Pain and analgesia (CCA week 6) Flashcards
What is the downside of using flunixin for post-op colics? But why used?
Slows the recovery of injured small intestine mucosa
Excellent visceral analgesia and mitigates clinical signs of endotoxaemia - no effective alternative to NSAIDs for this
How do NSAIDs work?
Most NSAIDs are nonselective and inhibit both COX-1 and COX-2 enzymes
COX-1 is expressed in most tissues and is responsible for the production of prostanoids involved in physiological functions in organ systems, such as the maintenance of GI mucosa, renal blood flow and platelet aggregation
COX-2 is an inducible enzyme in many tissues under proinflammatory stimuli, including GIT
But there is overlap between the two (COX-2 also constitutive in CNS, kidney, eye and repro organs)
Pain and inflammation associated with COX are attributed mostly to COX-2 - NSAIDs result in reduction of prostanoid levels at sites of inflammation (prostanoids increase pain by sensitising pain pathways) - PGE2 dominates this process in particular and also cause local vasodilation and attracts neutrophils (so NSAIDs will also reduce hyperaemia and hyperpermeability)
Side effects of NSAIDs are attributed to inhibition of COX-1
Is ketoprofen a good NSAID?
COX selective
But full dose of 2.2mg/kg was found not to reduce lameness to the same extent as phenylbutazone
What is the IASP definition of pain (2020)?
An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage
What is the difference between nociception and pain?
Nociception = information regarding a noxious insult relayed from periphery to CNS
Pain = integration and processing of nociceptive input by the brain, allowing it to be recognised as pain (implies recognition at the cortical level)
What are physiological and pathological pain?
Physiological pain - activation of nociceptors by extremes of temperature, pressure or chemical concentrations. Tends to be transient, localised and protective (Ad fibre mediated) and linked to withdrawal reflexes and behaviour adaptation.
Pathological pain - associated with actual tissue damage (ie haven’t managed to get away from the cause), ongoing noxious input and may produce chronic pain states, hyperalgesia and allodynia. Acute pathological pain may be protective, but if stimulus can’t be removed then it becomes chronic pain, which disrupts homeostasis, causes suffering and has a significant impact on animal’s behaviour and quality of life.
What are the two types of nociceptors?
Somatic nociceptors - on skin, muscle, bone and joints. Sensitive to chemical (inflammatory), thermal and mechanical stimuli. Pain tends to be sharp/stabbing at site of injury. Small receptive fields.
Visceral nociceptors - visceral tissues. Sensitive to distension, ischaemia and inflammation. Sparsely distributed with large overlapping receptive fields. Pain is poorly localised and diffuse. Can be ‘referred’. Tends to be dull/vague. Can be associated with autonomic effects e.g. sweating, nausea.
Definitions of acute and chronic pain?
Acute pain - associated with injury/surgery/disease, typically short duration persisting only as long as original insult
Chronic pain - persists beyond expected time frame (>3-6 months), may be associated with disease/injury that is not resolving, maladaptive response with no useful function, often poorly responsive to treatment
Why do chronic pain states happen, even in the absence of true continued stimuli?
Neuroplasticity = Adaptation of the nervous system (functionally and anatomically) in response to stimuli, resulting in sensitisation by peripheral and central mechanisms
- Hyperalgesia - exaggerated response to normally painful stimulus
- Allodynia - normally innocuous stimulus perceived as painful (e.g. standing under shower after sunburn - water pressure becomes painful due to sensitisation of receptors)
When can neuroplasticity happen and be difficult to treat the pain?
Single severe painful event
Multiple moderate to severe painful events
Memory or expectation of a painful event
How to avoid the devlopment of chronic pain?
Treat any pain (even mild) aggressively, to avoid sensitisation
As once chronic pain state has developed, can be difficult to treat
What are pre-emptive and multimodal analgesia?
Pre-emptive analgesia - adminstering analgesics prior to noxious stimulus maximises effect, reduces sensitisation and enhances post-operative analgesia
Multimodal analgesia - affecting as many of the nociceptive pathway stages as possible (transduction, transmission, modulation, perception)
What are the 4 stages of the nociceptive/pain pathway?
Transduction - Conversion of stimulus (mechanical, thermal or chemical) into an electrical signal (action potential) by activation of nerve end receptors. Nociceptors are free nerve endings of Ad and C nerve fibres (higher activation thresholds than specialised receptors). Also subpopulation of ‘silent nociceptors’ which are only activated with actual tissue damage.
Transmission - Conduction of impulses to and from the CNS. Sensory (afferent) impulses enter CNS via dorsal root of the mixed segmental spinal nerves. Motor (efferent) impulses exit CNS via the ventral root of the spinal nerves. Occurs through propagation of action potentials, dependent on voltage gated sodium channels.
Modulation - Amplification or suppression of nociceptive input at the level of the spinal cord due to altered neuronal sensitivity and neurotransmitter release.
Perception
What can activate/sensisise nociceptors?
Products of cellular damage - PGE2, leukotrienes, H+, K+, ATP
Sensory nerve endings - substance P, nerve growth factor, CGRP
Plasma, platelets, mast cells - histamine, serotonin, bradykinin
What is peripheral sensitisation?
Inflammatory mediators and products of cell damage lower nociceptor threshold and recruit silent nociceptors
–> Primary hyperalgesia (nociceptors at site of injury respond more vigorously to noxious stimuli)
–> Primary allodynia (normally innocuous stimuli now capable of triggering nociceptors at site of injury)
What is the 1st order neurone? Where is the cell body and axon?
Transmits information from the periphery to CNS
Cell body is in dorsal root ganglion
Axon extends into grey matter of dorsal horn of spinal cord
What are the 3 types of 1st order neurones?
Ad fibres - Initial pain. Mechanical and thermal pain.
C fibres - Dull persistent pain. Chemical, mechanical and thermal stimuli.
AB fibres - Innocuous mechanical stimuli.
What are the 2 types of 2nd order neurone?
Projection neurones - Ascend message to higher centres. Can be nociceptive specific (high threshold, input from Ad and C fibres only) or wide dynamic range (input also from AB fibres)
Interneurones - Excitatory or inhibitory (local processing and modulation of pain signals). Located within grey matter. May connect to somatic or sympathetic reflex arcs.
What are 3rd order neurones?
Occurs at higher centres
Responsible for processing, integration and recognition of a harmful or painful experience
Consists of physiological and psychological components
Animal has to be conscious to perceive a nociceptive signal as painful
Which mechanisms are involved in the modulation stage of the pain pathway?
Inhibitory interneurones (local level 2nd order neurones)
Descending inhibition (from higher centres)
Gate control theory
Central sensitisation
What is central sensitisation?
Increased second order neurone activity, due to recruitment and upregulation of post synaptic receptors, in response to sustained or massive release of excitatory neurotransmitters
Results in:
- Secondary hyperalgesia (spread of area of increased responsiveness to noxious mechanical, not thermal, around site of primary injury)
- Secondary allodynia (spread of area of increased perception of innocuous stimuli as painful)
Does an animal feel pain under GA?
All nociceptive processes will be occuring in response to the stimuli
But the animal will not be aware of the pain
When animal wakes up, neuroplasticity has probably already occurred and so the pain will likely be amplified
What is gate theory?
E.g. rub area where stung by stinging nettles will reduce the pain
Input from Ad or C fibres inhibits activity of inhibitory interneurones, facilitating nociceptive signalling
Innocuous sensory input from AB fibres activates inhibitory interneurones, suppressing nociceptive signalling
Which stages of the pain pathway do NSAIDs work on?
Transduction (and modulation)
Reduce production of inflammatory mediators responsible for receptor sensitisation
