lecture 25: an introduction to pain Flashcards
1
Q
What concepts to understand about pain?
A
- pain is a complex emotional response
- nerve or tissue damage can lead to pathological pain
- molecular pharmacology: a framework for patient care
- current approaches and limitations of pain management
2
Q
What are different types of pain?
A
- nociceptive: brief injury → neuron → CNS → brief pain (phase 1)
- inflammatory: inflammation → complex circuits → persisting pain (phase 2)
- neuropathic: not normally painful stimulus → abnormal pain response (phase 3)
3
Q
What makes pain complex?
A
- an individual experience influenced by culture, previous pain events, beliefs, mood, and ability to cope…
- IASP definition:
- an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage…
- the walking wounded:
- it is not the injury per se that determines the pain, but also the meaning of the injury (Henry Beecher 1945)
4
Q
What is acute nociceptive pain?
A
- immediate, short duration, localised
- nervous system is activated
- relay, amplification, attenuation
- dynamic feedback within system
- reflex withdrawal response
5
Q
How is pain transmitted?
A
- inflammatory reaction from injury
- receptor activation
- neural conduction
- spinal cord, brain modulation
- perception of pain
6
Q
What was the neuron doctrine in 1894?
A
- neuron: unit of nervous system function
- neurons communicate via the dendrites
- separated by a gap - “the synapse”
7
Q
What is nociception?
A
- detection of harm
- the neural encoding, processing of painful stimuli
- nociceptors: free nerve endings in skin, bone
- activation: mechanical, thermal, chemical stimuli
- triggers reflex withdrawal
- associated autonomic responses and pain
8
Q
What is receptor activation?
A
- transient potential receptor subunit- ion channel pore (TRPV1)
- responsive to acid (H+), Capsaicin (in chili), temperature
- general nociceptors that respond to a variety of stimuli
- ‘pain receptors’ as opposed to overreactive touch receptors
- also other specific receptors that can respond to stimuli
- ADI receptors (acidity)
- ENaC/DEG receptors (mechanical stimuli)
9
Q
What is tissue response to acute injury?
A
- cell lysis: acid H+, ATP release
- inflammatory response with COX2 induction
- release of multiple mediators:
- bradykinin, seretonin, histamine, prostaglandins, cytokines
- nociceptors activated: reflex axonal release of substance P, CGRP
- nociceptors sensitised: thresholds reduced
- localised pain hypersensitivty occurs
10
Q
What is receptor activation in tissue injury?
A
- nociceptor activated by:
- histamine, NGF
- bradykinin
- 5-HT
- prostaglandin
- ATP
- H+
- releases substance P → histamine and NGF production
- releases CGRP, substance P → oedema
- message goes up to dorsal horn of spinal cord
- Asprin/NSAIDs target production of prostaglandin
11
Q
What is peripheral sensitisation?
A
- early inflammation: amplification via receptor threshold and latency reduction
- long-term changes: transcription mediated by cytokines and growth factors increase production of receptors, ion channels and neurotransmitters. exaggerated responses occur
12
Q
What are hyperalgesia and allodynia?
A
- the normal injury response is to develop hypersensitivity at injury site
- hyperalgesia: “left-shift of curve” e.g. pain on showering when sunburnt
- allodynia: “pathological response” e.g. excruciating pain with light touch
13
Q
What is transmission of action potential?
A
- synaptic transmission
- sir john eccles 1943 : giant squid axon
- axonal transmission to spinal cord
- cell body in dorsal root ganglion
- synapse in spinal cord dorsal horn
- spatial arrangement or dermatomes
- relayed to specific sites within brain
14
Q
What are the different classes of nerve fibres?
A
Adelta and C fibres: 70 - 90% of peripheral nerve
- Adelta
- fast sharp, acute, pricking localised pain
- mechanical and thermal pain
- C fibres
- slow pain
- aching, throbbing, burning pain
- chemical pain
classification of nerve fivres: type, myelination, diameter, Vc (m/sec), function
- Aalpha
- heavy
- 12-20µm
- 70 - 120
- motor and proprioception
- Abeta
- moderate
- 5-12µm
- 30-70
- touch and pressure
- Agamma
- moderately
- 3-6µm
- 15-30
- motor to muscle spindles
- Adelta
- lightly
- 2-5 µm
- 12-30
- pain, temp, and touch
- B
- lightly
- 1-3µm
- 3-15
- preganglionic autonomic
- C
- none
- 0.4-1.2 µm
- 0.5-2
- pain and reflex responses
- none
- 0.3-1.3µm
- 0.7 - 2.3
- postganglionic sympathetic
15
Q
What is neural integration in the spinal cord?
A
- synaptic network: afferents, interneurons, microglia
- multiple neurotransmitters
- GABA, glycine, glutamate, Sub P, CRGP
- spinal attenuation of pain signals - dampen pain response
- a lot of neural integration
- interconnected
- drugs act as agonists or antagonists depending on the neurons - re
16
Q
What is the dorsal root horn?
A
- excitatory neurotransmitters: glutamate, aspartate
- inhibitory interneurons: GABAergic
- AMPA low threshold: rapid Na+, K+ flux
- NMDA high threshold
- voltage-gated Ca2+ channel
- AMPA and NMDA key receptors identified in pain transmission
17
Q
What is NMDA receptor activation?
A
- protracted nociception
- Mg2+ displaced
- cellular remodelling
- opioid resistance
- c-fos gene expression “wind up”
- ketamine acts to block it → key analgesic
- ioinic channel with Mg+ plug
- doesn’t get activated until you have a lot of pain transmission
18
Q
What is the gate control theory?
A
- endorphins inhibit pain
- vibration stimuli (Abeta) can attenuate or “gate” painful stimuli
- as pain transmission comes into spinal cord → interneuron has inhibitory effect → i.e. gating information cming
- endogenous opioid called endorphins
- key component to modulation of pain
- A fibres also transmit mechanical stimulation are initimately associated with pain fibres
- send mechanostimulation to fuzz out pain stimulation
19
Q
What is the opioid receptor?
A
- opioids: primary site of action spinal cord
- opioids act pre-synaptically to decrease neurotransmitter release
- post-synaptically to hyperpolarise dorsal root neurons
- discovered in 1973
20
Q
What is the rapidly conducting feedback loop in the spine?
A
- between ascending and descending pathways
- projections between dorsal horn and RVM
- descending noradrenergic and 5-HT3 fibres
- inhibition of spinal dorsal horn
- can dampen incoming signals
21
Q
What can treat central analgesia?
A
- tricyclic antidepressants
- morphine
- amitriptyline
- NS and 5-HT reuptake transporter inhibitor
- aspirin
- amitryptilline:aspirin potency 70:1
- not reversed by naloxone
22
Q
What is a spinal cord target for neuropathic pain?
A
- N type voltage gated calcium channel receptor
- gabapentin (anticonvulsant) binds to a2delta subunit, zirconotide (w-conotoxin)
23
Q
Where do pain pathways project?
A
- project to superior colliculus and periacqueductal grey matter (PAG)
- stimulation of PAG causes profound analgesia
- endogenous opioids activate this area
- basis for deep brain stimulation for intractable pain
24
Q
What are opiod peptide neurons in the rodent peptides neurons?
A
- rat brain
- PAG centre
- relays to a number of other areas
- endorphins, enkephalines, dynorphins
- links to mesolimbic dopaminergic system
25
Q
What is the cardiovascular response?
A
- pain pathways activate the CNS
- PAG - cardiovascular centre interaction
- hypertension
- tachycardia
- vasoconstriction
26
Q
What is integrated neural processing in the brainstem?
A
- orexin, cannabinoids?
- complex neuro transmitters
- naratriptan: 5-HT 1b/1d agonist
- quite effective in chronic migrane
- discovery that these circuits even other neuro transmitters
- drugs that can stimulate are under current study
- may act at higher levels to block pain transmission
27
Q
What is the brain response to noxious heat?
A
- used functional magentic resonance imaging
- specific pain areas that light up
- can use this technology to identify whether drugs have effect
28
Q
What is the effect of lamotrigine on facial neuropathic pain?
A
- lamotrine: antiepileptic drug
- chronic facial pain
- high light up
- when drug is given they have reduced activation
- attenuating the pain information going into the brain
- powerful tool to look at the effect of drugs on the brain
29
Q
What is chronic pain?
A
- some individuals have an excessive pain response, leading to abnormal hyperexcitability and structural remodelling
- phenotypic change
- pain signal embedded within nervous system
- 15-20% can develop chronic neuropathic pain after traumating injury
- pain that continues to be present more than three months after surgery or an injury or from various disease or other causes
- neuropathic “burning pain”
- depression
- opioid dependance
- e.g. post herpetic neuralgia “shingles”
- neuralgia caused by varicella zoster virus: resides in dorsal root neuron
- phantom limb pain after amputation
30
Q
What is pain as a health issue?
A
- pain is one of the biggest health issues in Australia today – every bit as a big as cancer, AIDS and coronary heart disease. Yet it remains one of the most neglected areas of health-care” -
- professor michael cousins, chair national pain strategy
31
Q
What are mutations of the sodium channel Nav 1.7?
A
- one of the key channels that opens up when you have axonal transmission
- genetic link that causes either chronic pain or pain insensitivity
- if absent → no pain
32
Q
What are genetic factors in pain?
A
- pain genes can determine pain response
- stargazing gene
- dopamine metabolism (COMT)
- susceptibility for neuropathic pain?
- genetic pain syndromes:
- familial hemiplegic migraine
- primary erythermaliga (PE)
- paroxysmal extreme pain disorder (PEPD)
- channelopathy-associated insensitivity to pain (CIP)
- drug metabolism
33
Q
What is the stargazer gene?
A
- CACNG2
- mutation in stargazin protein (36kD)
- VDCC, AMPA receptor gamma subunit defect
- absence seizures and ataxia in mice
- susceptibility to neuropathic pain
- human CACNG2 polymorphism (chr22) associated with chronic pain
34
Q
What are genetic polymorphisms in codeine metabolism?
A
- the liver enzyme CYP2D6 - deficiency
- inability to convert codeine to morphine
- slow acetylators - ineffective analgesia
35
Q
What is pain management?
A
- a fundamental human right
- declaration of montreal, 2010
36
Q
What is opium?
A
- among the remedies which it has pleased Almight God to give to man to relieve his sufferings, none is so universal and so efficacious as opium
- Thomas Sydenham 1624 - 1689
37
Q
What is analgesic medication?
A
- opioids (mainstay for severe to moderate pain)
- paracetamol
- aspirin
- non steroidal anti-inflammatory drugs (ibuprofen)
- adjuvants
- antidepressants - tricyclic antidepressants
- anticonvulsants - gabapentanoids
- membrane stabilisers - lignocaine
- clonidine, calcitonin, biphoshponates
- NMDA antagonists - ketamine, magnesium, cannabinoids….
38
Q
Who is credited with the isolation of morphine?
A
- Frederick Serturner 1804
*
39
Q
What are side effects of opioids?
A
- ventilatory depression
- drowsiness and sedation
- postoperative nausea and vomiting
- pruritis
- urinary retention
- ileus, constipation
- delay of hospital discharge
40
Q
What are pain management strategies?
A
- multimodal analgesia: use of smaller doses of opioids in combination with non-opioids in combination with non-opioid analgesic drugs. target pain transmission at multiple sites
- pre-emptive analgesia: analgesia prior to injury (i.e. surgery)
- theory: attenuate injury and the neuroplastic response (however in practice limited effect)
- target nerve transmission (regional anaesthesia)
- remove cognition - general anaesthesia
41
Q
What is multimodal pain management?
A
- target multiple receptors, peripheral and central
- multiple drug classes
- synergistic analgesic effect
- reduce opioid requirement
42
Q
What are the multiple targets?
A
- if we use multiple targets reduces opioid requirement
- NSAIDs affect inflamm response in periphery
- opioids have peripheral and spinal cord effect
- co analgesic drugs in spinal cord
- lignocaine can block axonal transmission → local anaesthetic
43
Q
What was the first local anaesthetic?
A
- cocaine
- sigmund freud, karl koller, william halstead
44
Q
What is general anaesthesia?
A
- pain perception and transmission removed
- enables modern surgical practice
- anaesthesia - loss of sensation
- analgesia - reduction of pain
45
Q
What are limitations of analgesic drugs?
A
- individual response
- inadequate pain control
- administration
- dependance, addiction
- multiple side effects
- e.g. phenacetin: analgesic nephropathy
- Bex tablets
- caused kidney damage
- closely related to paracetomol
46
Q
What is pain related to a heart attack?
A
- crushing severe pain “visceral pain”
- radiation to arm and neck termed “referred pain”
- aspirin en route to hospital
- morphine to relieve distress
- glyceryltrinitrate, thrombolysis
47
Q
What is pain in a child with a broken leg?
A
- distressed child
- immediate care by paramedics
- intranasal opioid → fentanyl
- rapid analgesia
48
Q
What would shoulder reconstruction analgesia be?
A
- paracetomol
- NSAIDs
- synthetic codeine
- nerve block with local anaesthetic
- morphine if requried
49
Q
What is analgesia for a migraine?
A
- analgesics: aspirin, ibubrufen
- vasoconstrictors:
- ergotamine (Ergots)
- 5-HT agonist (Triptans)
- CGRP antagonists (gepants)
50
Q
How is labour pain treated?
A
- inhalational nitrous oxide
- opioids can cause foetal respiratory depression - careful use in mother
- uterine contractions painful
- pain triggers birth (oxytocin)
- inhaled nitric oxide/oxygen
- epidural anaesthesia
51
Q
What is spinal anaesthesia?
A
- target dorsal horn
- injection into spinal canal
- surgical anaesthesia to lower body
- amide local anaesthetic, opioids used
- first spinal anaesthesia - Augustus Bier 1898
52
Q
What is epidural anaesthesia?
A
- block nerves to uterus
- local anaesthetic and opioid injected into epidural space
53
Q
What is molecular pharmacology research?
A
- animal pain models
- role of microglial activation
- novel analgesics
- NMDA antagonists
- TRPV antagonists
- addiction
54
Q
What was the philosophical view of pain?
A
- “pain, like pleasure is a passion of the soul” - one of the senses that warned us from things that would cause us harm
55
Q
What did Descartes describe?
A
- one of the first physiological views
- 1644: Minute particles of fire, travel with great velocity… pull on a thread… to strike a bell..”
- pain experience requires:
- neural processing
- perception
- don’t need to have physical tissue injury to have pain
56
Q
What happens when there is an injury e.g. car crash?
A
- immediate care
57
Q
What is the benefit of military combat?
A
- a lot of medical knowledge comes from combat trauma
- responding to challenges in modern combat casualty care: innovative use of advanced regional anaesthesia
- lost arms
- supraclavicular continuous peripheral nerve block in a wounded soldier: when ultrasound is the only option
- i.v. under each clavicle producing alleviation of suffering
58
Q
How has administration of morphine changed?
A
- rynd 1845: first injection of morphine , very rudimentary
- 1995: patient controlled analgesia
