Physiology of Pain 2 Flashcards
1
Q
Clinical pain
- Clinical pain, as the name suggests, is seen in clinics
- Associated with damage to tissues, including the nervous system
- Mechanisms can be nociceptive and/or neuropathic
- … - normal functioning of nociceptors in response to tissue injury
- … - Pain in response to injury to the nervous system
A
- Clinical pain, as the name suggests, is seen in clinics
- Associated with damage to tissues, including the nervous system
- Mechanisms can be nociceptive and/or neuropathic
- Nociceptive - normal functioning of nociceptors in response to tissue injury
- Neuropathic - Pain in response to injury to the nervous system
2
Q
Clinical pain
- Clinical pain, as the name suggests, is seen in clinics
- Associated with damage to tissues, including the nervous system
- Mechanisms can be nociceptive and/or neuropathic
- Nociceptive - normal functioning of nociceptors in response to tissue …
- Neuropathic - Pain in response to injury to the … …
A
- Clinical pain, as the name suggests, is seen in clinics
- Associated with damage to tissues, including the nervous system
- Mechanisms can be nociceptive and/or neuropathic
- Nociceptive - normal functioning of nociceptors in response to tissue injury
- Neuropathic - Pain in response to injury to the nervous system
3
Q
Pain < 3 months = …
A
Pain < 3 months = acute
4
Q
Pain > 3 months = …
A
Pain > 3 months = chronic
5
Q
Acute pain
- Due to tissue … or …
- E.g. following surgery, musculoskeletal injury, burn, headache, visceral pain
- … mechanism - when injury site recovers - pain stops
A
- Due to tissue injury or inflammation
- E.g. following surgery, musculoskeletal injury, burn, headache, visceral pain
- Nociceptive mechanism - when injury site recovers - pain stops
6
Q
Acute pain
- Due to tissue injury or inflammation
- E.g. following surgery, musculoskeletal injury, …, headache, … pain
- Nociceptive mechanism - when injury site … - pain …
A
- Due to tissue injury or inflammation
- E.g. following surgery, musculoskeletal injury, burn, headache, visceral pain
- Nociceptive mechanism - when injury site recovers - pain stops
7
Q
Acute pain mechanisms
- Acute pain is due to the excitation of nociceptors
- E.g. … activation via:
- ATP - binds to purinergic receptors sitting at the peripheral terminals of nociceptors
- Proton/acid binding to acid sensing ion channels
- serotonin binding to the 5-HT3 receptor sitting on the terminals of nociceptors
- E.g. … activation via:
- Overall - Compounds bind to receptor - switches on nociceptor - triggers spinothalamic tract - pain
- OR: Mechanisms of acute pain may also be due to … sensitisation - leads to hyperalgesia:
- … -reduces threshold for activation, opens more easy
- … - reduce threshold of firing of these channels
A
- Acute pain is due to the excitation of nociceptors
- E.g. Direct activation via:
- ATP - binds to purinergic receptors sitting at the peripheral terminals of nociceptors
- Proton/acid binding to acid sensing ion channels
- serotonin binding to the 5-HT3 receptor sitting on the terminals of nociceptors
- E.g. Direct activation via:
- Overall - Compounds bind to receptor - switches on nociceptor - triggers spinothalamic tract - pain
- OR: Mechanisms of acute pain may also be due to peripheral sensitisation - leads to hyperalgesia:
- Bradykinin -reduces threshold for activation, opens more easy
- Prostaglandins - reduce threshold of firing of these channels
8
Q
Acute pain mechanisms
- Acute pain is due to the … of nociceptors
- E.g. Direct activation via:
- ATP - binds to purinergic receptors sitting at the peripheral terminals of nociceptors
- …/… binding to … sensing ion channels
- … binding to the 5-HT3 receptor sitting on the terminals of nociceptors
- E.g. Direct activation via:
- Overall - Compounds bind to receptor - switches on nociceptor - triggers spinothalamic tract - pain
- OR: Mechanisms of acute pain may also be due to peripheral sensitisation - leads to …:
- Bradykinin -reduces threshold for activation, opens more easy
- Prostaglandins - reduce threshold of firing of these channels
A
- Acute pain is due to the excitation of nociceptors
- E.g. Direct activation via:
- ATP - binds to purinergic receptors sitting at the peripheral terminals of nociceptors
- Proton/acid binding to acid sensing ion channels
- serotonin binding to the 5-HT3 receptor sitting on the terminals of nociceptors
- E.g. Direct activation via:
- Overall - Compounds bind to receptor - switches on nociceptor - triggers spinothalamic tract - pain
- OR: Mechanisms of acute pain may also be due to peripheral sensitisation - leads to hyperalgesia:
- Bradykinin -reduces threshold for activation, opens more easy
- Prostaglandins - reduce threshold of firing of these channels
9
Q
Acute pain treatments
- Lots of acute pain treatments
- Very effective
- Sites of action are:
- … (i.e. at the site of injury)
- …
- Or both
A
- Lots of acute pain treatments
- Very effective
- Sites of action are:
- PNS (i.e. at the site of injury)
- CNS
- Or both
10
Q
Local anaesthetics
- Examples include …, …
- Act in periphery
- … applied to skin
- Mechanism of action:
- Prevents nociceptor firing by … sodium channels
A
- Examples include lidocaine, lignocaine
- Act in periphery
- Topically applied to skin
- Mechanism of action:
- Prevents nociceptor firing by blocking sodium channels
11
Q
Local anaesthetics
- Examples include lidocaine, lignocaine
- Act in …
- Topically applied to skin
- Mechanism of action:
- Prevents … firing by blocking … channels
A
- Examples include lidocaine, lignocaine
- Act in periphery
- Topically applied to skin
- Mechanism of action:
- Prevents nociceptor firing by blocking sodium channels
12
Q
NSAIDs
- Examples include …, ibuprofen
- Act in periphery
- Mechanism of action:
- Reduce the inflammatory response by inhibiting … synthesis
- Reduce peripheral sensitisation
- Cyclooxygenase (…) inhibited -> … synthesis reduced - > Prevents decrease in Na+ channel threshold
A
- Examples include aspirin, ibuprofen
- Act in periphery
- Mechanism of action:
- Reduce the inflammatory response by inhibiting prostaglandin synthesis
- Reduce peripheral sensitisation
- Cyclooxygenase (COX) inhibited -> Prostaglandin synthesis reduced - > Prevents decrease in Na+ channel threshold
13
Q
Paracetamol/Acetaminophen
- Paracetamol is not a … (no anti-… properties)
- Acts …
- Mechanism of action:
- Exact mechanism not known
- Inhibits cyclooxygenase enzymes in …NS
- Acts on … serotonergic pathway
A
- Paracetamol is not a NSAID (no anti-inflammatory properties)
- Acts centrally
- Mechanism of action:
- Exact mechanism not known
- Inhibits cyclooxygenase enzymes in CNS
- Acts on descending serotonergic pathway
14
Q
Topical capsaicin treatment
- Component of … …
- Acts in … - Topically applied to skin
- Mechanism of action:
- TRP… agonist - Persistent opening of TRP… -> Calcium overload -> … stops working
A
- Component of chili peppers
- Acts in periphery - Topically applied to skin
- Mechanism of action:
- TRPV1 agonist - Persistent opening of TRPV1 -> Calcium overload -> Nociceptor stops working
15
Q
Opioids
- Examples include …, …, tramadol
- Most … pain relief but numerous side effects
- Act … and …
- Mechanism of action - … of the endogenous opioid system:
- Brainstem (disinhibition)
- Spinal Cord
- Peripheral (inhibits channels on nociceptors)
A
- Examples include morphine, codeine, tramadol
- Most effective pain relief but numerous side effects
- Act centrally and peripherally
- Mechanism of action - agonists of the endogenous opioid system:
- Brainstem (disinhibition)
- Spinal Cord
- Peripheral (inhibits channels on nociceptors)
16
Q
Gate control theory
- Pain evoked by nociceptors can be reduced by the simultaneous activation of low threshold … (Aβfibres)
- Simply put, … or blowing on the painful area can … the pain
- … of pain at the spinal cord level
A
- Pain evoked by nociceptors can be reduced by the simultaneous activation of low threshold mechanoreceptors (Aβfibres)
- Simply put, rubbing or blowing on the painful area can reduce the pain
- Modulation of pain at the spinal cord level
*
17
Q
Mechanisms of gate control
- Stimulation of … fibres at injury site activates interneurons in dorsal horn, which … spinothalamic neurons
- Rubbing/blowing - activates … fibres
- C fibres inhibit inhibitory interneurons – opens gate
- … fibres activate inhibitory interneurons – closes gate
A
- Stimulation of Ab fibres at injury site activates interneurons in dorsal horn, which inhibit spinothalamic neurons
- Rubbing/blowing - activates Ab fibres
- C fibres inhibit inhibitory interneurons – opens gate
- Aβ fibres activate inhibitory interneurons – closes gate
18
Q
Mechanisms of gate control
- Stimulation of Ab fibres at injury site activates interneurons in dorsal horn, which inhibit spinothalamic neurons
- Rubbing/blowing - activates Ab fibres
- C fibres … inhibitory interneurons – … gate
- Aβ fibres … inhibitory interneurons – … gate
A
- Stimulation of Ab fibres at injury site activates interneurons in dorsal horn, which inhibit spinothalamic neurons
- Rubbing/blowing - activates Ab fibres
- C fibres inhibit inhibitory interneurons – opens gate
- Aβ fibres activate inhibitory interneurons – closes gate
19
Q
Chronic pain is pain that persists for over … months - it is very common
A
over 3 months
20
Q
chronic pain is very common -affects …-…% of population
A
20-50chronic pain is very common -affects 20-50% of population
21
Q
Examples leading to chronic pain:
A
Chronic back pain, cancer, carpal tunnel syndrome, arthritis, fibromyalgia, diabetes, migraine, post-surgery, postherpetic neuralgia (shingles), phantom limb pain, multiple sclerosis, trigeminal neuralgia
22
Q
Chronic pain can be … or …
A
Chronic pain can be nociceptive or neuropathic
23
Q
Neuropathic pain
- Nerve injury may be a compression, traction, sever, h…, demyelination, t… or n…
- Affects …% of the population
- However, a nerve injury may not always be obvious on … examination
A
- Nerve injury may be a compression, traction, sever, hypoxia, demyelination, tumour or neuroinflammation
- Affects 8% of the population
- However, a nerve injury may not always be obvious on clinical examination
24
Q
Neuropathic pain
- Nerve injury may be a c…, traction, s…, hypoxia, d…, tumour or neuroinflammation
- Affects 8% of the population
- However, a nerve injury may not always be obvious on clinical …
A
- Nerve injury may be a compression, traction, sever, hypoxia, demyelination, tumour or neuroinflammation
- Affects 8% of the population
- However, a nerve injury may not always be obvious on clinical examination
25
Q
Symptoms of neuropathic pain
A
26
Q
Neuropathic pain mechanisms
- Mechanisms are complex, involving both peripheral and central nervous systems
- Main peripheral mechanisms:
- Peripheral …
- Increased … of primary …
- Main central mechanisms:
- Central … - within spinal cord
- Changes in activation patterns/cortical … - within brain
A
- Mechanisms are complex, involving both peripheral and central nervous systems
- Main peripheral mechanisms:
- Peripheral sensitization
- Increased firing of primary afferents
- Main central mechanisms:
- Central sensitization - within spinal cord
- Changes in activation patterns/cortical remapping - within brain
27
Q
Neuropathic pain mechanisms
- Mechanisms are complex, involving both peripheral and central nervous systems
- Main peripheral mechanisms:
- Peripheral sensitization
- … firing of primary afferents
- Main central mechanisms:
- Central sensitization - within … …
- Changes in … patterns/… remapping - within brain
A
- Mechanisms are complex, involving both peripheral and central nervous systems
- Main peripheral mechanisms:
- Peripheral sensitization
- Increased firing of primary afferents
- Main central mechanisms:
- Central sensitization - within spinal cord
- Changes in activation patterns/cortical remapping - within brain
28
Q
Increased firing of primary afferents
- At nerve injury sites, the damaged tips of nociceptors fire spontaneously
- … nociceptor - ion channels formed still but … at site of injury - tips of nociceptors more … and send pain impulses up the … tract - site swells to form … at the injury site
- Responsible for spontaneous pain and also phantom limb pain
- Underlies … … pain mechanisms
A
- At nerve injury sites, the damaged tips of nociceptors fire spontaneously
- Severed nociceptor - ion channels formed still but accumulate at site of injury - tips of nociceptors more excitable and send pain impulses up the spinothalamic tract - site swells to form neuroma at the injury site
- Responsible for spontaneous pain and also phantom limb pain
- Underlies central neuropathic pain mechanisms
29
Q
Increased firing of primary afferents
- At nerve injury sites, the damaged tips of nociceptors fire …
- Severed nociceptor - ion channels formed still but accumulate at site of … - tips of nociceptors more excitable and send pain impulses … the spinothalamic tract - site … to form neuroma at the injury site
- Responsible for … pain and also … … pain
- Underlies central neuropathic pain mechanisms
A
- At nerve injury sites, the damaged tips of nociceptors fire spontaneously
- Severed nociceptor - ion channels formed still but accumulate at site of injury - tips of nociceptors more excitable and send pain impulses up the spinothalamic tract - site swells to form neuroma at the injury site
- Responsible for spontaneous pain and also phantom limb pain
- Underlies central neuropathic pain mechanisms
30
Q
Central sensitization
- Increase in the responsiveness of … neurons within the … … system
- Normal inputs begin to produce … responses
- Signal amplified due to the reduced threshold for activation (similar to …)
A
- Increase in the responsiveness of nociceptive neurons within the central nervous system
- Normal inputs begin to produce abnormal responses
- Signal amplified due to the reduced threshold for activation (similar to LTP)
31
Q
Central sensitization
- … in the responsiveness of nociceptive neurons within the central nervous system
- Normal inputs begin to produce … responses
- Signal … due to the … threshold for activation (similar to LTP)
A
- Increase in the responsiveness of nociceptive neurons within the central nervous system
- Normal inputs begin to produce abnormal responses
- Signal amplified due to the reduced threshold for activation (similar to LTP)
32
Q
Reduced threshold for activation - central sensitization
- Constant firing of axons from the periphery (following injury)
- Sustained release of …
- Prolonged depolarisation of the postsynaptic membrane
- Massive influx of calcium ions through … receptors
- Activation of …
- … of NMDA/AMPA receptors - alters kinetics of channels and causes insertion of more channels - neurons fire more easily - also channel protein …
A
- Constant firing of axons from the periphery (following injury)
- Sustained release of glutamate
- Prolonged depolarisation of the postsynaptic membrane
- Massive influx of calcium ions through NMDA receptors
- Activation of kinases
- Phosphorylation of NMDA/AMPA receptors - alters kinetics of channels and causes insertion of more channels - neurons fire more easily - also channel protein synthesis
33
Q
Reduced threshold for activation - central sensitization
- Constant firing of axons from the periphery (following injury)
- Sustained release of glutamate
- Prolonged … of the postsynaptic membrane
- … influx of calcium ions through NMDA receptors
- Activation of kinases
- Phosphorylation of NMDA/… receptors - alters … of channels and causes insertion of more channels - neurons fire more easily - also channel protein …
A
- Constant firing of axons from the periphery (following injury)
- Sustained release of glutamate
- Prolonged depolarisation of the postsynaptic membrane
- Massive influx of calcium ions through NMDA receptors
- Activation of kinases
- Phosphorylation of NMDA/AMPA receptors - alters kinetics of channels and causes insertion of more channels - neurons fire more easily - also channel protein synthesis
34
Q
Central hyperalgesia mechanism
- Following central …:
- Activation of nociceptors results in … spinal cord activation leading to …
A
- Following central sensitization:
- Activation of nociceptors results in amplified spinal cord activation leading to hyperalgesia
35
Q
Central allodynia mechanism
- Non-noxious A… fibres also synapse onto … order spinothalamic neurons
- Normally these are non-…
- Following central sensitization:
- Non-noxious afferents activate sensitized 2nd order neurons
A
- Non-noxious Aβ fibres also synapse onto 2nd order spinothalamic neurons
- Normally these are non-functional
- Following central sensitization:
- Non-noxious afferents activate sensitized 2nd order neurons
36
Q
Central allodynia mechanism
- Non-… … fibres also synapse onto 2nd order spinothalamic neurons
- Normally these are non-functional
- Following central …:
- Non-… afferents activate sensitized 2nd order neurons
A
- Non-noxious Aβ fibres also synapse onto 2nd order spinothalamic neurons
- Normally these are non-functional
- Following central sensitization:
- Non-noxious afferents activate sensitized 2nd order neurons
37
Q
Problem with central changes (pain) = not easily …
A
Problem with central changes (pain) = not easily reversible
38
Q
Chronic pain - treatments
- Difficult to treat - … pain treatments often do not work
- Good individual patient … is critical
- Important to manage primary condition as well as other associated symptoms
- Depression
- … disturbances
- …
A
- Difficult to treat - Acute pain treatments often do not work
- Good individual patient management is critical
- Important to manage primary condition as well as other associated symptoms
- Depression
- Sleep disturbances
- Fatigue
39
Q
Chronic pain - treatments
- … to treat - Acute pain treatments often do not work
- Good individual patient management is critical
- Important to manage primary condition as well as other associated symptoms
- …
- Sleep …
- …
A
- Difficult to treat - Acute pain treatments often do not work
- Good individual patient management is critical
- Important to manage primary condition as well as other associated symptoms
- Depression
- Sleep disturbances
- Fatigue
40
Q
Current neuropathic pain treatments
- Drugs:
- … antidepressants
- Anti…
- Topical … or …
- …puncture
- Physical therapies – e.g. manipulation of tissues, pacing
- Psychological therapies – e.g. … … therapy
- Surgery – e.g. spinal cord stimulator (activate a-beta fibres as they enter spinal cord - activate inhibitory interneurons which act on our second-order neurons - same as gate control)
A
- Drugs:
- Tricyclic antidepressants
- Anticonvulsants
- Topical capsaicin or lidocaine
- Acupuncture
- Physical therapies – e.g. manipulation of tissues, pacing
- Psychological therapies – e.g. cognitive behavior therapy
- Surgery – e.g. spinal cord stimulator (activate a-beta fibres as they enter spinal cord - activate inhibitory interneurons which act on our second-order neurons - same as gate control)
41
Q
Current neuropathic pain treatments
- Drugs:
- Tricyclic …
- …
- Topical capsaicin or …
- …
- Physical therapies – e.g. manipulation of tissues, pacing
- Psychological therapies – e.g. cognitive behavior therapy
- Surgery – e.g. spinal cord … (activate a-beta fibres as they enter spinal cord - activate inhibitory interneurons which act on our second-order neurons - same as gate control)
A
- Drugs:
- Tricyclic antidepressants
- Anticonvulsants
- Topical capsaicin or lidocaine
- Acupuncture
- Physical therapies – e.g. manipulation of tissues, pacing
- Psychological therapies – e.g. cognitive behavior therapy
- Surgery – e.g. spinal cord stimulator (activate a-beta fibres as they enter spinal cord - activate inhibitory interneurons which act on our second-order neurons - same as gate control)
42
Q
Tricyclic antidepressants
- Examples include … and duloxetine
- Act centrally
- Mechanism of action:
- Act on … … pathways
- Inhibits reuptake of … (and noradrenalin)
A
- Examples include amitriptyline and duloxetine
- Act centrally
- Mechanism of action:
- Act on descending inhibitory pathways
- Inhibits reuptake of serotonin (and noradrenalin)
43
Q
Anticonvulsants
- Examples include … - fewer side effects, gabapentin and carbamazepine
- Act centrally
- Mechanism of action: (proposed)
- Act in spinal cord to reduce …
- Blocks calcium (…) and … (carbomazepine) channels
- … blocks presynaptic voltage-gated Ca2+ channels - Prevent release of glutamate
A
- Examples include pregabalin - fewer side effects, gabapentin and carbamazepine
- Act centrally
- Mechanism of action: (proposed)
- Act in spinal cord to reduce excitability
- Blocks calcium (pregabalin) and sodium (carbomazepine) channels
- Pregabalin blocks presynaptic voltage-gated Ca2+ channels - Prevent release of glutamate
44
Q
Anticonvulsants
- Examples include pregabalin - fewer side effects, gabapentin and …
- Act centrally
- Mechanism of action: (proposed)
- Act in … … to reduce excitability
- Blocks calcium (pregabalin) and sodium (…) channels
- Pregabalin blocks presynaptic voltage-gated Ca2+ channels - Prevent release of …
A
- Examples include pregabalin - fewer side effects, gabapentin and carbamazepine
- Act centrally
- Mechanism of action: (proposed)
- Act in spinal cord to reduce excitability
- Blocks calcium (pregabalin) and sodium (carbomazepine) channels
- Pregabalin blocks presynaptic voltage-gated Ca2+ channels - Prevent release of glutamate
45
Q
NICE guidelines on treatment of neuropathic pain
- First-line of treatment:
- …, duloxetine, P… or gabapentin
- Second-line of treatment:
- … drugs or …
- Third-line of treatment:
- Refer patient to a … pain service and consider oral tramadol (opioid) or in combination with the second-line treatment consider topical lidocaine
A
- First-line of treatment:
- Amitriptyline, duloxetine, pregabalin or gabapentin
- Second-line of treatment:
- Switch drugs or combine
- Third-line of treatment:
- Refer patient to a specialist pain service and consider oral tramadol (opioid) or in combination with the second-line treatment consider topical lidocaine
46
Q
NICE guidelines on treatment of neuropathic pain
- First-line of treatment:
- …, duloxetine, pregabalin or gabapentin
- Second-line of treatment:
- Switch drugs or combine
- Third-line of treatment:
- … patient to a specialist pain service and consider oral … (opioid) or in combination with the second-line treatment consider topical …
A
- First-line of treatment:
- Amitriptyline, duloxetine, pregabalin or gabapentin
- Second-line of treatment:
- Switch drugs or combine
- Third-line of treatment:
- Refer patient to a specialist pain service and consider oral tramadol (opioid) or in combination with the second-line treatment consider topical lidocaine
47
Q
Placebo and complimentary alternative medicines
- Important to consider the … effect
- … analgesia has been demonstrated (in well controlled studies) for the treatment of neuropathic pain - Due to activation of descending inhibitory pathways
- Many Complementary Alternative Medicines
- Examples include …, massage therapy, homeopathy, hypnosis, reiki
- BUT - ‘Very few forms of CAM reduce pain in a clinically relevant way’
- Exceptions include … -trigger release of endorphins
A
- Important to consider the placebo effect
- Placebo analgesia has been demonstrated (in well controlled studies) for the treatment of neuropathic pain - Due to activation of descending inhibitory pathways
- Many Complementary Alternative Medicines
- Examples include acupuncture, massage therapy, homeopathy, hypnosis, reiki
- BUT - ‘Very few forms of CAM reduce pain in a clinically relevant way’
- Exceptions include acupuncture -trigger release of endorphins
48
Q
Placebo and complimentary alternative medicines
- Important to consider the placebo effect
- Placebo analgesia has been demonstrated (in well controlled studies) for the treatment of neuropathic pain - Due to activation of … … pathways
- Many … Alternative Medicines
- Examples include acupuncture, massage therapy, homeopathy, hypnosis, reiki
- BUT - ‘Very few forms of CAM reduce pain in a clinically relevant way’
- Exceptions include acupuncture -trigger release of …
A
- Important to consider the placebo effect
- Placebo analgesia has been demonstrated (in well controlled studies) for the treatment of neuropathic pain - Due to activation of descending inhibitory pathways
- Many Complementary Alternative Medicines
- Examples include acupuncture, massage therapy, homeopathy, hypnosis, reiki
- BUT - ‘Very few forms of CAM reduce pain in a clinically relevant way’
- Exceptions include acupuncture -trigger release of endorphins
49
Q
What’s gone wrong in chronic pain?
A
