2 - pathophysiology of pain and pain management lectures Flashcards
1
Q
what are nociceptors?
A
high-threshold sensory neurons of the peripheral somatosensory nervous system capable of transducing a range of noxious stimuli
2
Q
nociceptors are equipped with receptors sensitive to what types of stimuli?
A
mechanical, thermal and chemical
3
Q
what are high threshold noxious stimuli transduced into?
A
an electrical action potential
4
Q
what is TRPM8 activated by?
A
noxious cold temps
5
Q
what is TRPV1 activated by?
A
noxious heat
6
Q
how can a nocicpetor be activated?
A
- DIRECTLY — through painful stimuli
- INDIRECTLY — through activation and release of stimulatory molecules from neighbouring cells (eg. keratinocytes)
7
Q
what does the activation of a nociceptor lead to?
A
generation of an AP —> transmission of info to spinal cord
8
Q
nocicpetors are glutamatergic and some are also peptidergic. explain.
A
- release glutamate and neuropeptides (eg. substance P, calcitonin gene related peptide - CGRP) to the 2nd order neurons in the dorsal horn of the spinal cord
- this info is then transmitted
9
Q
where do pain pathways cross the midline?
A
spinal cord
10
Q
where do proprioceptive pathways cross the midline?
A
medulla
11
Q
where do 2nd order neurons synapse in pain processing?
A
thalamus
12
Q
what do nocicpetors detect?
A
pain, temperature, course touch
13
Q
sensory neurons are pseudo-unipolar. what does this mean?
A
- put out 1 axon which branches into 2:
- 1 branch goes centrally to SC
- 1 goes peripherally out to innervate target tissues
14
Q
where do cell bodies of sensory neurons reside within?
A
dorsal root ganglia
15
Q
Aa/Ab vs. Ad vs. C fibres
A
- Aa/Ab = largest, myelinated, fastest conduction
- C = smallest, not myelinated, slowest conduction
16
Q
what is rexed laminae?
A
- describes the organisation of the spinal cord grey matter based on size and packing density of neurons
17
Q
what are the 4 types of pain?
A
1) nociceptive
2) inflammatory
3) neuropathic
4) nociplastic
18
Q
what is nociceptive pain?
A
pain that arises from actual or threatened damage to non-neural tissue and is due to the activation of nociceptors
19
Q
what are the characteristics of nociceptive pain?
A
= good pain
- high-threshold stimulus-dependent pain
- thermal, mechanical or chemical stimuli
- pain evoked in a graded response by appropriate high intensity (noxious) stimuli
- adaptive and serves a purpose
- more noxious = more pain
20
Q
what are the characteristics of inflammatory pain?
A
= still good pain
- active inflammation
- sensitisation
- evoked by low and high threshold stimuli
- adaptive, protective during the healing response and reversible
21
Q
what is inflammatory pain?
A
the spontaneous hypersensitivity to pain that occurs in response to tissue damage and inflammation
22
Q
what is neuropathic pain?
A
pain caused by a lesion or disease of the somatosensory nervous system
23
Q
give some examples of neuropathic pain
A
24
Q
what are the characteristics of neuropathic pain?
A
= bad pain
- marked neuroimmune component
- sensitisation
- spontaneous and evoked by low and high intensity stimuli
- maladaptive and persistent
- abnormal amplification of all stimuli
- serves no useful purpose
- not well-managed
- spontaneous pain — no stimuli
25
describe sensitisation
= increased responsiveness of nociceptive neurons to their normal inputs, and/or recruitment of a response to normally subthreshold inputs
- can include a drop in threshold and an increase in suprathreshold response — doesn’t take as much to activat nocicpetors and they respond greater
- spontaneous discharges and increases in receptive field size may also occur
- clinically, sensitisation may only be inferred indirectly from phenomena such as hyperalgesia or allodynia
26
what is hyperalgesia?
increased pain from a stimulus that normally provokes pain
27
what is allodynia?
pain due to a stimulus that does not normally provoke pain
28
what does spontaneous pain feel like and what is it accompanied with?
often described as burning, tightness accompanied with parasthesia, tingling, shooting or stabbing pains
29
what co-morbidities is neuropathic pain associated with?
anxiety, depression and sleep-disturbance
30
what is nociplastic pain?
pain that arises from altered nociception despite no clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptors or evidence for disease or lesion of the somatosensory system causing the pain
31
what is post-hepatic neuralgia (PHN)?
the pain that persists after shingles has cleared
32
what is mechanical allodynia?
sensitivity to clothes, bedsheets etc
33
what are 4 mechanisms of neuropathic pain?
1. increased inflammatory cells and mediators
2. altered nociceptor activity (receptor/ion channel expression) peripheral sensitisation
3. altered spinal processing, central sensitisation, synaptic reorganisation
4. altered central processing, descending inhibition
34
how do mast cells cause AP generation?
- release histamine and cytokines
- these stimulate receptors on primary sensory afferent terminals to generate an AP
35
what does antidromic stimulation of afferent terminals lead to?
release of neuropeptides from these terminals — binds to receptors on mast cells — more degranulation, release of histamine — therefore larger area perceived as being painful
—> increased blood flow and vascular permeability
36
what are the first inflammatory cells to infiltrate damaged tissue?
neutrophils
37
what do neutrophils do?
produce inflammatory factors eg.TNFa and chemokines — attracts macrophages
38
what is the effect of histamine on firing rates?
rapid increase in firing rates even in the absence of stimuli
39
what does the injured axon release? what is the effect?
CGRP, substance P, bradykinin, nitric oxide — increase blood flow and vascular permeability
40
what do macrophages and schwann cells produce? effect?
MMPs — help break down the blood nerve barrier, enabling infiltrating cells through
41
how are voltage-gated sodium channels affected in neuropathic pain?
voltage-fated Na channel genes are upregulated in injured sensory neurons — more excitability/ectopic firing rate
42
what is the effect of an increase in C fibre activity?
more Glu release, SP etc
43
what is the effect of a sustained and increased release of Glu?
initiates secondary changes ion spinal processing eg. activation of NMDA receptors
44
why are NMDA receptors normally not active?
Mg block
45
how is the Mg block over NMDA receptors overcome?
an increase in glutamate
46
what are AB fibres?
low threshold mechanoceptors that are activated by low threshold touch
47
what are the endogenous inhibitory pain modulating pathways in the spinal cord?
inhibitory interneurons (GABAergic and glycinergic)
48
what are the endogenous inhibitory pain modulating pathways in the brain?
- descending inhibitory pathways originate in the anterior cingulate gyrus, amygdala and hypothalamus and are relayed to the spinal cord
- inhibitory neurotransmitters include NA, 5-HT, and opioids
49
how can the endogenous inhibitory pain modulating pathways be affected in neuropathic pain?
they can be reduced
50
what is the gate control theory of pain?
- oversimplified
- a balance of spinal input from large AB and small C fibres
- can get pain relief by increasing AB input — ‘shutting the pain gate’
51
what do Ad and C fibres normally conduct?
incoming pain signals
52
what do Aa and Ab fibres normally conduct?
no noxious physical stimuli eg. movement, vibration, pressure, temperature, electrical stimulation
53
what are the differences in pharmacological treatment for acute vs chronic pain?
acute — paracetamol and/or NSAIDs, opioids
chronic — antidepressants, anti-convulsants, opioids
54
what are calcium channel modifiers?
gabapentinoids — gabapentin, pregabalin
55
what part of the Ca channel do gabapetinoids bind to?
a2d part
56
describe the stepwise pharmacological management of pain
57
summary of spinothalamic tract
58
summary of pain
59
what do nociceptors belong to?
the slowly conducting afferent Ad and C fibres
60
describe NSAIDs - how they work, side effects etc
- non-selective COX-1/2 inhibitors
- reduce prostaglandins
- reduce tissue inflammation and nociception
- mainly act peripherally
- GI irritation and risk of GI bleeding, renal toxicity, potential drug interactions
- some selective COX-2 inhibitors have also been found to have CV side effects eg. MI, stroke and elevation of blood pressure
61
NSAIDs must be used with caution in who?
older patients with impaired renal function and heart failure
62
how do local anaesthetics work?
- blockade of Na channels
- small fibres are more sensitive than large nerve fibres
- myelinated fibres are blocked before non-myelinated fibres of the same diameter
- the loss of nerve function proceeds as loss of pain, temperature, touch, proprioception, and then skeletal muscle tone
- this is why some people may still feel touch but not pain when using local anaesthesia
63
how do opioids reduce pain signal transmission?
- by activating pre-synaptic opioid receptors
- leads to reduced intracellular cAMP conc
- decreased Ca ion influx
- thus inhibits the release of excitatory neurotransmitters (Glu, substance P)
64
how do opioids work at the post-synaptic level?
opioid-receptor binding causes the hyperpolarisation of the neuronal membrane which decreases the probability of the generation of an action potential
65
opioids function as inhibitory transmitters of what?
the descending inhibitory pathway
66
what is the effect of opioids on the supraspinous structures of pain processing, in particular the thalamus and limbic system?
they alter the emotional assessment of pain
- ie. nociceptive sensations are still perceived, but is no linger felt as being unpleasant or threatening
- addiction
67
describe morphine
- opioid
- acts on mu receptor
- inhibits release of several different neurotransmitters including acetylcholine, glutamate and substance P
68
what is chronic pain?
= pain that extends beyond the period of healing due to alteration in the processing of nerve signals and therefore has levels of identified pathology that often are low and insufficient to explain the presence and/or extent of the pain
- may also be defined as persistent pain that disrupts sleeps and normal living, ceases to serve a protective function and instead degrades health and function
CHRONIC PAIN HAS NO ADAPTIVE PURPOSE
69
acute vs. chronic pain
- chronic pain is a disease in its own right
- >3-6 months = chronic
- <1 month = acute
70
what is the link between depression and chronic pain?
- chronic pain is not masked depression
- depression may be a predictor of pain severity, pain behaviour, disability and treatment seeking/compliance
- depression is more likely to be a consequence of pain rather than a cause of pain
71
what is peripheral sensitisation?
a reduction in threshold and an increase in responsiveness of the peripheral ends of nociceptors
72
what is central sensitisation?
(implies changes in the spinal cord and brain)
= an increase in the excitability of neurons within the CNS, so that normal inputs begin to produce abnormal responses
73
what is hyperalgesia a result of?
central sensitisation, caused by the increased release of Glu to a given stimulus
74
primary vs secondary chronic pain
primary = not quite sure where they begin
secondary = occur as a consequence of something else
75
what is the biopsychosocial model of pain?
a way of thinking about pain that links:
1) biological factors eg. pain sensations/symptoms
2) psychological factors eg. thoughts/feelings/emotions/beliefs
3) social environment eg. family/professionals response
76
what is malingering?
the conscious fabrication of symptoms to achieve some form of benefits such as attention, to be relived or undesirable activities, to obtain prescription medication, or to qualify for disability compensation
77
what is catastrophising?
consists of extremely -ve thoughts about one’s plight, even with minor problems being interpreted as major catastrophes. impirnat in determining one’s reaction to pain
78
what are pain behaviours?
non-conscious modes of communicating pain and distress and unlike cases of symptom magnification and malingering are not produced intentionally
79
describe management based on biopsychosocial formulation
80
what are pain management programmes (PMPs)? what do they aim to do?
a psychologically based rehabilitation programme delivered in a group setting by an interdisciplinary team, the core members of which are a clinical psychologist, a physiotherapist and a medical practitioner
81
what does PHQ-9 questionnaire help monitor/diagnose?
depression
82
what does GAD 7 questionnaire help monitor/diagnose?
anxiety
83
what does TSK questionnaire help monitor/diagnose?
pain-related fear
84
what does RMDQ questionnaire help monitor/diagnose?
disability
85
where do antidepressants work?
descending inhibitory pathways
86
where do antiepileptics work?
manage hyperactive NS at level of spinal cord
87
what should be used in first line therapy for pain (if appropriate)?
paracetamol +/- NSAIDs
88
what is neuromodulation?
the alteration of nerve activity through targeted delivery of a stimulus, such as electrical stimulation or chemical agents, to specific neurological sites in the body
89
paroxysmal extreme pain disorder is caused by a gain-of-function mutation in what?
the Nav1.7 voltage-gated sodium channel
90
rare mutations of the Nav1.7 gene causes what?
a congenital insensitivity or indifference to pain
