have greater, longer lasting effects.

Method of administration

-It can be applied directly to the skin (eutectic mixture of local anaesthetics – EMLA) or injected directly into the target tissue (local)

-It can be directed into the bloodstream distal to a pressure cuff to prevent systemic distribution of the drug (regional); can be used in limb surgery.

-It can be injected into subarachnoid space leading to action on spinal roots and spinal cord (spinal); can be used in surgery of abdomen, pelvis or leg (particularly when general anaesthesia is not deemed appropriate)

-Epidural – infusion of LA into the epidural space surrounding the spinal cord – target area is delineated by level in the spine where the drug is administered (lumbar – lower abdomen and legs; thoracic – more global effect but carries risks to heart and muscles required for breathing) – used routinely to reduce pain of childbirth; increasingly used for abdominal surgery and even cardiothoracic surgery.

Risks

-Toxic actions of LAs result from the escape of excessive amounts into the systemic circulation.

-The CNS may be affected where initially there are stimulatory effects because the smallest neurons are inhibitory and are blocked first.

-This causes restlessness, tremor and convulsions.

-Greater leakage of LAs into the CNS will produce depression, usually in the form of respiratory depression, which can be fatal.

-The cardiovascular system is the other main site of toxic effects reduced heart output, vasodilation, low blood pressure.

Core: centrally-acting analgesics: opioids and their receptors

-Three major classes of opioid receptor have been identified; all are coupled to G_i. They were originally distinguished according to their affinity for various...