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NAB > 6d. Pharmacology of Pain > Flashcards

6d. Pharmacology of Pain Flashcards

1
Q

Pain

- Definition

A

An unpleasant and emotional experience associated with or resembling that associated with actual or potential tissue damage or described in terms of such danger

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2
Q

Nociception

- Definiition

A

The neural process of encoding noxious stimuli

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3
Q

Chronic Pain

- % of Population

A

Affects 43% of humans at some point in their lifetime

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4
Q

Chronic Pain

- Definition

A

Pain that occurs in >1 location in the body for >3 months

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5
Q

Chronic Pain

- Most Common Cause

A

Arthritis and osteoarthritis

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6
Q

% of Patients who Feel that Their Medication Provides Adequate Pain Relief

A

36%

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7
Q

2 Types of Nociceptive Fibre

A
  • Thinly myelinated A-delta fibres

- Unmyelinated C fibres

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8
Q

Ion Channels

- 4 Heat Activated

A
  • TRPV1
  • TRPV3
  • Anoctamin-1
  • TRPA1
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9
Q

Ion Channels

- 2 Cold Activated

A
  • TRPM8

- TRPA1

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10
Q

Ion Channels

- 3 Proton Activated

A

ASICs

  • TRPV1
  • TASKS
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11
Q

Ion Channels

- Mechanically Activated

A
  • Piezo1/2
  • TRPV4?
  • ASICs?
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12
Q

Heat Pain Threshold

A

> 42 degrees C

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13
Q

Nociceptor Sensitisation

- Definition

A

When a stimlulus is great enough to cause tissue damage the response to subsequent stimuli increases

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14
Q

Nociceptor Sensitisation

- Hyperalgesia

A

A stimulus that causes pain now causes more pain

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15
Q

Nociceptor Sensitisation

- Allodonia

A

A stimulus that usually causes no pain (innocuous stimuli) now causes pain

  • Taking a shower when sunburnt
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16
Q

Nociceptor Sensitisation

- Sensitising Agents Definition

A

Agents that active and sensitise nociceptors

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17
Q

Nociceptor Sensitisation

- Internal Sensitising Agents

A

Released upon cell stress or tissue damage

Can:

  • Sensitise nociceptors
  • Directly activate nociceptors
  • Both
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18
Q

Internal Sensitising Agents

- 3 Excitatory Agents

A

Directly activate nociceptors

  • ATP from damaged cells
  • Bradykinin formed by kallikrein cleavage of kininogen
  • Acid released by anaerobic metabolism during anoxia or metabolic overload
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19
Q

Internal Sensitising Agents

- 2 Sensitising Agents

A
  • Prostaglandins

- Nerve growth factor

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20
Q

Nociceptor Sensitising Agents

- 3 Excitatory and Sensitising Agents

A
  • ATP
  • Bradykinin
  • H+
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21
Q

Non-Sensitising Agents Released by Nociceptor Terminals

A

Release:

  • CGRP
  • Substance P

Trigger vasodilation and increase the permeability of blood vessels

Directly and indirectly trigger mast cell degranulation through substance P

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22
Q

Substance P

A

Creates a flare at the site of injury called neurogenic inflammation, by:

  • Inducing mast cell degranulation releasing histamine
  • Vasodilation
  • Increasing vascular permeability
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23
Q

Neurogenic Inflammation

A

Activated nociceptor terminals release GCRP and substance P, which trigger vasodilation, increase in vascular permeability and mast cell degranulation (substance P).

Causes the development of a flare surrounding the site of injury.

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24
Q

Prostaglandins

- Synthesis

A
  1. Arachidonic acid is metabolised to prostaglandins by COX
    - AA is cyclised and oxygenated forming PGG2
    - PGG2 is reduced to form PGH2
  2. PGE synthase converts PGH2 into PGE2

Arachidonic acid and COS-2 are up-regulated in inflammation, increasing PGE2 synthesis

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25
Q

Prostaglandins

- Action

A

PGE2

- Enhances bradykinin excitation of nociceptors, sensitising them

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26
Q

Prostaglandins

- Receptors

A

EP1-4

EP4 is up-regulated in inflammation, so is important for inflammatory pain.
- Gs coupled so activated AC, increasing cAMP, activating PKA which phosphorylates voltage gated Na+ channel Nav1.8, reducing its activation threshold. Therefore smaller depolarisation is able to evoke action potential firing.

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27
Q

Nociceptive Afferents

- Cell Body Locations

A
  • Dorsal root ganglion (body)

- Trigeminal nucleus (head)

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28
Q

Nociceptive Afferents

- Termination Locations

A

Dorsal horn

  1. Lamina I (marginal soleria)
    - Myelinated A-delta fibres
    - Unmyelinated C fibres
  2. Lamina II (substantia)
    - Myelinated A-delta fibres
    - Unmyelinated C fibres
  3. Lamina V
    - Large diameter Aβ fibres (mechanoreceptors)
    - Myelinated A-delta fibres
    - Unmyelinated C fibres
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29
Q

Nociceptive Afferents

- Higher Pathways

A
  • Synapse in dorsal horn
  • Fibres decussate
  • Run up anterolateral system

Either:

  • Synapse in the PAG or reticular formation within the trigeminal nucleus , synapse in the thalamus and then to the ACC and insula
  • Bypass PAG or reticular formation, synapse in the thalamus and run to the primary somatosensory cortex
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30
Q

Cortical Representation of Pain

- Primary Somatosensory Cortex

A

Discriminate pain or nociception:

  • Comparing 2 different painful stimuli to determine which is greatest
  • Determining when pain stimulus is increasing
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31
Q

Cortical Representation of Pain

- ACC

A

Part of the limbic system responsible for the emotional/motivational element of pain.

Increases firing in response to witnessing someone elses pain, perhaps underlying empathy

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32
Q

Cortical Representation of Pain

- Insula Cortex

A

Homeostatic pain, contributing to the autonomic component of the overall pain response

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33
Q

Intensity Theory of Pain

A

Transmission neurones have a wide dynamic range so can increase spike discharge frequency over a wide range of intensities

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34
Q

Dynamic Range

- Wide

A

Transmission neurones have a wide dynamic range so can increase spike discharge over a wide range of intensities

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35
Q

Dynamic Range

- Narrow

A

Can only signal changes in intensity over a narrow range of amplitudes

Several different types of narrow dynamic range neurones are required, each responding to a different stimulus intensity.

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36
Q

Projections

  • Lamina I
  • Lamina V
A

Neurones travel prefernetially to the insula and ACC

Neurones travel preferentially to the primary somatosensory cortex (S-I)

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37
Q

Pain Modulation

- 3 Descending Systems

A
  • PAG of midbrain
  • Raphe nuclei
  • Other nuclei of the rostral medulla
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38
Q

Pain Modulation

- Function

A

Allows integration of pain perception with many other body systems, including:

  • Skin reflexes
  • Autonomic regulation
  • Emotion
  • Attention
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39
Q

Pain Modulation

- PAG Inputs

A

Inputs from:

  • Ascending anterolateral systems (nociceptors)
  • Higher cortical centres (cortex, thalamus, hypothalamus)

Electrical stimulation of the PAG produces sufficient analgesia to perform abdominal surgery, while non-painful sensations are left intact

40
Q

Pain Modulation

- PAG Stimulation

A

Electrical stimulation of the PAG produces sufficient analgesia to perform abdominal surgery, while non-painful sensations are left intact

41
Q

Pain Modulation

- Naloxone

A

Injection of naloxone, which is an opiate antagonist, into the PAG blocks

  • Morphine-induced analgesia
  • Electrically-induced analgesia

Suggests that the electrical system evokes the internal analgesic system giving an opioid response.

42
Q

Pain Modulation

- Dorsolateral Funiculus Transection

A

Blocks:

  • Electrically evoked analgesia
  • Morphine induced analgesia
43
Q

Pain Modulation

- Raphe Nucleus

A

Raphe nuclei neurones project to the substantia genaltinosa in the dorsal horn.

Produce 5-HT which activates opioid containing interneurones, triggering the release of opioids which depress transmission from nociceptors.

  • At least part of depression is via presynaptic inhibition
  • Opioids influence Aβ nociceptive transmission so are involved in gate control
44
Q

Pain Modulation

- PAG Termination

A

Raphe nuclei in the medulla

45
Q

Pain Modulation

- Specific Raphe Nucleus

A

Raphe magnus (NRM)

46
Q

Placebo Effect

- Definition

A

Administration of a substance known to be non-analgesic produces an analgesic response when the subject is told it is analgesic.

47
Q

Placebo Effect

- Examples

A
  • Asthma
  • Cough
  • Diabetes
  • Ulcers
  • Multiple sclerosis
  • Parkinsonism
48
Q

Placebo Effect

- Experiment

A

IV injection of capsaicin into all 4 limbs

Placebo cream applied to one limb only gave placebo analgesia only in that limb, not in the whole body as expected.

Spatially specific placebo response was abolished with IV infusion of naloxone (opioid antagonist), suggesting that it is mediated by an endogenous opioid system.

49
Q

Placebo Effect

- Somatotopicity

A

Somatotopicity is found in the PAG, which is maintained through the endogenous opioid system, allowing the endogenous opioid systems to give analgesia.

In rats, stimulation of different areas of the PAG gives analgesia in different cutaneous regions

50
Q

Referred Pain

A

Pain from internal organs is often felt as pain from a more superficial region due to viscero-somatic convergence onto the same neurone in the dorsal horn of the spinal cord

51
Q

Neuropathic Pain

- Defintiion

A

peripheral nerve damage that results in pain that outlasts the initial injury, often indefinitely, with on-going hyperalgesia and allodynia.

Caused by changes in nociceptive processing at spinal and higher centres, which are likely involved in disease progression

52
Q

Neuropathic Pain

- Examples

A
  • Phantom limb pain
  • Infectious disease (HIV, leprosy, heptatitis)
  • Diabetic neuropathy
  • Trigeminal neuralgia
  • Postherpetic neuralgia
53
Q

Congenital Pain Insensitivity

- Causes

A

Mutation in either:

  • Nerve growth factor NGF gene
  • Nerve growth factor receptor (TrkA)

Cause nociceptive fibres to fail to innervate their target during development and subsequently die.

54
Q

Congenital Pain Insensitivity

- Causes of Death

A
  • Traumatic injury

- Respiratory infection as nociceptors in the lungs are required to trigger coughing

55
Q

NSAIDs

- Mechanism of Action

A

Inhibit COX enzymes, preventing prostaglandin production which decreases nociceptor sensitisation and therefore pain.

NSAIDs enter the hydrophobic channel in COX and form hydrogen bonds with Arg120, preventing the entrance of fatty acids, such as arachidonic acid, into the catalytic domain

Reversible inhibition

56
Q

NSAIDs

- COX-2 Activation

A

Up-regulated in inflammation and activated by cytokines such as TNF-α

57
Q

NSAIDs

- COX-2 and COX-1 Inhibition

A

COX-1 inhibition:
- Results in unwanted side effects

COX-2 inhibition:

  • Anti-inflammatory
  • Analgesic
58
Q

NSAIDs

- Selective COX-2 Inhibition

A

Bulky side group of COX-2 allows NSAIDs with large sulfur containing side groups to selectively inhibit it

59
Q

NSAIDs

- Aspirin

A

Weakly COX-1 selective.

Aspirin is an a-typical NSAID as it irreversibly acetylates COX. COX can be resynthesised in cells but thromboxane production by platelets is halted for their lifetime (10 days).

Longer duration of action due to irreversibly inhibition

60
Q

NSAIDs

- Analgesic Action

A
  • In the CNS headache may result from vasodilation, so NSAIDS inhibit prostaglandin-mediated vasodilation
  • In the periphery, preventing nociceptor sensitisation and subsequent inflammation
61
Q

NSAIDs

- 4 Drugs

A
  • Aspirin
  • Ibuprofen/Phenylbutazone
  • Paracetamol
  • Etoricoxib/Robenacoxib
62
Q

NSAIDs

- Ibuprofen/Phenylbutazone

A 
Ibuprofen = humans
Phenylbutazone = animals

Weakly COX-1 selective

Used to treat:

  • Rheumatoid arthritis
  • Gout
  • Soft tissue disorders
63
Q

NSAIDs

- Paracetamol

A
  • Analgesic
  • Antipyretic
  • Poor anti-inflammatory drug
64
Q

NSAIDs

- Etoricoxib/Robenacoxib

A 
Etoricoxib = humans
Robenaxocib = animals

COX-2 selective

Used to treat chronic inflammatory pain conditions such as:

  • Osteoarthritis
  • Rheumatoid arthritis

Only advised in patients for whom conventional NSAIDs pose a significant GI risk after cardiovascular risk assessment

65
Q

NSAID

- Side Effects

A

Due to COX-1 inhibition

  1. GI bleeding and ulceration
    - PGs inhibit gastric acid secretion and increase mucin production
    - Patients are given a drug to counteract gastric acid secretion
  2. Renal insufficiency
    - PGE2 and PGI2 are involved in maintaining renal blood flow
  3. Stroke/myocardial infarction
    - COX-2 is constitutively expressed in endothelial and vascular smooth muscle so a decrease in PGI2 production causes platelet aggregation
  4. Bronchospasm
    - COX inhibition is implicated in bronchospasm bu an unclear mechanism
66
Q

Opioids

- Opioid Definition

A

Substance producing morphine-like effects that are reversed by antagonists such as naloxone

67
Q

Opioids

- Opiate Definition

A

Substance found in the opium poppy

68
Q

Opioids

- Mechanism of Action

A

Free OH and nitrogen atom on the benzene ring are important for opioid activity

69
Q

Opioids

- Receptor Types

A

4 Types

  • µ
  • Kappa
  • Delta
  • ORL1
70
Q

Opioids

- Receptor Cascade

A

All Gi/o coupled

  1. α subunit
    - Inhibits adenylyl cyclase
  2. βy subunit
    - Activates inwardly rectifying K+ channels (GIRKs) to hyperpolarise the cell
    - Inhibit opening of Cavs, mainly N-type, which decreases Ca2+ entry and neurotransmitter release
71
Q

Opioids

- Peripheral Analgesia

A

Adenylyl cyclase inhibition counteracts sensitising effects of prostaglandins

72
Q

Opioids

- Spinal Level Analgesia

A

Opioids act:

  • Presynaptically to decrease neurotransmitter release
  • Postsynaptically to reduce dorsal horn neurone excitability
73
Q

Opioids

- Supraspinal Level Analgesia

A

Activation of the endogenous inhibitory systems, which is largely mediated by µ receptors

Also induce euphoria

74
Q

Opioids

- Uses

A
  • Acute pain
  • Chronic pain

Not used for neuropathic pain as doses required give excessive side effects

75
Q

Opioids

- Examples

A
  • Morphine
  • Diamorphine
  • Codeine
  • Buprenorphine
  • Etorphine
76
Q

Opioids

- Morphine

A

Widely used for aute and chronic pain

77
Q

Opioids

- Diamorphine

A

Heroin

Pro-drug that is metabolised to morphine

Acts more rapidly than morphine when injected IV because of its higher solubility and ability to cross the blood brain barrier

78
Q

Opioids

- Codeine

A

Pro-drug

Given in combination with NSAIDs for mild pain

More reliably absorbed when administered orally

Less analgesic effect and fewer side effects than morphine

79
Q

Opioids

- Buprenorphine

A

Partial opioid receptor agonist with high affinity and low efficacy allows it to antagonise other opioids.

Moderate analgesia with less respiratory depression than full agonists

Uses:

  • Post-surgery pain
  • Patch treating chronic pain in humans
80
Q

Opioids

- Etorphine

A

1,000x more potent than morphine, so is given with a vial of naloxone to counteract effects from a pinprick injury, which causes respiratory depression.

large animal use

81
Q

Combination Analgesics

- Principle

A

Opioids and NSAIDs are commonly combined because they induce analgesia via different mechanisms giving additive analgesia.

Less of each can be given, which reduces side effects

82
Q

Combination Analgesics

- Co-Codamol

A

Combination of paracetamol and codeine

83
Q

Naloxone

A

Opioid receptor antagonist that reverses respiratory depression following:

  • Overdose
  • Newborns following use of opioids during labour
84
Q

Opioids

- Side Effects

A
  • Respiratory depression
  • Nausea and vomiting
  • Constipation
85
Q

Opioids

- Respiratory Depression

A

µ receptors

  • Inhibition of respiratory rhythm
  • Inhibition of central chemoreceptors
86
Q

Opioids

- Nausea and Vomiting

A

Delta receptors

µ receptors

87
Q

Opioids

- Constipation

A

µ receptors
Kappa receptors
Delta receptors

88
Q

Opioids

- Chronic Use

A
  • Tolerance

- Physical dependence

89
Q

Future Analgesics

- 4 Examples

A
  • Antidepressants
  • Gabapentin/Pregabalin
  • Voltage gated Na+ inhibitors
  • Ziconotide
90
Q

Future Analgesics

- Antidepressants

A

Serotonin selective reuptake inhibitors are largely inefficacious to block pain
- Fluoxetine

Serotonin-noradrenlaine reuptake inhibitors (SNRIs) and tricyclic antidepressants, provide pain relief for neuropathic pain

  • Duloxetine (SNRI)
  • Amitriptyline (TCA)

Shows importance of the descending inhibitory modulation of pain system from locus coeruleus involving noradrenaline

91
Q

Future Analgesics

- Gabapentin/Pregabalin

A

GABA analogue to treat epilepsy but has no efficacy at GABA receptors but is efficacious against neuropathic pain but not acute pain

Decreases cell surface expression of voltage gated Ca2+ α2delta1 subunit, which usually increases voltage gated Ca2+ current density and is up-regulated in some forms of neuropathic pain.
Decreasing voltage gated current density decreases spinal cord neurotransmitter release .

Pregabalin is a gabapentin successor has favourable pharmacokinetics.

92
Q

Future Analgesics

- Voltage Gated Na+ Channel Inhibitors

A

Lidocaine is a local anaesthetic that blocks vg Na+ channels and provides analgesia when applied topically as a patch.

Prevents spontaneous neurone discharge associated with neuropathic pain

Used in trigeminal neuralgia patients to provide pain relief when eating

Carbamezepine blocks vg Na+ channels and is used as an ani-epileptic and to treat neuropathic pain such as trigmeinal neuralgia

93
Q

Future Analgesics

- Ziconotide

A

Synthetic analogue of N-type vg Ca2+ blocker W-conotoxin (MVIIA)

Administered intrathecally.

Expensive, invasive and potentially dangerous route of administration, so is only recommended in cases where other treatments have failed.

94
Q

Analgesics

- Pain Ladder

A

WHO published

Developed for cancer pain

  1. Non-opioid treatment such as NSADIS with or without an adjuvant
  2. Weak opioid treatment such as codeine, with or without a non-opioid adjuvant
  3. Strong opioid, such as morphine, with or without a non-opioid and with or without an adjuvant

Adjuvants are additional painkillers such as gabapentin

95
Q

Future Analgesics

- Further Targets

A
  • Subtype specific vg Na+ blockers as vg NA+ 1.7-9 have key roles in nociception and pain
  • Anti-NGF antibodies such as tanezumab which is currently in phase 3 clinical trials
96
Q

Future Analgesics

- Unsuccessful Cases

A
  • NK1 receptor antagonists are efficacious in animal models but non-efficacious in humans
  • TRPV1 antagonists may be useful but cause hyperthermia

NAB (37 decks)

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