lecture 25: an introduction to pain Flashcards
(58 cards)
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
What is the cardiovascular response?
* pain pathways activate the CNS
* PAG - cardiovascular centre interaction
* hypertension
* tachycardia
* vasoconstriction
26
What is integrated neural processing in the brainstem?
* 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
What is the brain response to noxious heat?
* used functional magentic resonance imaging
* specific pain areas that light up
* can use this technology to identify whether drugs have effect
28
What is the effect of lamotrigine on facial neuropathic pain?
* 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
What is chronic pain?
* 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
What is pain as a health issue?
* 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
What are mutations of the sodium channel Nav 1.7?
* 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
What are genetic factors in pain?
* 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
What is the stargazer gene?
* 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
What are genetic polymorphisms in codeine metabolism?
* the liver enzyme CYP2D6 - deficiency
* inability to convert codeine to morphine
* slow acetylators - ineffective analgesia
35
What is pain management?
* a fundamental human right
* declaration of montreal, 2010
36
What is opium?
* 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
What is analgesic medication?
* 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
Who is credited with the isolation of morphine?
* Frederick Serturner 1804
*
39
What are side effects of opioids?
* ventilatory depression
* drowsiness and sedation
* postoperative nausea and vomiting
* pruritis
* urinary retention
* ileus, constipation
* delay of hospital discharge
40
What are pain management strategies?
* 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
What is multimodal pain management?
* target multiple receptors, peripheral and central
* multiple drug classes
* synergistic analgesic effect
* reduce opioid requirement
42
What are the multiple targets?
* 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
What was the first local anaesthetic?
* cocaine
* sigmund freud, karl koller, william halstead
44
What is general anaesthesia?
* pain perception and transmission removed
* enables modern surgical practice
* anaesthesia - loss of sensation
* analgesia - reduction of pain
45
What are limitations of analgesic drugs?
* 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
What is pain related to a heart attack?
* 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
What is pain in a child with a broken leg?
* distressed child
* immediate care by paramedics
* intranasal opioid → fentanyl
* rapid analgesia
48
What would shoulder reconstruction analgesia be?
* paracetomol
* NSAIDs
* synthetic codeine
* nerve block with local anaesthetic
* morphine if requried
49
What is analgesia for a migraine?
* analgesics: aspirin, ibubrufen
* vasoconstrictors:
* ergotamine (Ergots)
* 5-HT agonist (Triptans)
* CGRP antagonists (gepants)
50
How is labour pain treated?
* 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
What is spinal anaesthesia?
* target dorsal horn
* injection into spinal canal
* surgical anaesthesia to lower body
* amide local anaesthetic, opioids used
* first spinal anaesthesia - Augustus Bier 1898
52
What is epidural anaesthesia?
* block nerves to uterus
* local anaesthetic and opioid injected into epidural space
53
What is molecular pharmacology research?
* animal pain models
* role of microglial activation
* novel analgesics
* NMDA antagonists
* TRPV antagonists
* addiction
54
What was the philosophical view of pain?
* "pain, like pleasure is a passion of the soul" - one of the senses that warned us from things that would cause us harm
55
What did Descartes describe?
* 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
What happens when there is an injury e.g. car crash?
* immediate care
57
What is the benefit of military combat?
* 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
How has administration of morphine changed?
* rynd 1845: first injection of morphine , very rudimentary
* 1995: patient controlled analgesia
