Pain And Analgesia Flashcards
LECTURE: PAIN
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What is pain?
- an unpleasant sensory and emotional experience associated with actual or potential tissue damage
- combination of sensory (discriminative) and affective (emotional) components
What is noiception?
· sensory nervous system’s process of encoding noxious stimuli. This may include sensing pain
What are the functions of nociceptors?
- Recognise pain sensitive afferent fibres, or neurons (whole neuron can be a nociceptor)
- Only respond to potentially damaging (noxious) stimuli
pick up signal
Why are free nerve endings termed “free”?
- they are devoid of connective tissue capsule or Schwann cell covering
What is nociceptive transmission?
- Conduction of the electrical impulses to the CNS which corresponds to the pain that is felt
- Transfers information about intensity, duration and location
Where are noxious stimuli picked up by free nerve endings?
skin, muscle and viscera
What are examples of noxious stimuli?
o Injury
o Heat extreme
o Cold
o Inflammation
o pH
What determines whether a stimulus can be picked up by a nerve ending?
What determines whether a stimulus can be picked up by a nerve ending?
What happens after reception of the noxious stimuli?
- receptor generates AP
- intensity of pain is encoded via firing rate of the action potential
Where are the nerve endings located in relation to the axon fibre?
at the end of the axon
pillock
What are primary sensory neurons?
Neurons that conduct impulses along efferent pathways -> CNS for interpretation
Where are primary sensory neurons located?
cell body is located in the dorsal root ganglion
NT release
How many axons come from 1 cell body (in dorsal root ganglion)?
2 separate axons - peripheral (down) and central end (up)
What is the mechanism that occurs when a stimulus is received by nociceptors?
- reception of stimulus => AP fired at the nerve
- AP travels up axon -> SC, where there is NT release at central nerve ending
- axons are afferent (take info TO brain) and primary ( first of a multi-synaptic pathway)
What are the 2 types of nociceptor?
· Mechanical – A-delta fibres (hammer blow)
· Polymodal – C fibres (majority of signals picked up)
What is the mechanism once the primary afferent neurones reach the CNS?
- Primary afferent axons -> SC and synapse to a second order neuron
- Synapse formed in dorsal horn of SC (substantia gelitanosa)
- Axon can split. 1 branch -> straight to brain (in touch not pain)
- In pain the axon -> SC
- In a motor reflex, sensory info -> ventral horn where motor neurons are, and exit SC via the ventral root
… withdraw hand from fire- unconscious
What is the gate theory of pain?
- SC contains a neurological “gate” that blocks pain signals OR allows them to continue to brain.
- Pain signal must overcome inhibition (gate) to be sent to brain (by network of dorsal horn neurons)
How does analgesic effect relate to the gate theory of pain?
close gate
- prevent overcoming of the inhibition = analgesic effect as we are not allowing pain signals to be passed to the brain (wont feel pain)
What is TENS and how does it work?
Transcutaneous electrical nerve stimulation (TENS)
- non-invasive peripheral stimulation technique used to relieve pain.
- ⬆ activity of non-noxious axons and amount of non-noxious info -> SC for analgesic effect…closing the spinal gate
given to women during childbirth/ to dec back pain too
What is the ascending spinothalamic pathway?
the pathway in which the signal travels up to the brain once it leaves the dorsal horn
What happens to the sensory information once it reaches the brain? (Spinothalmic pathway)
- axon reaches thalamus and synapses to the tertiary neurons which sends signal -> cortex
- synapse -> tertiary neuron is located at the subcortical level – this is where the perception of pain occurs
Where is pain localised within the brain?
cortical level:
cortex
What is the limbic system?
- subcortical level of the brain
- this is an affective component - involved in our behavioural and emotional responses
What are the descending pathways?
- They are pathways that are carrying info down SC from the brain
- this can increase/decrease the amount of pain we can feel
What is the function of the cortex in the descending pathway?
can send signals down to the brain stem nuclei and then the dorsal horn of the spinal cord, and can modulate the circuitry here
What does the brainstem nuclei contain?
- rich in endogenous opioids (pleasure peptides)
- responsible for release of serotonin (5-HT), NAd, and enkephalin – these close the spinal gate and cause analgesia (this is the Intrinsic Analgesia system)
What is persistent pain in relation to normal pain?
- Increased sensitivity of pain
- happens through mechanisms of peripheral + central sensitization via modification of neurotransmission
how is sensation of pain felt?
primary afferent input (duration and intensity)
What is allodynia?
- Type of pain.
- People with allodynia are extremely sensitive to touch.
- Activities that aren’t usually painful (like combing one’s hair) can cause severe pain
What is Hyperalgesia?
- Increased sensitivity to feeling pain and an extreme response to pain.
- may occur when there is damage to the nerves or chemical changes to nerve pathways involved in sensing pain
How can sensitisation of peripheral nociceptors occur?
- stimulus damages tissue, triggers inflamm mechanisms (redness, welling, vasodilation, immune cell migration)
- immune cells produce inflamm soup: Prostaglandins, H+, Bradykinin, NGF, Cytokines
- immune cell products signal back -> nerve ending = sensitization of polymodal nociceptor (⬇ stimulus threshold for AP to occur)
- this is primary hyperalgesia - increased sensitivity in damaged tissue alone
How does increased peripheral sensitisation affect central sensitisation?
- increases central sensitisation
- more APs being fired which will enter the spinal cord
· more APs = increased response of the dorsal horn second order neuron
What are the major neurotransmitters present in the synapse of the dorsal horn?
- Glutamate - bind to AMPA and NMDA receptors (post-synaptic)
- Substance P - bind to NK-1 receptor (post-synaptic)
Which neurotransmitter is released into the synaptic cleft following action potential of a primary afferent neuron (normal signalling)?
- Glutamate alone
- binds to AMPA receptor alone to signal the pain and active the second order neuron
What is the relationship between pain received by second order neuron and pain signal released to the brain (in normal signalling)?
- they are EQUAL
- this is Fidelity signalling
Which neurotransmitter is released into the synaptic cleft following action potential of a primary afferent neuron (Sensitised pain signalling)?
- Glutamate and Substance P
- Substance P release depends on rate of primary afferent firing
- NMDA is now bound by glutamate (was blocked before)
p654
How is blockage of NMDA removed on the post synaptic neuron?
- via the activation of the other receptors (causing a high level of membrane depolarization)
Why is the involvement of NMDA key to responsiveness of the post synaptic neuron?
- unblocking allows for the influx of calcium ions
- Calcium influx triggers secondary messenger cascades and prostaglandin production.. amplification of signal
What are the results of increased responsiveness of the post synaptic receptors?
-> increased frequency of signals sent to brain from second order neuron
– this is facilitated signalling
What is the relationship between pain received by second order neuron and pain signal released to the brain (in sensitised pain signalling)?
Presynaptic signalling < post synaptic signalling
2 mechanisms underlying heightened pain sensation?
peripheral sensitisation
central sens…
L ANALGESIC DRUGS
How do NSAIDs work?
- inhibition of COX enzymes (cyclooxygenase)
- COX enzymes produce prostoglandins
- NSAIDS blocks the ability for prostaglandins to cause pain
How do COX enzymes produce prostaglandins?
2 modes. 1= unwated SEs, 1= clinical effects
COX1 constitutive - make PGs
protection of gastric mucosa
haemostasis
:(
COX2 inducible - make PGs
mediate pain, inflamm, fever
:)
What is the importance of COX-1?
- made in the body and is required for life
- Helps with homeostasis and protection of the gastric mucosa
What is COX-2 used for?
- mediate pain and inflammation
What are the consequences of inhibiting COX-1?
- may get unwanted side effects
In which 2 locations can the productions of prostaglandins be stopped?
- site of pain
- Dorsal horn
At the the site of pain how are prostoglandins produced and what is the effect of the lack of prostoglandins?
- produced by inflammatory cells
- ⬇ PG production -> ⬇ nociceptor sensitization – analgesic effect
How is analgesic effect caused by prostoglandins in the dorsal horn?
⬇ prostaglandin will ⬇ the central sensitization
What are the Different types of NSAIDs?2
- Non selective INhibitors (aspirin/ ibuprofen)- weakly COX 1 selective
- COX-2 selectives (Coxibs)
What are the side effects of non-selective COX inhibitors? e.g. aspirin, ibuprofen
· GI disturbance
· discomfort
· dyspepsia
· diarrhoea
· nausea and vomiting
· gastric bleeding and ulceration
· skin reactions (idiosyncratic)
kidney damage (o.d. chronic use)
What are the Different classes of Coxibs (COX-2 selective)
- Weakly selective (Diclofenac/ Celecoxib)
- Very selective (Etoricoxib/ Etoricoxib/ Parecoxib)
- Highly selective (Rofecoxib)
Is paracetamol an NSAID?
- No, It is a centrally acting analgesic
- has no anti-inflammatory activity
- There is some suggestion that there is inhibition of A 3rd COX enzyme in the brain
Paracetamol OD-> what
potentially fatal liver damage
What are the mechanisms of Opioids? morphine, codeine
- stimulate the µ-opioid receptors
- > mimics effects of endogenous opioids which produce and analgesic effects
Where do opioids act within the body?
lot of places as their receptors are present in a lot of places
brain…
How do opioids work in the periphery?
- inhibit AP firing from the primary afferent neuron
- inhibit release of inflammatory mediators from immune cells once a stimulus is received
How do opioids work in the CNS?
- Inhibition of NT release in brain + SC
- have excitatory effect on brain (⬆ descending pathways)
- used to close the spinal gate and produce analgesic effect
What are some weak opioids? 4
· Codeine
· Dihydrocodeine
· Dextropropoxyphene
· Tramadol
What are some strong opioids?
· Morphine
· Methadone
· Fentanyl
· Hydromorphone
· Diamorphine (heroin)
· Pethidine (meperidine)
· Oxycodone
· Buprenorphine
· Levorphanol
· Dextromoramide
What are some problems of Opioids?
· Nausea and vomiting
· Decreased GI tract motility – leading to chronic constipation
· Depression of respiratory center (overdose risk)
· Increased Tolerance (more drug required to have same effect)
· Dependence – there are euphoric effects (leading to addiction)
What are common combination drugs for Opioids?
- Co-proxamol = Paracetamol + dextropropoxyphene
- Co-codamol = Paracetamol + Codeine
- Nurofen Plus = Ibuprofen + Codeine
What can adjuvant analgesics be used for?
Commonly used ‘off-label’ for difficult to treat pain caused by injury to the nervous system (‘neuropathic’ pain)
What are some examples of adjuvant analgesics?
· Anticonvulsants: gabapentin (Neurontin®), pregabalin - (Lyrica®); carbamazepine
· Antidepressants: amitriptyline
good at low doses
what drugs used for difficult to treat neuropathic pain?
off label use of anticonvulsants + antidepressants (adj analgesics)
