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Pain case Flashcards

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1
Q

What are the two main somatosensory receptor systems?

A
  1. Mechanoreceptors and thermoreceptors – detect touch and temperature 2. Nociceptors – detect noxious (painful) stimuli
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2
Q

What fibres are responsible for pain conduction and how do they differ?

A

Aδ (A-delta) fibres: myelinated, fast conducting for sharp and well- localised pain sensation, glutamate
C-fibres: unmyelinated for dull persistent and poorly localised pain (tendon pain and most of visceral pain: throbbing), glutamate, sub P, CRGP

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3
Q

What is hyperalgesia vs allodynia?

A

Hyperalgesia: Increased pain response to a mildly noxious stimulus. Allodynia: Pain in response to a non-noxious stimulus.

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4
Q

What are the stages of pain processing?

A
  1. Transduction
    Noxious stimulus → neurotransmitter release (e.g. glutamate, substance P) → receptor activation → action potential (AP) generation
  2. Transmission
    AP travels along peripheral afferents → synapse in dorsal horn → glutamate release → 2nd order neuron → decussation → spinothalamic tract → thalamus
  3. Modulation
    Up/down-regulation via neurotransmitters and receptor activity at dorsal horn synapses (e.g., inhibitory interneurons release GABA, enkephalins, etc.)
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5
Q

Which neurotransmitters are released in transduction of pain?

A

Glutamate (main) -A delta

Glutamate, substance P, CRGP -C fibres (wind up)

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6
Q

Describe the ascending pain pathway.

A
  1. Noxious stimulus → 1st order nociceptor fires. 2. Releases Substance P & CGRP. 3. Glutamate activates AMPA/NMDA in dorsal horn. 4. Second order neuron decussates & travels via spinothalamic tract to thalamus. 5. Third order neuron → somatosensory cortex.
    NMDA -wind up
    AMPA - fast acting
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7
Q

What is the function of AMPA vs NMDA receptors in pain?

A

AMPA: Fast synaptic transmission. NMDA: Slower (ramp up)

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8
Q

What is the role of the periaqueductal grey (PAG) in pain modulation?

A

*Th PAG can be stimulated by numerous areas of the brain: cortex, hippocampus and amygdala
*The descending first order neuron projects to the ostroventral medulla part (nucleus raphe magnus) to synapse with the secondary order neuron

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9
Q

How does noradrenaline modulate pain?

A

Binds α2 receptors → Gi pw activation -> PKA inhib -> ↓ Ca²⁺ influx at NT released due to inhibition of NT release from the vesicle

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10
Q

How does serotonin modulate pain?

A

Stimulates interneurons to release GABA → opens Cl⁻ & K⁺ channels → inhibits AP in primary nociceptors.

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11
Q

How do enkephalins modulate pain?

A

Released by spinal interneurons from 5-HT receptors, bind to u receptors. “endogenous morphine”

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12
Q

Which area of the CNS releases serotonin and noradrenaline in descending pain inhibition?

A

Rostroventral medulla (nucleus raphe magnus) → dorsal horn of spinal cord.

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13
Q

How does inflammation contribute to pain sensitisation?

A

Localised inflammation induces the release of free arachidonic acid (AA) from the phospholipids, which are converted into prostaglandins (PG) via the cyclooxygenase (COX) pathways

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14
Q

What cellular changes occur in inflammatory pain?

A

CGRP: increased vasodialtion (redness, swelling)
Substance P: overall inflammatory response
mass cell breaking (essentially degranualation) (histamine release)

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15
Q

What NaV channel changes occur in acute vs chronic neuropathic pain?

A

Acute: ↑ NaV1.7 neuropathic: ↑ NA V1.8 ectopic firing

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16
Q

What is Gate Control Theory?

A

Aβ fibres (touch/pressure) activate inhibitory interneurons in spinal cord → inhibit pain signals from Aδ and C-fibres.

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17
Q

Why does rubbing a stubbed toe reduce pain?

A

Activates Aβ fibres → engages spinal interneurons that inhibit nociceptive transmission (Gate Control Theory).

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18
Q

What is the main neurotransmitter released in the spinal cord during pain?

A

Glutamate.

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19
Q

What happens at the first synapse in the ascending pain pathway?

A

Glutamate activates AMPA (fast) and NMDA (slow) receptors on second-order neurons in dorsal horn.

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20
Q

Which fibres are involved in inflammatory pain: acute vs chronic?

A

Acute: Aδ fibres. Chronic: C-fibres (ongoing input → central sensitisation).

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21
Q

What is central sensitisation?

A

Increased excitability of CNS neurons due to prolonged input → lowers activation threshold → hyperalgesia/allodynia.

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22
Q

What is the effect of prolonged peripheral ectopic discharges?

A

Leads to central sensitisation and persistent chronic pain.

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23
Q

What is the mechanism of action of paracetamol?

A

Weak COX1/2 inhibitor but in reality no one fucking knows stay humble

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24
Q

What are paracetamol’s safety and dosing considerations?

A

Max 4 g/day. Safe in pregnancy and breastfeeding. Risk with liver disease

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25
What is N-acetylcysteine (NAC) used for?
Reverses paracetamol overdose by restoring glutathione → detoxifies toxic NAPQI metabolite.
26
What is the general mechanism of NSAIDs?
Inhibit COX enzymes → reduce prostaglandins → decrease pain
27
What are the functions of COX-1 vs COX-2?
Cox-1: located in the GIT, important for mucous production COX-2: more systemic on cerebrovascular tissues -prostalandin and inflammatory response
28
What are common NSAIDs and their classes?
Non-selective: ibuprofen selective (cox 2 inhib): celecoxib (Celebrex)
29
What are key NSAID contraindications?
GI bleed risk, asthma
30
What are NSAID ‘sick day rules’?
If NSAIDs are taken during an acute illness that can lead to dehydration (e.g. fever, sweating, vomiting, diarrhoea), there is an increased risk of developing Acute kidney injury (AKI) due to reduced renal afferent vasodilation. Patients should be advised to stop NSAIDs in this situation and when the patient is feeling better and is able to eat and drink for 24–48 hours, may restart NSAID with caution if appropriate.
31
What is the mechanism of action of opioids?
Bind μ/κ/δ receptors → inhibit cAMP
32
What are μ
morphine receptors (enkaphalin endogenous), inhibit cAMP (VG Ca and K)
33
What are common opioid side effects?
Common side effects: N+V, dry mouth, sedation, constipation, drowsiness, respiratory depression, hypotension, tolerance, dependence Higher risk of respiratory depression with other CNS depressants Gabapentin, pregabalin, BDZ
34
Which opioids are weak vs strong?
Weak: codeine, toradol (step 2 WHO pain ladder) strong: morophine (step 3 WHO pain ladder)
35
What does 'opioid naïve' mean?
A patient who hasn’t taken opioids for >7 consecutive days in past 30 days.
36
What is the WHO pain ladder?
Stepwise approach: 1. Non-opioid 2. Weak opioid ± non-opioid 3. Strong opioid ± adjuvants.
37
What is the mechanism of gabapentinoids?
Bind α2δ subunit of VG Ca²⁺ channels → reduce glutamate release → decrease excitability → analgesia and sedation.
38
What is the mechanism of benzodiazepines in pain?
Enhance GABA-A (Cl⁻ influx) and GABA-B (K⁺ efflux) → hyperpolarisation → decreased AP firing.
39
Which antidepressants are used in chronic neuropathic pain?
Tricyclic Antidepressants (TCA) inhibit the reuptake of serotonin and noradrenaline (NA) from the synaptic cleft Increase serotonin + NE availability = enhance descending pathway’s secondary neuron’s effect High adverse side effects: cardiovascular side effects and anticholinergic (parasympatholytic) side effects Selective serotonin + noradrenaline (NA) (SNRI) Inhibit serotonin + NE reuptake from the synaptic cleft Increase serotonin + NE availability = enhance descending pathway’s secondary neuron’s effect Less adverse effects than TCA Usd for trigeminal (CNV) neuralgia Basically severe episodic face pain, stimulus/sensation triggered by compression of trigeminal nerve (often vascular swelling induced) = demyelination/nerve damage
40
What is the first-line drug for trigeminal neuralgia?
Carbamazepine. Induces CYP450. Monitor blood count
41
How is chronic primary pain managed?
Prioritise non-pharmacological treatments (CBT), allied health (PT, OT), SNRIS/TCAs, AVOID ALL STRONGER ANAGELICS
42
What is the mechanism of local anaesthetics?
Block voltage-gated Na⁺ channels from inside neuron → prevent AP → stop pain transmission. Lower potency, receptor is intracellular.
43
Why is local anaesthetic not given IV?
Risk of cardiac Na⁺ channel block → arrhythmia or death. Safer via local routes.
44
What is the mechanism of general anaesthetics?
Most enhance GABA-A. Some activate K⁺ channels or block NMDA/Na⁺ channels to suppress neuronal activity.
45
What are the 4 stages of general anaesthesia?
1. Induction/Analgesia 2. Excitement 3. Surgical anaesthesia 4. Overdose (respiratory depression
46
What is the MOA of TENS?
Stimulates A-β and A-δ fibres → inhibits pain via Gate Control and descending pathways. Releases endorphins
47
How do triptans work in migraine?
Agonists at 5-HT1B/1D receptors → cranial vasoconstriction and CGRP inhibition.
48
What are examples of triptans?
Sumatriptan
49
How does botulinum toxin A help in migraine?
Cleaves SNAP-25 → inhibits CGRP vesicle release → reduces trigeminal nerve pain signalling.
50
What are CGRP-targeting drugs for migraine?
Monoclonal antibodies: erenumab
51
How does capsaicin relieve local neuropathic pain?
TRPV1 agonist → overstimulation → Substance P depletion + TRPV1 downregulation → reduced pain sensitivity.
52
Mechanoreception / Mechanoreceptors / Aβ fibres
Touch, pressure, vibration; fast conduction; large receptive fields
53
Thermoreception / Thermoreceptors / Aδ & C-fibres
Cold sensation (Aδ), warm sensation (C); small receptive fields; temperature-sensitive
54
Nociception (Pain) / Nociceptors / Aδ-fibres
Myelinated; fast, sharp, well-localised somatic pain
55
Nociception (Pain) / Nociceptors / C-fibres (polymodal)
Unmyelinated; slow, dull, burning, poorly localised visceral/tendon pain
56
Myelin Sheath Width
Thicker = faster conduction, more localised; thinner = slower, duller pain
57
Step 1: Transduction
Noxious stimulus → neurotransmitter release (e.g., glutamate, substance P) → receptor activation → action potential generation
58
Step 2: Transmission
Action potential travels peripheral afferents → dorsal horn synapse → glutamate release → 2nd order neuron → decussation → spinothalamic tract → thalamus
59
Step 3: Modulation
Up/down regulation by neurotransmitters at dorsal horn synapses (e.g., inhibitory interneurons release GABA, enkephalins)
60
Neurotransmitters involved in pain
Glutamate (excitatory), Substance P & CGRP (peripheral inflammation), GABA, Enkephalins, Noradrenaline, Serotonin (modulatory)
61
Ascending Pain Pathway Overview
Nociceptors → pseudounipolar neurons (1st order) → dorsal horn → 2nd order neurons → decussate → thalamus → cortex
62
Glutamate role in pain transmission
AMPA receptor mediates fast transmission; NMDA receptor mediates slower transmission, wind-up, central sensitisation
63
Descending Pain Pathway
Starts in brain (PAG, cortex, hippocampus, amygdala) → nucleus raphe magnus → dorsal horn interneurons
64
Descending pathway neurotransmitters
Noradrenaline (α2 receptors), Serotonin (5-HT), Enkephalins, GABA; inhibit pain signals at spinal level
65
Gate Control Theory
Aβ fibres stimulate inhibitory interneurons which dampen Aδ and C-fibre pain signals; explains why rubbing reduces pain
66
Ascending Pain Pathway - Activation
Peripheral noxious stimuli activate nociceptors; 1st order neurons release substance P, CGRP, glutamate, ATP in dorsal horn
67
Ascending Pain Pathway - Signal Relay
Glutamate acts on AMPA receptors for fast response; NMDA receptors contribute to wind-up (temporal summation)
68
Ascending Pain Pathway - Decussation & Projection
2nd order neurons cross spinal cord; ascend via spinothalamic tract → thalamus; 3rd order neurons project to somatosensory cortex
69
Descending Pain Modulation - Noradrenaline
Released from thalamus; binds α2 receptors on primary neurons; reduces Ca²⁺ influx & increases K⁺ efflux; dampens excitability
70
Descending Pain Modulation - Serotonin
Acts on spinal interneurons; induces GABA release; hyperpolarises primary neurons by increasing Cl⁻ and K⁺ conductance
71
Descending Pain Modulation - Enkephalins
Bind opioid receptors on primary neurons; inhibit action potential generation by reducing Ca²⁺ channel activity
72
Descending Circuitry
Originates in PAG; receives input from cortex, hippocampus, amygdala; projects to nucleus raphe magnus → dorsal horn to regulate pain
73
Pain Type: Hyperalgesia
Tissue injury/inflammation → increased response to mild noxious stimuli; involves nociceptor sensitisation and central sensitisation
74
Pain Type: Allodynia
Pain due to normally non-noxious stimulus; caused by altered central processing
75
Pain Type: Acute Inflammatory Pain
Short-term injury with high intensity pain; mediated by Aδ fibres; prostaglandins via COX cause inflammation
76
Pain Type: Chronic Inflammatory Pain
Prolonged pain mediated by C-fibres; central sensitisation, increased afferent input, kinase pathway modulation
77
Pain Type: Neuropathic Pain
Nerve injury; VGSC subtype changes (Nav1.7 and Nav1.8) causing ectopic discharges; central sensitisation
78
Neuropathic Pain - Sodium Channel Changes
Acute: Nav1.7 upregulated, Nav1.8 downregulated; Chronic: Nav1.8 upregulated sustaining ectopic firing
79
Local Neuropathic Pain Pathway
Tissue damage → immune cells (macrophages, mast cells, neutrophils) → kinases (PKA, PKC, MAPK) phosphorylate Nav1.7/1.8 → ectopic firing
80
Gate Control Theory - Concept
Aβ fibres activate inhibitory interneurons which inhibit pain signals from Aδ and C fibres
81
Gate Control Theory - Clinical Correlation
Explains why rubbing a stubbed toe reduces pain temporarily
82
Neurotransmitter: Glutamate
Ions: Na⁺ (AMPA), Ca²⁺ (NMDA); Receptors: AMPA, NMDA; Role: primary excitatory NT; initiates and sustains AP in 2° neurons
83
Neurotransmitter: Substance P
G-protein coupled; receptor: NK1; Role: enhances/prolongs pain signal; promotes inflammation
84
Neurotransmitter: CGRP
G-protein coupled; receptor: CGRP receptor; Role: inflammatory mediator; enhances transmission and vasodilation
85
Neurotransmitter: GABA
Ion: Cl⁻; receptors: GABA-A (ionotropic), GABA-B (GPCR); Role: main inhibitory NT; hyperpolarises 2° neurons
86
Neurotransmitter: Enkephalins
Bind μ- and δ-opioid receptors; inhibit NT release; increase K⁺ efflux causing hyperpolarisation
87
Neurotransmitter: Serotonin (5-HT)
GPCRs (5-HT1–5-HT7); Role: descending modulation; inhibitory or excitatory depending on receptor subtype
88
Neurotransmitter: Noradrenaline
Ions: K⁺ indirectly; receptor: α2-adrenergic; Role: inhibitory descending control; hyperpolarises dorsal horn neurons
89
Neurotransmitter: Dopamine
Receptor: D2-like; Role: modulatory; may influence descending inhibition
90
Neurotransmitter Effects in Pain
Excitatory: Glutamate, Substance P, CGRP; Inhibitory: GABA, Enkephalins, Noradrenaline, Serotonin (some receptors); Dual: Serotonin, Dopamine
91
Neurotransmitters by Neuronal Order
First order: Glutamate, Substance P, CGRP, ATP; Second order: Glutamate (AMPA & NMDA), Substance P; Third order: Glutamate; Descending: Noradrenaline, 5-HT, Enkephalins, GABA
92
Medication MOA: NSAIDs
Examples: Ibuprofen, Aspirin; MOA: inhibit COX → ↓ prostaglandin synthesis → ↓ peripheral sensitization; NT: Prostaglandins
93
Medication MOA: Paracetamol
Weak COX inhibition + activates descending serotonergic pathways; NT: 5-HT
94
Medication MOA: Opioids
Examples: Morphine, Fentanyl; MOA: μ, κ, δ receptor agonists → inhibit Ca²⁺, activate K⁺ → ↓ NT release; NT: Glutamate, Substance P
95
Medication MOA: gabapentoids
Examples: Gabapentin, Pregabalin; MOA: bind α2δ subunit of Ca²⁺ channels → ↓ excitatory NT release; NT: Glutamate
96
Medication MOA: TCAs / SNRIs
Examples: Amitriptyline, Duloxetine; MOA: block 5-HT & NA reuptake → ↑ descending inhibition; NT: 5-HT, Noradrenaline
97
Medication MOA: Local Anesthetics
Example: Lidocaine; MOA: block Na⁺ channels → prevent AP propagation
98
Medication MOA: NMDA Antagonists
Examples: Ketamine, Memantine; MOA: block NMDA receptors → prevent wind-up and central sensitisation; NT: Glutamate
99
Medication MOA: Triptans
Example: Sumatriptan; MOA: 5-HT1B/1D agonists → vasoconstriction + inhibit CGRP release; NT: CGRP, 5-HT
100
Medication MOA: CGRP Antagonists
Examples: Erenumab, Rimegepant; MOA: block CGRP or receptor → reduce migraine vasodilation; NT: CGRP
101
Medication MOA: Capsaicin
MOA: TRPV1 agonist → Substance P depletion after repeated use
102
Medication MOA: Botox A
MOA: inhibits SNAP-25 → ↓ CGRP release
103
Medication MOA: Benzodiazepines
Example: Diazepam; MOA: enhance GABA-A → ↑ Cl⁻ influx → hyperpolarisation; NT: GABA
104
Medication MOA: General Anesthetics
"Examples: Propofol, Sevoflurane; MOA: potentiate GABA-A, inhibit Na⁺

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