Scenario 26: Pain Flashcards
What detects noxious stimuli?
Nociceptors
Where are the cell bodies of the nociceptors?
In the dorsal root ganglion
What is the difference between the primary sensory neurone fibres?
AB - heavily myelinated, touch
C- thinly myelinated, dull/slow pain
Ad - fast, pain
What are the main modalities of nociceptor?
Thermal nociceptors (over 45 degrees), chemical nociceptors, polymodal nociceptors, mechano-nociceptors and silent
Which modalities have C fibres and which have Ad?
Thermal nociceptors (over 45 degrees), chemical nociceptors, polymodal nociceptors = C Mechano-nociceptors= Ad
Where in the spinal cord do most neurones involved in pain terminate?
Laminae I and II
Which part of pain is the spinothalamic pathway responsible for?
Discriminative part of nociception, fast pain
Which part of pain is the spinoreticular pathway responsible for?
Arousal and affective (unpleasantness) aspects of pain, dull pain
Where are nociceptive inputs processed?
Pain matrix
Describe the gate control theory of pain
Best visualised as the concept that activation of Ad fibres (pain of a hit) followed by that of C fibres (rubbing the area) can provide relief from pain. Activation of other nerve fibres can modify or block the pain response.
What regulates the gate in the gate control theory?
Activity of other pain fibres, activity of other peripheral fibres, messages descending from higher cortex (emotions, mental condition)
What is the role of glycinergic neurones in the deep dorsal horn of the pain in pain?
Inhibit it, so that if they are blocked, the pain or itch response to a given stimuli is much higher
What is plasticity in regards to pain pathways?
The concept that neural substrates which modify pain are modifiable depending on use or modulatory influences
What are the three components of pain?
Sensory- discriminative (sense of intensity, duration, location) affective-motivational (unpleasantness and desire to escape it) and cognitive component (involves judgements, beliefs, memories, perception of enviroment and patient’s history)
How are PAG and RVM involved in pain?
PAG- full of opioid receptors and enkephalins. Electrical stimulation here causes analgesia. (neurones -> serotonergic)
RVM- inhibition and facilitation of nociceptive processing, bidirectional control of nociception
What are the two types of pain hypersensitivity and what characterises them?
Allodynia- normal non-painful stimulus is painful
Hyperalgesia- responsiveness is increased so noxious stimuli provide exaggerated and prolonged pain
What are the two mechanisms involved in hypersensitivity to pain?
Peripheral sensitisation- reduction in threshold and increase in responsiveness (due to inflammatory chemicals)
Central sensitisation- increases in excitability of neurones within CNS triggered by burst of activity in nociceptors which alters the strength of synaptic connections
Which channelopathy causes an inability to feel pain?
SCN9A mutation. Codes for Nav1.7 which is strongly expressed in nociceptive neurones
What happens in Nav1.7 deletion?
Increase in enkephalin precursor Penk mRNA and met-enkephalin protein in sensory neurones
What characteristic congenital inability to feel pain?
Insensitive to acute tissue damaging stimuli, no pain with chronic injury, no sweating, variable cognitive impairment, recurrent episodic fever, normal touch, motor function and senses
What is the role of NGF in pain mechanisms?
Promotes survival of sympathetic and sensory neurones so can feel pain. If knocked out in animal models, response to noxious stimuli is gone. Most HSN IV patients show loss of small diameter sensory neurones in peripheral nerves
How can a point mutation in SCN9A increase pain sensitivity?
More expression of Nav1.7, leads to primary erythromelalgia and paroxysmal extreme pain disorder
Which genes are thought to be involved in those insensitive to pain?
trkA/NGF and Nav1.7
Which genes are thought to be involved in those hypersensitive to pain?
Nav1.7
Which genes are thought to be involved in those with migrane?
SNP
Which genes are thought to be involved normal pain mechanisms?
COMT, GCH, MOR, CGRP
What is the mechanism of nociceptive pain?
Tissue damage activating nociceptors
What is the mechanism of inflammatory pain?
Inflammatory mediators activating nociceptors
What is the mechanism of neuropathic pain?
Nerve damage activating nociceptors
What is involved in a hyperplasia response to mechanical stimulus?
Pain occurs outside injury site and involves a central mechanism
What is involved in a hyperplasia response to thermal stimulus?
Pain occurs at injury site and involves peripheral mechanism
What happens in peripheral sensitisation?
Nociceptors are responding more to same stimulus. Ligands act on receptors, set off second messenger systems which modulate pain:
1) change sensitivity of receptor often by Pi
2) second messengers change voltage gated channels so can be activated more easily
3) coupled to axon transport systems which modulate gene expression
What happens in central sensitisation?
Altered CNS processing. Amplification of pain signal. Repetitive nociceptive stimulation- increases sensitivity of CNS (wind up) anatomical reorganisation, reduced inhibition, glial activation
What are the four stages of pain processing?
Transduction, transmission, perception (not always present, general anaesthesia) and modulation
What are the features of fast pain?
Sensation: pricking, well localised, rapid onset.
Fibre: Ad
Synapse location: laminae I and V
What are the features of an Ad neurone fibre?
2-5 nm diameter, myelinated, velocity 5-15 m/s
What are the features of an C neurone?
0.5-2 nm diameter, non or thinly myelinated, velocity 0.5-2 m/s
What are the features of slow pain?
Sensation: dull aching, diffuse, slow onset
Fibre: C
Synapse location: laminae II
Where are tranductive molecules found?
On free nerve endings of nociceptive neurones
What do TRPV1 or TRPA1 sense?
Heat and noxious chemicals
What does Ad HTMR sense?
High threshold mechanoreceptors
What does P2X3 sense?
ATP response after tissue trauma
What does H1 sense?
Histamine receptor, itch
What does B2 sense?
Bradykinin
What does PGE2 sense?
PGE2
What do ASIC, Piezo2 and TRP sense?
Mechanical stimulation
What will a cold nociceptor express?
TRPM8 and others
What will a heat nociceptor express?
TRPV1 and non TRPV1 heat sensitive channel
How is stimulus intensity of a noxious stimulus transmitted?
By increased firing frequency
Where do nociceptive neurones synapse when they reach the spinal cord?
Immediately in the ipslateral dorsal horn, only have short collaterals
Where do Ad neurones synapse in the DH?
Projection neurones of laminae I, interneurons of laminae II and projection neurones of laminae V
Where do C neurones synapse in the DH?
Projection neurones of laminae I and interneurones of laminae II
Where do AB neurones synapse in the DH?
Travel up spinal cord and also send branches to synapse to with laminae IV neurones
Where do neurones in laminae I travel to from DH?
Thalamus via spinothalamic
Where do neurones in laminae V travel to from DH?
To thalamus via spinothalamic and to brainstem
What is referred pain? Why does it happen?
Pain from viscera referred to other body parts because nociceptors from viscera converge on dorsal horn also receiving cutaneous nociceptive input and has no way of knowing where it has received the information from
What is the role of neurones which project to the ventral posterior nucleus in pain sensation?
Location of pain lesion information,
What is the role of neurones which project to the subcortical structures in pain sensation?
Arousal, modulation, reticular formation projection to medial nucleus
What is the role of neurones which project to the medial nucleus of the thalamus in pain sensation?
Input from deep dorsal horn laminae. Projection to basal ganglia and cortex
What is antinoception?
Blockage of nociception
What is the effect of naloxone?
Blocks opioid receptors so can block endogenous opioids or exogenous ones in overdose
When will chronic pain respond well to opioids and when won’t it?
If due to chronic nociceptive activation it will respond well to opioids, however if it is due to adaptive changes it will respond poorly to opioids
Name a local anaesthetic
Lidocaine
Name three NSAIDs
Asprin, ibuprofen, paracetamol
Name two opioids
Morphine, codeine
When would a nitrate be used in pain control?
Angina
When would triptons be used in pain control?
Migraines
When would carbamazepine be used in pain control?
In trigeminal neuralgia
What drugs could be used in neuropathic pain?
TCAs (like amitriptyline), anticonvulsants (like pregabalin and gabapentin)
How do local anaesthetics work?
Na+ channel blockers to slow the rate at which they revert to resting stat. This blocks AP generation.
How do local anaesthetics cross the neuronal membrane?
In non-ionised form which dissociates when inside the membrane to give a free base
How can local anaesthetics be administered?
Topically or infused near nerve to block. Locally to spinal cord as epidural/intrathecal
How do NSAIDs work?
Inhibit COX so prevent eicosanoid production. Prostaglandins sensitise nociceptors to other mediators so NSAID’s provide analgesia by preventing this
Where are NSAIDs active?
In the periphery
Which NSAID is an irreversible COX inhibitor?
Asprin
Which NSAID is a reversible COX inhibitor?
Ibuprofen
Which NSAID is an indirect COX inhibitor?
Paracetamol
What is the structure of Leu5 and Met5 enkephalins?
Tyr-Gly-Gly-Phe with either Leu or Met
What are the three families of opioid receptors?
Mu delta and kappa
What are the three families of endogenous opioid peptides?
Endorphins, enkephalins and dynorphins
What do mu opioid receptors respond to?
Morphine
How do opioid receptors work?
Increase K+ conductance, inhibit AC and VGCC causing neuronal hyperpolarisation and inhibiting neurotransmitter release
What do delta opioid receptors respond to?
Leu5 and met5 enkephalin
What do kappa opioid receptors respond to?
Dynorphin
Which areas in the brain have the highest levels of opioid receptors?
Periaqueductal gray (PAG), nucleus raphe magnus (NRM), nucleus reticularis paragigantocellularis (NRPG) and dorsal horn of spinal cord esp laminae II (substantia gelatinosa)
Where do opioids work in the pain pathways?
In dorsal horn to inhibit NT release, at NRPG and at PAG
What will morphine do in the descending pain pathway?
Activate PAG and NRM, increase firing to DH, sertonergic pathway is disinhibited because GABA is inhibited so nociceptive info is not transmitted through DH
Why does morphine cause emesis?
Stimulation of chemical trigger zone of area postrema
What are the side effects of morphine?
Emesis, constipation, respiratory depression, cough suppression, pin-point pupils, euphoria, itch, hypotension, hypothermia, gall bladder and sphincter contraction
Why does morphine cause respiratory depression?
Decreased sensitivity to CO2
Why does morphine cause itch?
Histamine release
What are the issues with long term morphine use?
High levels of tolerance and dependance
What are the early signs of morphine withdrawal?
Yawning, lacrimation, runny nose, perspiration,
Why is morphine contradicted in biliary colic?
Gall bladder and sphincter contraction
What are the intermediate signs of morphine withdrawal?
Mydriasis, piloerection, tachycardia, twitching, tremor, restlessness
What are the late signs of morphine withdrawal?
Muscle spasm, fever, vomiting, nausea, abdominal cramps, diarrhoea
When is oxycodone given?
Cancer pain
How is fentanyl administered?
Cancer, long acting patches or short acting in preparation for surgery
When is methadone used?
In addict maintenance
What is diamorphine?
More lipophilic and potent opioid than morphine, converted to morphine in body
When is pethidine used?
For labour or minor surgery
What is buprenorphine?
Lipophilic partial agonist opioid given sublingually
What are the weak opioids?
Codeine, dihydrocodeine, tramadol, tapentadol
What is given in opioid overdose?
Naloxone, naltrexone, alvimopam (peripherally active)
How can we treat opioid induced constipation?
Alvimopam, methynaltrexone, pruclopride (5HT agonist) , lubiprostone (Cl- channel agonist)
What is the placebo effect?
Psycho-social-biological phenomenon activated when patients believe in effective therapy so expects a reduction in symptoms
How does the placebo effort work?
Psychological context tells the brain to expect therapeutic effect and as a result neurobiological events occur in the brain via conscious/unconscious mechanisms bringing about the release of effector molecules causing physiological changes in the brain and other organs that can generate a therapeutic effect. Clinical context and verbal suggestions of improvement/worsening induce expectations of outcome
What mechanisms are induced by the placebo effect?
Unconscious- conditioning
Unconditioned stimulus- drug
Conscious- anticipation, expectation, belief, trust, hope
Outline the cascade of chemical events following a placebo for a pain stimulus
Exception/condition (this will reduce my pain):
1) endogenous opioid activation and non opioid mediators act on pain pathways
2) pituitary gland releases GH and ACTH to release cortisol from adrenals
3) CCK acts on pain pathway
How does expectation of clinical benefit induce placebo-induced analgesia?
Results in enhanced release of dopamine in nucleus accumbens, as well an increased mu opioid activity and descending pain inhibition by PAG and anxiety modulation by prefrontal cortex
How does classical conditioning induce placebo-induced analgesia?
Repeated associations between conditioned stimulus the environment around patient (e.g. colour of pill) and unconditioned stimulus (drug) mean that the CS can have a conditioned response similar to that induced by the drug
Which areas of the brain are involved in the placebo response?
Dorsolateral prefrontal cortex (conditioning) nucleus accumbens (reward) and orbitofrontal cortex (anxiety)
How is non-opioid placebo analgesia mediated?
By cannabinoid receptors (CB1)
What are some potential problems with placebo?
Spontaneous remission, false positive errors caused by regression to the mean (1st measurement always peak) co-intervention responsible for remission, have to tell patient there is a chance of placebo (larger effects if told placebo is powerful analgesic) spontaneous variation
What is the open-hidden treatment effect?
If patient can see treatment (e.g. IV morphine) being given there is a larger analgesic effect
What are the 4 systems that the placebo effect is centered around?
Dopamine, opioid, serotonin, endocannabinoid systems
How has imaging provided proof for the placebo effect?
fMRI showed decrease in activity of pain pathways following placebo administration
