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Med 4 > CNS Week 1 Pain > Flashcards

CNS Week 1 Pain Flashcards

1
Q

Define pain

A

An unpleasant sensory and emotional experience associated with or resembling that associated with actual or potential tissue damage

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2
Q

What factors can change pain

A

Movement (on, during, after)

Weight bearing

Isometric contraction

Pressure (trigger points, gout)

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3
Q

Diagnosis of musculoskeletal pain

A

pain arising from a disease process affecting bone, joint, tendon, muscle, spine or related soft tissue eg osteoarthritis

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4
Q

Diagnosis of neuropathic pain

A

Pain caused by a lesion or disease of the somatosensory nervous system

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5
Q

Diagnosis of chronic primary pain

A

Pain without probable musculoskeletal origin (eg fibromyalgia)

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6
Q

Where does arthritis pain come from

A

Synovium

Tendons / ligaments

Meniscus

Bone

Muscle

Peripheral nerve

CNS
(Not entirely known yet)

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7
Q

Structural associations of pain in osteoarthritis

A

Synovitis: inflammation in the lining of the joints

Osteochondral pathology: bone marrow lesions in the subchondral bone

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8
Q

What is the effect of having more mediodorsal thalamus connectivity

A

Negative affect in people with chronic knee pain as there is increased connectivity between emotional and sensory centres in the brain and this is associated with the emotional dimension of pain

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9
Q

Steps of taking a pain history

A

Precipitating / alleviating factors

Quality eg sharp, dull, stabbing, burning

Radiation / localisation -

Severity- descriptive, numeric or visual scales

Timing - constant / intermittent, recent, acute, chronic

Emotional components - mood

Beliefs - causation, diagnosis, blame, catastrophising / acceptance

Associated features - comorbidities, sleep / fatigue

Previous treatments

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10
Q

Reasons why amount of medication used is not a measure of pain severity

A 
Illness beliefs: pain is a warning sign 
Medication beliefs: fear of ADRs, fear of tolerance 
Adverse events 
Accessibility 
Varying efficacy 
Social norms: man or wimp, giving in? 
Social endorsement 
Non analgesic effects: it relaxes me, makes me feel better despite the pain, helps me sleep
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11
Q

How to assess pain in children, dementia and patients unable to communicate

A

Observation:

  • facial expression
  • verbalisations
  • body movements
  • changes in interpersonal interactions
  • changes in activity patterns or routines
  • mental status changes
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12
Q

Effect size of painkillers for pain relief in OA

A

57% contextual
43% pharmacological

Contextual = placebo - is still a benefit

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13
Q

Anatomical terminology relating to the brain

A

Superior / dorsal - above
Inferior / ventral - below

Medial - towards midline
Lateral - away from midline

Anterior / rostral - towards the front
Posterior / caudal - towards the back

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14
Q

Location of cerebellum

A

Inferior to brain very close to brain stem

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15
Q

Weight of average human brain

A

1.5kg

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16
Q

Outward portion (bumps) of brain

A

Gyrae- unique to human brains and other higher order primates

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17
Q

Layers of the scalp (meninges)

A

Scalp
Periosteum (fibroblasts, osteoblasts- anchors the scalp to the skull)
Bone -
Dura mater- tough
Arachnoid mater- not always continuous, cerebrospinal fluid - spider web appearance
Pia mater- delicate, easy to break, surrounds all structures including blood vessels

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18
Q

Folds of the dura mater

A

Falx cerebri - fold in the dura that sits in between 2 hemispheres of the brain up to a certain point

Tentorium cerebelli - tent for cerebellum (where it sits) additional protection and support

Falx cerebelli - divides the hemispheres of the cerebellum

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19
Q

2 types of tentorial tumours

A

Infratentorial - beneath the tentorium cerebelli - most common type of paediatric brain tumour (age 5-15) located around cerebellum can lead to problems with movement and balance - quite successful rate of removal

Supratentorial - tumour is located above tentorium cerebelli

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20
Q

Benefits of meninges

A

Protect and support the brain

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21
Q

Disadvantages of meninges

A

They are so strong that if there is bleeding or swelling to the brain then they cause it to become compressed as they don’t allow it to move

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22
Q

What is a meningeal haematoma

A

A bleed within the meninges. Several types:
Subarachnoid: blood accumulates in the arachnoid space so dura and skull aren’t going anywhere and brain is being compressed

Subdural: blood accumulates under dura which has same effect and compresses Brain downwards

Epidural: bleeding located above dura and skull is broken but this means blood has an outlet to leave so doesn’t press as hard on the brain

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23
Q

Location of the lateral sulcus

A

Separates the temporal lobe from the parietal lobe and frontal lobe

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24
Q

Use of sulci

A

Lobular brain organisation

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25
Q

What does the central sulcus separate

A

Frontal lobe and parietal lobe

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26
Q

4 lobes of the brain

A

Frontal: personality, attention, motivation, planning movement

Parietal: integrating sensory information, language processing

Temporal: memory, sensory processing, language, comprehension

Occipital: vision

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27
Q

Parieto-occipital sulcus

A

Separates parietal from occipital lobe

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28
Q

Precentral sulcus

A

Separates anterior to central sulcus

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29
Q

Calcarine sulcus

A

Visual cortex

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30
Q

Cingulate sulcus

A

Parallel with corpus callosum

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31
Q

Divisions of the hindbrain

A

Metencephalon - pons and cerebellum

Myelencephalon - medulla oblongata

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32
Q

Division of the midbrain

A

Mesencephalon - tectum (colliculi), tegmentum, cerebral peduncles

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33
Q

Divisions of the forebrain

A

Diencephalon- thalamus and hypothalamus

Telencephalon - basal ganglia and cortex

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34
Q

What are the pons

A

Part of the brain stem

A bulge

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35
Q

What is the midbrain

A

Centre of the brain

Close proximity to most structures of the brain even though it is part of the brain stem

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36
Q

What is the diencephalon

A

Contains the thalamus - all information from body comes into thalamus before cortex - integration centre of the brain

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37
Q

Purpose of hippocampus

A

Memory

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38
Q

Function of basal ganglia

A

Regulate movement
Constant communication with cortex

Caudate nucleus - curls in posterior and anterior direction well connected to the putamen

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39
Q

Function of substantia nigra

A

Source of dopamine in the brain
Dark coloured due to melatonin
These are the cells that die out if someone has Parkinson’s

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40
Q

red nucleus

A

Highly vascularised

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41
Q

Function of hypothalamus

A

Fluid filled cavities that protect and bath the brain

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42
Q

3 parts of the brain stem

A

Midbrain - cerebral peduncles (motor tracts), substantia nigra, red nucleus, tectum (vision and hearing), reticular formation (consciousness)

Pons - some direct connections with the cortex

Medulla oblongata - respiration, heart rate, vomiting and sneezing

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43
Q

What are ventricles of the brain filled with

A

Cerebrospinal fluid

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44
Q

How much CSF do we have

A

150ml that is exchanges 3 times each day

Produce approx 500ml every day

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45
Q

What is CSF

A

Colourless liquid that baths the brain, assists in circulating substances
Provides cushioning and absorbs shock

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46
Q

Where is CSF produced

A

In the choroid plexus (a group of cells that line the ventricles) and production induces CSF circulation
The choroid plexus also acts as a medium of exchange between the extracellular fluid and the blood stream

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47
Q

What is hydrocephalus

A

Accumulation of cerebral spinal fluid

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48
Q

What are ventricles

A

A series of inter-connected, fluid filled cavities that cushion the brain and bathe it in cerebral spinal fluid

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49
Q

Route of CSF

A

CSF enters the cisterns and sub arachnoid space via a series of apertures before being circulated upwards and reabsorbed by the arachnoid granulations

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50
Q

4 main arteries that supply the brain

A

2 Posterior: vertebral arteries

2 anteriorly : carotid arteries

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51
Q

Where is basilar artery located

A

Sits on the top of the pons

Has a network of branches that feed the pons and the brain stem in general

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52
Q

Superior cerebellar artery

A

Feeds the cerebellum (majority)

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53
Q

What does the inferior posterior cerebellar artery supply

A

Inferior aspects of the temporal lobes and the hippocampus and medial aspects of occipital lobes

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54
Q

Role of the circle of Willis

A

A major anastomosis for the brain (connects blood vessels)
Combines the posterior circulation with the anterior circulation in the brain
If there is a deficit in one it can be supplied by the other

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55
Q

Where does anterior circulation come from

A

Carotid arteries
Middle cerebral artery (main branch) one of the biggest arteries runs through lateral sulcus
Largest cerebral artery with the largest territory

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56
Q

What is the blood brain barrier

A

An interface that ensures the circulatory system (Blood) is kept separate from the extracellular fluid / CSF

Blood vessels composed of a layer of endothelial cells, fit together tightly and their membranes form tight junctions that only allows selected materials to pass between the blood and brain

Pericytes and astrocytes also play a role in maintaining the BBB

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57
Q

What molecules are and are not allowed to pass into the brain

A

Oxygen, CO2, glucose and select amino acids are allowed to pass into the brain but pathogens and larger molecules (Antibodies) cannot

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58
Q

Function of pericytes

A

Support endothelial cells in maintaining the blood brain barrier
Role in vasodilation

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59
Q

Different components of the blood brain barrier

A

Endothelial tight junctions - small gaps between endothelial cells that line the blood vessels

Basement membranes - thin, fibrous connective tissues that separate the endothelial cells from surrounding tissue

Pericytes communicate with endothelial cells and contribute to debris removal. In capillaries they control blood flow

Astrocytes - stabilise the blood brain barrier containing water channels (aquaporins) that allow water to enter the brain

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60
Q

What % of patients with chronic pain experience depression

A

49%

25% of sufferers lose their jobs and 16% of sufferers feel their chronic pain is so bad that they want to die

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61
Q

Different types of pain

A

Acute v chronic

Cancer v non cancer

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62
Q

Multi dimensions of pain

A 
Location 
Intensity 
Temporal aspects 
Quality 
Impact 
Meaning
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63
Q

What are the pain mechanisms

A

Nociceptive and inflammatory: allow body time to recover (seen as good pain)
Neuropathic : nervous system functioning in an unintended way
Dysfunctional

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64
Q

Describe the characteristics of acute pain

A

Pain of recent onset and probable limited duration (hours / days)
Obvious tissue injury eg injury, operation, burn
Varying severity
Intensity related to extent of injury: release of inflammatory chemicals (prostaglandins)
Predictable time course
Treatments usually successful

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65
Q

Characteristics of chronic pain

A

Pain lasting for more than 3 months (continuously or episodically)
Pain lasting after normal healing
Sometimes no identifiable cause (sometimes a trigger)
May be no obvious pathological process
Intensity related to tissue injury (distress making it worse)
Unpredictable time course
Difficult to treat - most drugs are unhelpful or only help a minority of patients

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66
Q

Why is duration of symptoms not a good discriminator

A

Acute pains may go on for a long time eg burns dressings, sickle cell disease, flare ups of RA

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67
Q

Describe cancer pain

A

Progressive
May be a mixture of acute and chronic
Opiod treatments often used towards end of life

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68
Q

Describe non cancer pain

A

Many different causes
Acute / chronic
Opiods found to lead to more deaths sue to overdosing (drive in the NHS to reduce opiod prescribing in non cancer pain)

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69
Q

What is nociceptive pain

A

‘Good’ pain
Sensation associated with the detection of potentially tissue damaging noxious stimuli
Protective

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70
Q

Action of nociceptive pain

A

Noxious stimuli (heat / cold/ intense mechanical force/ chemical irritants detected by the sensory neurone in the PNS

Spinal cord causes an automatic response and withdrawal reflex
Adaptive high threshold pain
The early warning system is a protective primitive defence to detect tissue damage

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71
Q

Describe inflammatory pain

A

Obvious tissue injury or illness
Associated with tissue damage and infiltration of immune cells and can promote repair by causing pain hypersensitivity until healing occurs

Protective function

Descriptors:

  • sharp and / or dull
  • aching
  • throbbing
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72
Q

Describe pathological pain

A

Maladaptive
Results from abnormal functioning of the nervous system

Disease states caused by damage to the nervous system (neuropathic pain)
Or by its abnormal function (nociplastic pain)

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73
Q

Describe neuropathic pain

A

Caused by a lesion or disease of the sensory nervous system

Tissue injury may not be obvious

Does not have a protective function

Descriptors:

  • burning, shooting, pins and needles or numbness
  • less well localised (affects a large area of the body)
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74
Q

describe nociplastic (dysfunctional pain)

A

Substantial pain but no noxious stimulus and no or minimal peripheral inflammatory pathology

No neuronal damage ( no obvious stimulus, tissue or nerve damage but nervous system is acting in an unintended way)

Conditions include fibromyalgia, IBS, tension headache, temopormandibular joint disease, interstitial cystitis (difficult to treat with drugs)

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75
Q

Acute non cancer pain

A

Eg fracture, appendicitis, MI
- symptom of tissue injury or illness

Usually nociceptive
Occasionally neuropathic eg sciatica

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76
Q

Chronic non cancer pain

A

Chronic back pain, arthritis
Cause may not be obvious

Complex, may be mixed nociceptive and neuropathic
Different treatments may be needed

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77
Q

Burdens of long term pain

A 
Depression
Sleep disturbances 
Fatigue 
Impaired physical functioning 
Impaired concentration 
Time off work 
Less active
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78
Q

Cancer pain

A

Eg uterine cervical cancer, breast cancer
Bone metastases
Nerve compression

Often mixed nociceptive and neuropathic pain
Usually gets worse over time if untreated

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79
Q

Function of the somatosensory system

A

Receives information from numerous body parts - skin, muscle, tendons, ligaments, connective tissue

Detected a wide range of stimuli - touch, brush, pressure, tickle, temperature, pain

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80
Q

Difference between nociception and pain

A

Nociception is a neural process - activation of C fibres

Pain is a feeling / perception and includes a psychological component

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81
Q

Different types of sensory receptors

A

Mechanoreceptors: touch, pressure, vibration
Proprioceptors: position of body
Thermoreceptors: warm, cool, hot
Nociceptors: mechanical, thermal, chemical

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82
Q

What is convergence

A

The idea that a single sensory neurone in the CNS can receive inputs from many sensory receptors

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83
Q

What are the steps of transduction in the sensory nerve

A

Deformation of membrane

Opening of Na+ and K+ channels

Receptor (generator) potential
Local depolarisation of receptive membrane

Action potential propagated to CNS

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84
Q

What is recruitment

A

Increased number of responsive receptors and fibres - more sensory input to ensure message is sent to the CNS

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85
Q

Difference between pain tracts and tactile tracts

A

Pain tracts cross in the spinal cord

Tactile tracts cross in the medulla

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86
Q

What are tactile pathways

A

Central branches of touch afferent fibres ascend in the dorsal columns

Synapse in the dorsal column nuclei

Cross the midline in the medulla

Ascend through the brain stem as the medial lemnisus

Send projections to the primary somatosensory cortex (S-I) post central gyrus of the parietal lobe

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87
Q

What are the components of pain

A

Sensory-discriminative component: tells you that you have been hurt and where it is

Emotional affective component: the association of unpleasant emotions with the nociceptive stimulus. The suffering of pain comes from the bad emotions that are generated by the painful sensations

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88
Q

What are A B fibres

A

Myelinated fibres
Fast conduction velocity (non painful stimuli)
Terminate in the intermediate lamina (III-IV) of the dorsal horn
Responses sensitive to glutamate receptor (AMPA receptor) antagonists (fibres release neurotransmitter glutamate)

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89
Q

What are C fibres

A

Unmyelinated fibres
Slower conduction velocity
Terminate in the superficial lamina (I-II) of the dorsal horn
Responses sensitive to glutamate receptor (AMPA and NMDA receptor) and peptide receptor antagonists

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90
Q

Difference between AB fibres and C fibres

A

What they release into the spinal cord.
AB release glutamate neurotransmitter
C release glutamate and peptide receptor antagonists

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91
Q

Plasticity of spinal responses

A

Neuronal responses to repeated stimulation of C fibres are not fixed and are not always proportional to the intensity of the stimulus applied

Enhanced responses (wind up) for a given noxious stimulus are associated with repeated higher stimulation

Spinal neurones are sensitised to the noxious stimulus

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92
Q

What is allodynia

A

When the normal nociceptor threshold is sensitised so something that wouldn’t usually cause pain eg touch does cause pain

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93
Q

What is hyperalgesia

A

A sensitised response to a normally painful stimulus

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94
Q

Brainstem

A

Through the spinoreticular tract and branches of the STT, nociceptive signals activate brainstem systems giving rise to changes in BP, respiration and orientation towards stimulus

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95
Q

Thalamus

A

VPL is main somatosensory area of thalamus, but other components may also be involved. Acts as the final relay before sensory signals reach the cortex

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96
Q

Cortex

A

Consciousness of pain, plus the limbic system for emotional response

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97
Q

Hypothalamus

A

The responses to pain as a stressor are mediated through the hypothalamus: neuroendocrine changes and some behaviours

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98
Q

What is the main area for pain processing

A

The ventral posteromedial nucleus (VPL)

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99
Q

What is inflammation

A

Immediate response of the body to a harmful stimulus

Treatment of patients with inflammation is to:

  • relieve symptoms (pain, swelling, increased temp)
  • slow or stop tissue damaging process

Reduction of inflammation often also results in pain relief

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100
Q

What are eicosanoids

A

Small bioactive lipid molecules derived from the lipid membrane
Play an important role in inflammation, generated from phospholipids ( arachidonic acid)

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101
Q

What is synthesis of eicosanoids driven by

A

Many different stimuli including cell damage

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102
Q

What is arachidonic acid metabolised by

A

One of 2 fatty acid cycle-oxygenase enzymes

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103
Q

What is COX 1

A

Maintains normal tissue function
Constitutive enzyme
Present in most of the tissues in the body (kidney and platelet function)
- tissue homeostasis

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104
Q

What is COX2

A

Induced in activated inflammatory cells (IL-1 and TNF a) following stimulation from cytokines

Responsible for production of prostaglandin mediators of inflammation and so drives local inflammation

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105
Q

Action of drugs that target cyclooxygenase enzymes

A

They inhibit cox2 but not cox1

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106
Q

What are the 5 main prostanoids receptors

A 
PGD2: DP receptor 
PGF 2a: FP receptor 
PGI2: IP receptor 
TXA2: TP receptor 
PGE2: EP receptor - number of sub groups
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107
Q

Why are there multiple prostanoid receptors but all with the same function

A

A large number of molecules are generated but all with the same effect (all produce inflammation and pain)
If we only had one we would be quite vulnerable if it wasn’t working as multiple systems working alongside one another means you’ll still get inflammation even if one isn’t working

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108
Q

What do mast cells release

A

PGD2

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109
Q

What happens in chronic inflammation in terms of prostanoids

A

Monocytes and macrophages release PGE2 and TXA2 which drive inflammation

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110
Q

What do histamine and bradykinin induce

A

Histamine - itch

Bradykinin - pain

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111
Q

Actions of PGE2, PGI2 and PGD2

A

Powerful vasodilators, synergise with histamine and bradykinin causing redness and increased blood flow

Prostaglandins potentiate the actions of bradykinin and histamine on blood vessels and peripheral nerves

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112
Q

What is bradykinin

A

Causes pain if injected
De novo synthesis during tissue injury
Made in vasculature and local tissue by activated enzymes

Activates nociceptors by B1 (induced after a few days of inflammation) and B2 (always present on sensory nerves) receptors

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113
Q

Role of prostaglandins in relation to bradykinin

A

Bradykinin increases the production of prostaglandins

Prostaglandins enhance nociceptor responses to bradykinin- increased excitability of nerve fibres

Prostaglandins sensitise nociceptors

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114
Q

Effect of tissue damage

A

Leads to inflammation ( which releases H+)
Release of bradykinin (acts on B2 receptors of sensory nerves)
Action potentials fired up sensory nerve to the CNS

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115
Q

What are NSAIDs

A

Anti inflammatory
Analgesic
Antipyretic (lower body temp if it is elevated)

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116
Q

Mechanism of actions of NSAIDs

A

Inhibition of cyclooxygenase enzymes

Reduced generation of eicosanoids

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117
Q

Why are glucocorticoids given to people with chronic inflammatory disease

A

Glucocorticoids inhibit the induction of the COX enzymes and when COX is blocked, cyclic endoperoxides are inhibited

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118
Q

What are cyclic endoperoxides

A

PGI2: hyperalgesic vasodilator- decreases platelet aggregation

PGE2: hyperalgesic vasodilator

PGD2: vasodilator, decreases platelet aggregation

TXA2: thrombotic vasoconstrictor

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119
Q

What is the antipyretic effect

A

Normal body temp is regulated by the hypothalamus and fever is due to a disturbance in the hypothalamic thermostat
NSAIDs reset the thermostat

Mechanism mainly due to inhibition of prostaglandin production in hypothalamus
Temperature regulating mechanisms reduce temperature

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120
Q

How are NSAIDs analgesic

A

Pain is associated with inflammation / tissue damage

NSAIDs reduce inflammation (oedema and vasodilation) which causes pain

In combination with opioids to decrease postoperative pain

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121
Q

Clinically used NSAIDs

A

Analgesia (acute / post operative)
Short term: aspirin, paracetamol (not an NSAID), ibuprofen
Longer acting: naproxen, piroxicam

Taken in conjunction with opiods for chronic pain

122
Q

What is acetylsalicylic acid (aspirin)

A

Irreversible inactivation of COX 1/2

Oral, rapid absorption, 75% metabolism in liver

First order elimination, half life = 4 hr

MI therapy - antiplatelet function (prevents heart attacks)

123
Q

What can large, therapeutic and toxic doses of aspirin cause

A

Large: dizziness, deafness and tinnitus
Therapeutic: gastric bleeding (5/6 mls blood loos) (2nd highest cause of gastric ulcers)
Toxic: uncompensated respiratory acidosis, metabolic acidosis

124
Q

Side effects of NSAIDs

A

GI disturbances: dyspepsia, diarrhoea, nausea, vomiting, 1/5 chronic NSAID users have gastric damage
Piroxicam and meloxicam have the highest risk

Skin reactions

125
Q

Effects of paracetamol (not an NSAID)

A

Analgesic, antipyretic, weak anti inflammatory
Metabolised in liver (Half life 2-4 hours)

Few side effects with therapeutic doses
Regular intake at high doses over long period increases the risk of kidney damage

Toxic doses: nausea and vomiting, 24-48 hours later fatal liver damage

126
Q

describe COX2 inhibitors

A

Studied for analgesic / anti-inflammatory effects in arthritis
Recent warning about use of COX2 inhibitors due to risk of heart attack, stroke and cardiovascular death

127
Q

What are resolvins protectin maresins

A

Molecules (chemical signals) that decrease pain, reduce bacterial and viral infections, increase wound healing and increase tissue regeneration

An inability to sustain these molecules can mean you have chronic inflammation

(Thought that these molecules are hugely increased following covid 19 infection)

128
Q

Substance that blocks opiods (used if someone has overdosed)

A

Naloxone

129
Q

Effects of opiods

A

Produces euphoria, analgesia and sleep

130
Q

What are u, ó and k receptors

A

7 transmembrane spanning receptors coupled to G proteins (G0 / Gi) when coupled they are inhibitory

Inhibit adenylate cyclase and reduce cAMP

Alter ion channels through G protein coupling to channels

Open K+ channels - when opened on a sensory nerve, nerve is inhibited, helps maintain hyper polarisation of membrane (less easy to excite)
Close Ca2+ channels - important for fusion of vesicle with pre synaptic membrane and release of neurotransmitter

131
Q

Effects if opiods on neuronal transmission

A

Opens K+ channels meaning membrane excitability is reduced,

Shuts off Ca2+ channel

132
Q

Effects of morphine

A

Acts via a u receptor
Feeling of analgesia, euphoria and dysphoria - these are hard to separate as mediated by the same receptors

Tolerance

Dependence

Constipation

Anti-tussive (inhibits cough reflex)

133
Q

Describe the issue of tolerance with morphine

A

Bigger dose for the same effect (can be seen within 7 days) due to number of receptors that can be activated being reduced

134
Q

Percentage of pre and post synaptic opiod receptors

A 
Presynaptic= 70% 
Postsynaptic = 30%
135
Q

Describe the two neurone network

A

The idea of multiple neurones synapsing onto each other
Glutamate causes excitation but action potentials cannot fire all the time as they will cause hyperexcitation

GABAergic neurone ensures action potentials fire regularly and at the right time so less glutamate is released and less action potentials fired

136
Q

What is opiod induced hyperalgesia

A

Sustained opioid use can drive pain sensitivity

137
Q

What type of pain are opiods effective for

A

Good for post operative pain and end of life cancer pain (when given spinally)
Not very effective with chronic pain

138
Q

How does high intensity pain influence opiod effects

A

An acute type of pain where opiod receptors cause a protective effect (signal is inhibited)

139
Q

How does tissue damage influence opiod effects

A

A chronic type of pain where the opiod can cause hyperalgesia
Opiod inhibits the pain but not forever

140
Q

How does nerve damage influence opiod effects

A

A fibres (touch fibres) cause allodynia (touch evoked pain) due to messages to the spinal cord being misinterpreted as painful

141
Q

Alternative options when opiods don’t work

A

Change drug or route:

  • switch to subcutaneous or epidural morphine
  • changes in metabolism : effects of a single injected dose is 6x that of a single oral dose

Spinal opiod:

  • epidural / intrathecal give little benefit over subcutaneous but is good for combination therapy
  • infusion for chronic pains (end of life pain management)
142
Q

Onset / duration of effect of opioids

A

Route of administration / formulation is not important for continual analgesia but is essential for as needed basis of treatment

Intravenous - 2 min average for most opioids
Intramuscular - lipophilic drug : 20 min
Oral: normal release 1 hour, sustained for 2-4 hours

143
Q

Describe diamorphine (heroin)

A

High lipophilicity = brain penetration is rapid
Broken down to morphine in the CNS
More potent and addictive than morphine

144
Q

Describe codeine

A

Weak opiate (20% of morphine)
Little or no addiction ??
Less respiratory depression
Good anti-tussive

145
Q

What is respiratory depression

A

Inhibits respiratory medulla - eventually is fatal

146
Q

Describe pethidine

A

A synthetic opiod

  • orally active
  • less potent
  • short duration
  • used in labour
147
Q

Describe fentanyl

A 
A synthetic opiod 
Often used in patches 
Highly potent 
Short duration 
High abuse rate 
Used in anaesthesia
148
Q

Risk of taking opiods pre surgery eg osteoarthritis

A

OA often leads to a joint replacement and it has been found that using opiods to manage pain beforehand leads to about 50% of patients taking opiods 12 months after compared to 10% still taking it if they didn’t beforehand
This is due to hyperalgesia, dependency or surgery not working

149
Q

Describe methadone

A 
Plasma half life of >24 hours 
Used to reduce opiod abuse 
Physical abstinence syndrome is reduced 
Psychological dependence similar 
- in the presence of methadone, morphine / diamorphine less euphoria due to methadone being bound to the receptor
150
Q

What is opiod tapering

A

The reduction of opiod doses over time

151
Q

How is the opiod crisis being targeted

A

Opiod tapering to lower opiod consumption but this is challenging as there are limited alternatives and an increased risk of suicide has been reported in the US

Despite NICE guidelines chronic pain patients are given opiods which may exacerbate pain mechanisms

152
Q

Types of anaesthesia

A

General anaesthesia
Regional anaesthesia: spinal, epidural, peripheral nerve block
Local anaesthetic

153
Q

Define general anaesthesia

A

A drug induced reversible state consisting of unconsciousness, amnesia, anti-nociception and immobility with maintenance of physiological stability

154
Q

What is propofol

A

1 or 2% lipid emulsion at room temp

Mild pain on injection

Licensed in UK since 1986

155
Q

What does binding of agonists do (propofol)

A

Enhances affinity of the receptor for endogenous ligand ie gamma aminobutyric acid
Chloride influx causes hyperpolarisation

156
Q

CNS effects of propofol

A 
Loss of verbal contact within 10 seconds 
Atonia (lack of tone or energy) 
Unresponsiveness 
Loss of brainstem reflexes 
Apnoea
157
Q

Brain and blood effects of propofol

A

Decrease in cerebral metabolic requirement for oxygen (CMRO2)

Decreased cerebral blood flow (CBF)

Decreased intracranial pressure (ICP)

158
Q

Cardiovascular effects of propofol

A 
BP = CO x SVR 
CO = SV x HR

SV determines by preload, afterload and contractility

159
Q

Practicalities of propofol

A

Administered only by anaesthetists
Smooth induction and emergence from unconsciousness
Titratable for anxiolysis, sedation, anaesthesia
Predictable side effect profile
Reduces muscle tone in pharynx

160
Q

Rocuronium pharmacology

A

Administered by IV bolus or infusion

Skeletal muscle paralysis in 30 seconds, lasting >30 mins

Offset is by diffusion away from NMJ to plasma

Deacetlyated in liver and excreted in urine

161
Q

Rocuronium practicalities

A

Paralysis to facilitate intubation and surgery

Not an agent of unconsciousness

Anaphylaxis risk

162
Q

What is sugammadex

A

Encapsulates Rocuronium molecules in its centre
A sugar molecule
Alternative to neostigmine

163
Q

Chemistry of local anaesthetics

A 
Amphipathic bases (both lipophilic and hydrophilic) 
Esters - cocaine, prilocaine, chloroprocaine 
Amides- lidocaine, bupivacine, ropivacine, levobupivacine

Inhibit action potentials in nociceptive nerve fibres and block transmission of pain impulses

164
Q

Phases of nerve action potentials

A

Phase 1 : threshold potential
Phase 2: depolarisation, voltage gates Na+ channels open -> Na influx
Phase 3 : repolarisation, N+ channels close, K+ channels open -> K+ efflux
Phase 4: hyperpolarisation

165
Q

Types of A fibres

A 
All are myelinated 
A (alpha): somatic: motor / proprioception 
B (Beta): touch and pressure 
Y (gamma): muscle spindles 
D (delta) : fast pain, cold
166
Q

B fibres

A

Myelinated , pre ganglionic, sympathetic

167
Q

C fibres (unmyelinated)

A

Dorsal root, slow pain, heat

Post ganglionic sympathetic

168
Q

Trends with A, B and C fibres

A

Decreasing diameter and velocity decrease
Increasing sensitivity to local anaesthetics
Eg A has biggest diameter but is least sensitive to local anaesthetics

169
Q

Feelings after a local anaesthetic

A

May feel sick
Won’t be able to feel anything sharp or painful but may still feel touch or pressure
Will know something is going on but wont be painful

170
Q

Define pKa of a drug

A

The pH at which ionised and unionised forms are present in equal amounts
Lower pKa = greater unionised form = faster onset of action (don’t work as well in inflamed / infected tissue

171
Q

Lipid solubility of a drug

A

Quantified by oil : water partition co efficient

More lipid soluble = more able to cross the phospholipid bilayer = need less drug

172
Q

Protein binding of a drug

A

Bind to a1 - acid glycoprotein
More protein bound = larger protein depot = longer duration of action.
Hypoxia, hypercarbia, acidaemia all lead to decreased protein binding and therefore toxicity

173
Q

Local anaesthetic system toxicity

A

Na+ channel induced arrhythmia and neurotoxicity -> seizures -> cardiac arrest
Overdose or accidental intravenous injection

174
Q

What is meningitis

A

Inflammation of meninges and CSF

These are usually sterile and have no microorganisms

175
Q

What is encephalitis

A

Inflammation of the brain

176
Q

What is myelitis

A

Inflammation of the spinal cord

177
Q

What is neuritis

A

Inflammation of peripheral nerves

178
Q

Routes of infection

A

Blood-borne
Parameningeal suppuration eg otitis media, sinusitis

Direct spread through defect in the dura eg post surgery and trauma

Direct spread through cribriform plate (base of skull) rare

179
Q

Constituents of cerebrospinal fluid

A

Low protein - no complement
Low IgG
No lymphatics
Blood brain / CSF barrier (lipophilic compounds only)

180
Q

Most common origin of bacterial meningitis

A

Nasopharynx

IgA protease, Pili, endocytosis, separate tight junction

181
Q

Why are bacteria from meningitis not susceptible to breakdown from phagocytosis?

A

They have a thick cellular capsule which protects them from it.

182
Q

Symptoms of meningitis

A

Headache global (all over)
Neck and back stiffness due to CSF coating and spinal cord
Nausea and vomiting
Photophobia (non specific) avoiding bright light
Don’t like legs being bent due to irritation of spinal cord

183
Q

Other conditions that meningitis can occur from

A 
UTI 
Dysentery 
SAH 
Malignancy 
NSAIDs
184
Q

Physical signs of meningitis

A

Fever (not always present especially in elderly / young children)
Rash petechial / purpuric- usually meningococcal but also streptococcal
Meningeal irritiation : photophobia and irritation of motor roots by inflammation

185
Q

Examples of irritation to motor roots by inflammation

A

Kernig’s positive due to hamstring spasm
Neck stiffness - unable to put chin on chest
Brudzinkis sign- flexing the patients neck causes flexion of the patients hips and knees
In mild meningism may not be present : unable to curl forward to put nose on knee

186
Q

Meningitis in infants

A 
Typical signs often not present 
Flaccid 
Bulging fontanelle due to increased ICP 
Fever and vomiting often the only sign 
Strange cry 
Convulsions
187
Q

Lumbar puncture for meningitis diagnosis

A

Most rapid diagnostic test

Helps to distinguish between bacterial and viral causes in most cases (sometimes even fungal causes)

188
Q

Contraindications of lumbar puncture in meningitis

A

Risk of herniation (CT head as raised ICP)

Risk of bleeding (abnormal clothing)

189
Q

Why should you do a CT scan for suspected meningitis is patient is experiencing focal neurology, drowsiness or fitting etc

A

Because papilloedmea can be slow in its development - bulging around the optic nerve

190
Q

Normal CSF white cell count

A

<5 white cells

191
Q

CSF white cell count in bacterial meningitis

A

100-5000

Neutrophils are the predominant cell type

192
Q

Source of listeria

A

Can survive in fridges eg unpasteurised cheese and pate

193
Q

Causes of a lymphocytic mononuclear CSF (aseptic meningitis)

A 
TB 
Partially treated bacterial infection 
Intracranial abscess 
Spirochaetes 
Viral meningo-encephalitis 
Lymphocytic leukaemias
194
Q

Gram stain rapid diagnostic test for meningitis

A

Approx 50% sensitivity, 48hr culture and PCR more sensitive but slower

195
Q

Zn rapid diagnostic test for meningitis

A

For AAFB but low sensitivity as few organisms are present / ml of CSF

196
Q

PCR (detection nucleic acid) rapid diagnostic test for meningitis

A

Can be done on CSF or blood
Meningococcal on EDTA and CSF
HSV / enteroviruses on CSF
TB on CSF

197
Q

Predisposing factors of pneumococcal meningitis

A 
Immunosuppression 
Alcohol 
Diabetes 
Hyposplenism 
Myeloma
198
Q

Describe pneumococcal meningitis

A

Pneumonia and / or otitis media present in <50%
Impaired consciousness, neurological signs and seizures more common
Mortality roughly 30% even with therapy
Pneumococcal vaccine provides some protection

199
Q

Most at risk demographic for listeriosis

A

The immunocompromised, neonates and >50 years with rising incidence in age

200
Q

How prevalent is listeriosis

A

It is present in 5% of healthy human stools
64% of fridge items contain at least 1 contaminated food item
Mortality >20%

201
Q

Consequences of listeriosis

A

Meningo-encephalitis, abscesses, brainstem with ataxia (loss of muscle control in arms and legs) and movement disorders

202
Q

Treatment of listeriosis

A

Amoxicillin +/- gentamicin (cephalosporins NO activity)

Normal meningitis treatment doesn’t treat listeriosis

203
Q

Complications of meningitis

A 
Death 
Subdural collection / empyema
Cerebral vein thrombosis 
Hydrocephalus 
Deafness 
Convulsions 
Visual / motor / sensory deficit
204
Q

How to manage meningitis

A

Antibiotics - has to be high dose agents that can cross the blood- CSF barrier- changes commonly as bacterias become more resistant

Adequate oxygenation

Prevention of hypoglycaemia and hyponatraemia

Anticonvulsants

Decrease intracranial hypertension
Alongside monitoring on ICU

205
Q

Why can benzylpenicillin and gentamicin be used to treat meningitis only in neonates

A

Because it can only get into the CSF in the neonates

206
Q

Antimicrobial therapy to treat N meningitidis

A

Ceftriaxone (benzylpenicillin if sensitive - no longer 1st choice due to resistance)

207
Q

Antimicrobial therapy of H influenzae type b meningitis

A

Ceftriaxone (chloramphenicol)

208
Q

Antimicrobial therapy of S pneumoniae meningitis

A

Ceftriaxone (benzylpenicillin if sensitive) Nb add vancomycin if risk resistant strain eg travel assoc

209
Q

Antimicrobial therapy for an unknown organism meningitis in children >2 months and adults

A

Ceftriaxone and amoxicillin if >50 years or immunocompromised

210
Q

Antimicrobial therapy of an unknown organism of meningitis for children <2 months (neonates)

A

Benzylpenicillin and gentamicin.

211
Q

Dexamethasone (steroidal) treatment of meningitis

A

Hib meningitis reduces long term morbidity

Give prior to antibiotics for beneficial effect

Nb risk of GI bleeding

Data for pneumococcal infection as well but concern if resistant strain antibiotic penetration may be affected

212
Q

Vaccination of meningitis

A

Conjugated Hib, meningococcal group C and pneumococcal vaccines protection in <2 years old

Meningococcal group ACWY conjugate 14 years

Men B vaccine

Polyvalent pneumococcal polysaccharide vaccine

213
Q

Chemoprophylaxis of meningitis

A

Reduce secondary cases in close contacts and households of meningococcal and Hib disease

Rifampicin or ciprofloxacin clear nasopharyngeal carriage

214
Q

What is neuritis

A

Inflammation of peripheral nerves (less common)

Infections eg leprosy, trypanosomes, CMV, Lyme neuroborreliosis

215
Q

What is myelitis

A

Inflammation of the spinal cord - with or without encephalitis

Transverse - acute transaction of the cord

  • Vasculitis of anterior spinal artery
  • direct invasion of cord
  • ascending - ascending flaccid paralysis and sensory loss
  • anterior horn cells eg polio- flaccid paralysis muscle pain no sensory or bladder dysfunction - polio
216
Q

What is encephalitis

A

Inflammation of the brain

Cerebral irritation / dysfunction can include

  • irritability
  • ataxia
  • excessively brisk tendon reflexes
  • signs of cerebral / brainstem failure
  • signs of brain swelling eg focal neurological signs
217
Q

Case definition for encephalitis

A

Encephalopathy (altered level of consciousness, cognition, behaviour or personality persisting for more than 24 hours)
And
>2 or more of the following
- fever or history of fever >38c
- seizures and / or focal neurological findings
- CSF pleocytosis
- EEG findings compatible with encephalitis
- abnormal results of neuroimaging

218
Q

What is dependence syndrome

A

Strong desire or sense of compulsion to take the substance
Difficulties in controlling use
Physical withdrawal state
Tolerance
Progressive neglect of other interests, increasing time spent obtaining and taking substance

219
Q

Functions of serotonin pathways

A

Mood
Memory processing
Sleep
Cognition

220
Q

Functions of dopamine pathways

A 
Reward (motivation) 
Pleasure, euphoria 
Motor function 
Compulsion 
Preservation
221
Q

Which drugs increase dopamine release in the NAC (however all by different mechanisms)

A 
Opiates 
Nicotine 
Amphetamine 
Cocaine 
Ethanol 
Cannabis 
Ecstasy 
Caffeine
222
Q

Which drugs enhance serotonin function (5HT) N

A

LSD

Ecstasy

223
Q

Which drugs block N methyl D aspartate- NMDA antagonists

A

Phencyclidine (PCP) and ketamine - hallucinogenic

224
Q

Effect of amphetamines

A

Taken into nerve endings and causes dopamine release

225
Q

Effects of cocaine

A

Blocks the reuptake mechanism of dopamine so more dopamine hangs around

226
Q

Effects of morphine / cannabinoids

A

Major action on receptors on GABA neurons

Eg morphine inhibits inhibitory receptor leading to increased release of dopamine

227
Q

How does microdialysis work

A

Substances from either side of the brain go into the dialysis fluid and then out so any neurotransmitters can be analysed

228
Q

How does formulation of a drug affect its effect

A

IV heroin has a greater effect than methadone by mouth

Inhaling cocaine is better than chewing coca leaves

Smoking cigarettes is better than chewing tobacco

Due to faster and higher peaks in brain dopamine levels resulting in a greater rush

229
Q

What are bromocriptines

A

A group of medicines called dopamine agonists that may be used for:

  • stopping breast milk production for medical reasons
  • problems usually caused by not having the right amount of prolactin (tumours)
  • treating non cancerous tumours in the brain called prolactinomas
  • treating Parkinson’s disease by activating receptors and helping motor skills
230
Q

Why should you take bromocriptine with caution

A

Can cause some people to develop urges or cravings to behave in unusual ways, not being able to resist the impulse, drive or temptation to carry out certain activities that could harm yourself or others
(Impulse control disorders) : addictive gambling, excessive eating, spending, abnormally high sex drive

231
Q

Alternative option to bromocriptine

A

Roprinole

232
Q

Action of opiates

A

All agonists at G protein coupled opioid receptors (u receptors mainly) that lower neurotransmitter release in brain and periphery (are also located throughout GI tract hence causing constipation)

233
Q

Effects of opiates

A

Analgesia, euphoria, positive reinforcement, respiratory depression (fatal caused by overdosing), dysphoria, sedation

234
Q

Withdrawal symptoms

A

Craving, restlessness, muscle and bone pain, insomnia, diarrhoea, vomiting, cold flashes with goose bumps, kicking movement

235
Q

How long do withdrawal symptoms typically last

A

Peak 48-72 hours after the last dose and subside after about a week

Sudden withdrawal by heavily dependent user in poor health is occasionally fatal, although heroin withdrawal is less dangerous than alcohol or barbiturate withdrawal

236
Q

How does cocaine work

A

Increases catecholamine neurotransmitter function by preventing reuptake
Most important for CNS behaviour - high conc has anaesthetic properties

237
Q

How do amphetamines work

A

Release monoamines from neuronal storage vesicles and block reuptake transporters causing increased synaptic DA, NA and 5HT

238
Q

Psychological effects of amphetamines

A

Euphoria, increased libido, energy, self esteem, self confidence, aggression, excessive feelings of power, obsession, paranoia

239
Q

Action of cannabis

A

Inhibits a wide range of neurotransmitter release in the brain and periphery via specific Gi protein coupled cannabinoid receptors

240
Q

Effects of cannabis

A

Mild euphoric effect in moderate doses, dysphoric in high doses particularly in naive users

Very low acute toxicity but some concerns about precipitation of psychosis in chronic heavy users

Stimulates appetite through actions on feeding centres in the hypothalamus and gut

241
Q

What is agonist substitution

A

Eg methadone treatment for opiate abuse (receptor agonist but stays in system for longer so reduced withdrawal and drug seeking)

Long acting synthetic opiate agonist, administered orally for sustained period at dose sufficient to prevent opiate withdrawal
Reduced effects of illicit opiate use and decreases opiate craving

242
Q

What are antagonist treatments (naltrexone)

A

Naltrexone: therapy for opiate addiction. Patients must be de-toxified and opiate free for several days before naltrexone can be taken to prevent precipitating opiate asbtinence syndrome (helps someone who has overdosed to carry on breathing)

243
Q

What is the agonist treatment (mecamylamine)

A

Nicotine acetylcholine receptor antagonist

Blocks rewarding actions of nicotine and cue-induced craving

244
Q

How can naltrexone also be used as an anti craving medication

A

Reduces alcohol craving as well as treating opioid dependence as it interferes with positive reinforcement and possibly alcohol conditioned cues

Possibly acts by blocking endogenous opioid dis-inhibition of GABA neurones in VTA thereby reducing firing of dopamine releasing neurones

245
Q

How is acamprosate used as an anti craving medication

A

Registered for use as adjunct in maintaining abstinence in alcohol dependent patients

Reduces neuronal excitability that occurs during alcohol withdrawal

246
Q

What is a migraine

A

Painful pulsing headache
Lasting 4 hours to 3 days often unilateral and associated with photophobia and phonophobia
Prevalence peaks in middle age

247
Q

Prodrome of migraine

A

A warning phase that occurs in 60%

Yawning, mood or appetite change

248
Q

2 types of migraine

A

Migraine with and without aura

249
Q

What is an aura in a migraine

A

Initial visual disturbance (around 30 mins)
Visual area lost, surrounding area shimmers
(15% of sufferers)

250
Q

Symptoms of migraine

A

Unilateral throbbing headache lasting 4-72 hours
Photophobia
Nausea and vomiting
(85% of sufferers)

251
Q

Heritability of migraines

A

Estimated 42%

38 genomic loci that affect migraine risk

252
Q

Genetic mutation causing migraine

A

50% cases cause= point mutation in the CACNA1A gene that encodes pore forming a1A subunit of the P/Q voltage gated sodium channel. Mutations result in an altered channel conductance and density of expression in vitro in cell lines

30% of patients mutation in ATP1A2 gene that encodes the Na+ / K+ pump a2 subunit

Mutation in TRESK K2P potassium channel in spinal neurones associated with common migraine

SCN1A (sodium voltage gated channel alpha subunit 1) encodes NaV1

253
Q

What is cortical spreading depression (CSD)

A

Likely cause of aura
Slowly propagating cortical waves of neuronal and glial cell depolarisation, start in the visual cortex and are followed by long lasting depression of activity

CSD activates the meningeal pain fibres by an unknown mechanism

254
Q

Association of vasodilation and migraines

A

Role of vasodilation debated as unclear findings of imaging studies of meningeal and cortical vessels in humans during migraine attack, vasodilation not seen with spontaneous migraine

255
Q

What causes pain in a migraine

A

Trigeminal nerve - 3 divisions innervate the forehead and eye, cheek and lower face and jaw

Activated by facial touch, pain and temperature

TGVS (trigeminovascular system) pain likely caused by activation of this system. Meningeal and superficial cortical blood vessels innervated by TG sensory nerves
TG nerves project to trigeminal nucleus caudalis neurones onwards to thalamus and cortex

256
Q

Innervation of the opthalmic division of the trigeminal nerve

A

Innervates frontal and parietal cortex and meninges vascular beds

257
Q

International classification of headache disorders (migraine without aura)

A

A: at least 5 attacks fulfilling criteria B-D
B: headaches lasting 4-72h (when untreated or unsuccessfully treated)
C: at least 2 of following characteristics:
- unilateral location
- pulsating quality
- moderate or severe pain intensity
- aggravation by or causing avoidance of routine physical activity

D: nausea, vomiting, photophobia and phonophobia
E: not better accounted for by another ICHD-3 diagnosis

258
Q

International classification of headache disorders (Migraine with aura)

A

A: at least 2 attacks fulfilling criteria B and C
B: one or more of the following reversible aura symptoms
- visual, sensory, speech or language
- motor, brainstem, retinal
C: at least 3 of the following 6 characteristics:
- one aura symptom spreads gradually over >5 min
- 2 or more aura symptoms occur in succession
- each individual aura symptom lasts 5-6pm in
- one aura symptom is unilateral
- one aura symptom is positive
- aura is accompanied or followed within 60 min by headache

D: not better accounted for by another ICHD-3 diagnosis

259
Q

Benefits of migraine diaries

A

Encourage patients to record details of migraine attacks: help doctors make a firm diagnosis; recognise warning signs of an attack; identifying triggers; assessing whether acute or preventative medication is working

Record: when pain begins, frequency, symptoms, length of attacks, pain location, type of pain, aspects of daily life, menstrual cycle

260
Q

Trigger factors for migraines

A 
Stress (75%)
Refractory errors in glasses 
Chocolate, eggs, fruit 
Alcohol 
Oral contraceptive 
Time zone shifts 
Physical exertion
261
Q

Medication for mild and / or occasional attacks (migraine)

A

Acute treatment: analgesic / NSAIDs (paracetamol, ibuprofen, diclofenac)

Anti emetics for nausea
Combine with rest and sleep

262
Q

Step 2 of migraine medication therapy

A

Triptans (5HT 1b and 5HT 1d receptor agonists) causes constriction of cranial blood vessels and subsequent inhibition of neuropeptide release

Triptans available over the counter
Short acting poor CNS penetration
May cause chest pain due to coronary artery vasoconstriction so contraindicated in ischaemic heart disease
Will not prevent aura so take during headache attack

263
Q

Prophylactic (preventative) migraine therapy

A

B blockers (propranolol, metoprolol), calcium channel blockers, anti-epileptics or pre menstrual oestrogen can be effective

NICE recommends acupuncture or gabapentin in treatment resistant cases and Botox (stops localised nerves firing) option for adults with frequent chronic migraine

CGRP receptor antagonists and monoclonal antibodies showing promise in clinical trials

264
Q

How does IV injection CGRP provoke migraine attacks

A

Poor BBB permeability suggests peripheral mechanism

Dural application of CGRP causes vasodilation but not nociceptor activation

265
Q

Importance of CGRP in migraines

A

CGRP is released during a migraine attack
In trigeminal ganglia CGRP is expressed in the C fibres and receptor expressed by Ad-fibres
Trigeminal ganglia is central to trigeminovascular reflex which is triggered during migraine and leads to perception of pain

Trigeminal ganglia and dura not being the BBB, and are likely target of anti-CGRP antibodies

also CGRP receptor antagonists and anti CGRP antibodies are effective for migraine pain relief supporting hypothesis that CGRP has major role in migraine pathophysiology

266
Q

Association between migraines and COVID 19

A

25% present with migraine like features (no history)
Suggests activation of the trigeminovascular system

SARS COv2 protein has been found in the olfactory mucosa and bulbs, trigeminal branches and trigeminal ganglion

Brain vessel inflammation and cytokine responses may also contribute

267
Q

Define emesis

A

A protective reflex to expel ingested toxins evident in man and most meal feeding mammals and is associated with nausea

268
Q

Define nausea

A

Unpleasant sensation that immediately proceeds vomiting. A cold sweat, pallor, salivation, self absorption, loss of gastric tone, duodenal contractions and reflux of intestinal contents into the stomach often accompany nausea

269
Q

Vomiting centre inputs

A

The chemoreceptor trigger zone (CTZ) at the base of the 4th ventricle has multiple receptors (dopamine D2, 5HT3, opioid and acetylcholine), a neurokinin (substance P) is the major output transmitter

270
Q

Role of area postrema

A

(Not within the BBB), detects blood chemicals

271
Q

Role of vestibular system

A

Via the vestibulocochlear nerve; plays a major role in motion sickness and is rich is muscarinic cholinergic and histamine H1 receptors

272
Q

Role of the vagal nerve afferent in vomiting

A

Activated when the pharynx is irritated, leading to the gag reflex. Nucleus tracts solitarius has a high density of 5HT3 and NK1 receptors

Vagal and other gastrointestinal afferent responding to irritation of the GI mucosa by chemotherapy, radiation, distension or acute gastroenteritis via gut 5HT3 receptors

273
Q

Role of intracranial pressure receptors in vomiting

A

Mediating nausea after head injury or meningitis

274
Q

Best anti sickness treatment

A

Best single agent therapy is NK1 receptor antagonism (aprepitant)
Substance P is the major output transmitter from the vomiting centre; active against most cause s

275
Q

How to control chemotherapy induced emesis

A

Controlled by a combination of a corticosteroid and a dopamine antagonist but 5HT3 antagonists are effective

Multiple neurotransmission systems are involved - combination therapy shows additive benefits and clinical trials have shown a combination of a NK1 antagonist, a 5HT3 antagonist, and a corticosteroid give 85-90% protection against highly emetic chemotherapy induced emesis

276
Q

How to reduce severe nausea

A

More difficult to control even with the best anti emetics
Because it involves interactions with higher centres and is partly a learned response

A combination of anti-emetics and mild sedation (benzodiazepine) can be used to reduce severe nausea

277
Q

What is a polymorphism

A

A mutation that exists in the population and can be present in 1-50% of the population
Not a 1:1 correlation, people having one of the variants may have a higher risk of disease but people without the variant can also get the disease

278
Q

How to mutations and polymorphisms influence how people respond to pain killers

A

There are genes involved in how fast a drug gets into the bloodstream

Genes that influence how fast the drug breaks down in the body and how efficacious it is

And genes that determine side effects of drugs and all of these apply to pain medication

279
Q

What is man on fire syndrome

A

Erythromelaglia (very rare)
Putting on a sweater, putting on shoes, going into a warm room, mild exercise all feel like hot lava being poured into their bodies

280
Q

Mutation causing ‘man on fire’ syndrome

A

Mutations in the SCN9A gene
Encoding Nav1.7 which is involved in propagating electrical signals along nerves

The Nav1.7 channel is hypersensitive to stimulus in the man on fire syndrome

281
Q

What is the Nav 1.7 molecule responsible for

A

Responsible for transmitting the pain signal in the neurons specialised in pain (nociceptive neurons)- regulating pain transmission

It is a voltage gated sodium channel
Is expressed only in sensory and nociceptive neurons
Mediate the inward sodium current of excitable cells regulating the action potential generation and propagation in neurons

282
Q

Disadvantages of not being able to feel pain

A

People with congenital insensitivity to pain tend to die in childhood due to injuries or illnesses going unnoticed

  • damage in and around oral cavity due to biting tip of their tongue
  • Suffer fractures to bones
  • Have unnoticed infections
  • suffer burn injuries
283
Q

What does a mutation in the Zfhx2 gene result in

A

Lower levels of potassium voltage gated channels
People with this mutation have some pain sensitivity and don’t have the problems that people with total pain insensitivity

284
Q

What does reduced expression and activity of the FAAH enzyme result in

A

Painless injuries, frequent cuts and burns, heal quickly

285
Q

What os fatty acid amide hydrolyse (FAAH)

A

One of the enzymes in the endocannabinoid system (similar to cannabis but endogenous)
Endocannabinoids are molecules produced by our own cells that bind the same cell surface receptors targeted by the active component of marijuana

286
Q

3 basic components of the endocannabinoid system

A

Endocannabinoids
Cannabinoid receptors
Enzymes that break down Endocannabinoids (FAAH)

287
Q

What is the transient receptor potential vanilloid (TRPV1)

A

Non selective cation channel activated by exogenous and endogenous physical stimuli

Activation of TRPV1 leads to a painful burning sensation. TRPV1 are found mainly in nociceptive neurons of the peripheral nervous system but are also present in other tissues including the CNS
Involved in transmission and modulation of pain as well as integration of diverse painful stimuli

288
Q

Exogenous Activators of TRPV1

A

Heat greater than 43c
Capsaicin (compound in chilli peppers)
Allyl isothiocyanate (found in mustard and wasabi)

289
Q

Endogenous activators of TRPV1

A 
Low pH (acidic) 
N-arachidonoyl - dopamine (an endocannabinoid that acts as an agonist of the CB1 receptor) 
The endocannabinoid anandamide
290
Q

How do Endocannabinoids and phytocannabinoids result in lower pain even though they activate TRPV1

A

They are agonists of TRPV1 and activate TRPV1 but the receptors are saturated (flooded) (immune to further stimulation) so no longer transmit pain

291
Q

What happens to the drugs we take

A

Phase I metabolism:
Oxidation (cytochrome P450 enzyme), becomes more polar, chemically active drug

Phase II:
Conjugation with acetyl, methyl, glutathione and an ionisable group that increased water solubility and decreased drug activity

Renal excretion

292
Q

What are cytochrome P450s

A

A superfamily of enzymes
Involved in drug metabolism and bio activation
Carry out the degradation of xenobiotics in humans
Happens mainly in liver
P450s transform drugs into soluble molecules that can then be excreted

293
Q

Describe phase I metabolism of codeine

A

Codeine only has mild opioid properties while most of its analgesia and CNS depressant effects are based to its biotransformation to morphine, a reaction catalysed by CYP2D6 (a cytochrome P450)

294
Q

Therapeutic recommendation for tramadol in a ultrarapid metaboliser phenotype

A

Reduce dose by 30% and be alert to ADEs eg nausea, vomiting, constipation, respiratory depression, confusion, urinary retention or select alternative drug

295
Q

Therapeutic recommendation for intermediate metaboliser phenotype

A

Be alert to decreased efficacy. Consider dose increase. If response is still inadequate, select alternative drug (not oxycodone or codeine) be alert to symptoms of insufficient pain relief

296
Q

Therapeutic recommendation for poor metaboliser phenotype

A

Select alternative drug!!

Not oxycodone or codeine or be alert to symptoms of insufficient pain relief

297
Q

What is PCA

A

Patient controlled analgesia
Provides a small dose of (usually) morphine by a small button pressed by the patient as often as they need but not more than once within 5 mins

298
Q

Why is it necessary to consider the morphine dose prior to a joint replacement surgery

A

Likely that the patient will already be on some sort of slow release morphine so they will have become tolerant to opioid and will need additional analgesia for the surgery

299
Q

Describe the multimodal approach of managing pain after surgery

A

Using different analgesics that have different mechanisms of action:
Dose of paracetamol
NSAID
Opioid

Also use of a local anaesthetic: continuous infusion of a local anaesthetic into the area

300
Q

Describe step down analgesia

A

(After a few days of PCA)

Multimodal approach: paracetamol, NSAID, opioid changes from IV to oral

301
Q

What is a mu-opioid receptor antagonist

A 
A new class of medication 
Used to specifically treat opioid caused constipation work by binding to opioid receptors in the gut and so preventing the GI side effects

Allows the opioid agonist eg morphine to get into systemic circulation eg brain which is where it is needed to have its effect

302
Q

What is the PHQ-9

A

Patient health questionnaire
The depression model which scores each of the 9 DSM -IV criteria as 0 (not at all) to 3 (nearly every day)

Score of 5 = mild
10 = moderate
15 = moderately severe
20 = severe depression

Med 4 (12 decks)

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