Pain Flashcards

(73 cards)

1
Q

What are the 4 types of pain?

A

 Acute: Post-operative, trauma, medical emergencies, sickle cell crisis
duration less than 3 months

 Chronic Back pain, neck pain, vascular, neuropathic pain, headaches, phantom limb pain, complex regional pain syndrome,

 visceral - usually trauma or repeated infections

 Cancer pain

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2
Q

What are the 7 classes of pain?

A

 Nociceptive - tissue damage - nociceptors

 Inflammatory - inflammatory mediators - Peripheral and central sensitization

 Neuropathic - nerve injury - Including ectopic activity, neuroimmune int. central sensitization

 Mixed

 Visceral

 Sympathetically maintained

 Psychological

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3
Q

See diagram in intro lecture on first page for the pathogens is of pain

A

-

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4
Q

Is the PAG important in pain pathways?

A

Very

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5
Q

Page 2 of intro lecture for mood and state of mind diagram

A

-

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6
Q

Summarise how pain is managed?

A

 Understanding and explaining the mechanisms of pain

 Diagnosis of the pain

 Investigations

 Advice about managing pain on a daily basis

 Pacing of activities, goal setting, relaxation, doing something for enjoyment, coping with bad days

 Simple pharmacotherapy

 Physiotherapy

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7
Q

Summarise specialised pain management

A

 TENS

 Acupuncture

 Physical therapies

 Psychological therapies

 Pharmacotherapies
 Tricyclic antidepressants, gabapentinoids,
 Analgesics, opioids
 Topical agents
 Combinations
 Injections
 Trigger point, nerve blocks, epidurals, facet joint injections

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8
Q

Can we test for pain?

A

No

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9
Q

Read notes on final page of intro lecture

A

-

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10
Q

What is the intensity theory of pain?

A

Intensity theory (pain not a unique modality but emotional state produced by stronger than normal stimuli)

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11
Q

What is today’s pain definition?

A

An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage

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12
Q

How does nociception work?

A

 Noxious stimuli detected by damage-sensing neurons, nociceptors whose specialized free nerve endings are in skin, muscle and viscera and cell bodies in the dorsal root ganglia (DRG);

 They respond to multiple types of stimuli (high mechanical pressure, high/low temperatures, chemicals) which will only generate electrical activity if they are over a certain threshold.

 Receptors at sensory terminals convert such stimuli into electrical activity (e.g. TRPV1): the larger the change in voltage at the terminal, due to influx of Na+ and Ca2+ through receptors forming ion channels, the greater the number of action potentials generated.

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13
Q

What are the 4 main modalities of nociception and what type of fibres carry them?

A

A-Delta:
Mechano nociceptors:
- Tissue damaging stimuli.
- Pressure

C (most common)
Thermal nociceptors 
-(N.B. 10% of C-fibres signal innocuous thermal information)  
- > 45 degrees
Chemically sensitive Nociceptors 
- (Mechanically insensitive) 
- Algogens, pH irritants
Polymodal nociceptors (N.B. Most abundant) 
- Thermal, mechanical, chemical
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14
Q

Where do pain pain pathways from the periphery end up?

A

Termination points of sensory neurons in the spinal cord. Most neurons involved in pain signals terminate in laminae I and II at the top, or dorsal end of spinal cord contacting cells transmitting information in regions of brain involved with the responses to pain and its perception

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15
Q

What are the main 2 ascending pain pathways?

A

Spinothalamic: Discriminative aspect of nociception. Fast pain

Spinoreticular: Responsible for arousal and affective (unpleasantness) aspects. Dull pain

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16
Q

Where is pain processed in the brain? (L02)

A

 Pain matrix (areas in the brain responsible for processing nociceptive inputs and generating the pain experience; for more details see Prof Thompson’s lecture)

 Pain matrix revisited (see papers from G Iannetti, UCL)

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17
Q

What is the Gate Control theory?

A

Melzack and Wall suggested that small interneurons in the dorsal horn act as a gate which controls the amount of excitation of the transmission cells.

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18
Q

What factors regulate the gate control mechanism?

A
  1. Amount of activity in pain fibres
  2. Amount of activity in other peripheral fibres (activation of mechanoreceptors Aß fibres)
  3. Messages descending from brain, e.g. emotions (anxiety, relaxation), mental conditions (boredom, learning)
    Thus: psychological factors influence pain perception by regulating the gate mechanism
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19
Q

What do you know about the PAG?

A

PAG: periaqueductal gray, rich in opioid receptors and enkephalins(electrical stimulation of PAG produces analgesia); PAG neurons’ axons end on serotoninergic neurons in the medulla

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20
Q

What do you know about the RVM?

A

RVM: rostro ventromedial medulla: important area both for inhibition and facilitation of nociceptive processing; bidirectional central control of nociception

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21
Q

Pain is a subjective experience and has what three components?

A

sensory-discriminative:
- sense of intensity, location and duration
affective-motivational:
- unpleasantness and desire to escape it
cognitive component:
- involving judgments, beliefs, memories, perception of environment and patient’s own history

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22
Q

Are pain pathways rigidly hardwired?

A

 Neural substrates that mediate pain are plastic, i.e., modifiable depending on use or modulatory influences

 To note: the central role of the dorsal horn which integrates peripheral, local and descending input. Change in excitability at this level will control output to the brain

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23
Q

How can we divide up types of pain?

A

Nociceptive

Clinical

  • inflammatory
  • neuropathic
  • functional
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24
Q

What are the 2 forms of pain hypersensitivity?

A

◦ Thresholds are lowered so that stimuli that would normally not produce pain now begin to, so called ALLODYNIA

◦ Responsiveness is increased, so that noxious stimuli produce an exaggerated and prolonged pain or HYPERALGESIA

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25
What is peripheral sensitisation to pain and what causes it?
Reduction in threshold and increase in responsiveness of peripheral ends of nociceptors. Sensitization arises due to the action of inflammatory chemicals (ATP, PGE2, NGF)
26
What is central sensitisation to pain and how is it caused?
an increase in the excitability of neurons within the central nervous system, triggered by a burst of activity in nociceptors, which alters the strength of synaptic connections (activity-dependent synaptic plasticity) between nociceptors and spinal cord neurons
27
What does a SCN9A channelopathy cause?
- congenital inability to experience pain - SCN9A codes for an α-subunit of a voltage-gated Na channel, Nav1.7, strongly expressed in nociceptive neurons (autosomal-recessive trait to human chromosome 2q24.3). In three consanguineous families from Pakistan, this gene presents homozygous non-sense mutations which result in total absence of nociception
28
What's the difference between A-Beta and A-delta and C fibres
A Beta - Big - Sensitive mechanoreceptors Ie. to coral columns A Delta/C - Small -Thermoreceptors, Nociceptors Ie. to spinothalamic tract Aδ: large (2-5 mm), fast conducting, myelinated C: small (0.4-1.2 mm), slower conducting, non-myelinated fibres (Stub toe etc - sharp pain and then throbbing - a delta and then c fibres)
29
What part of the brain is responsible for pain?
Area of the brain activated by the nociceptors - was said to be the primary sensory cortex - now use fMRI - pain matrix - cant tell you which area is responsible for the actual perception of pain But pendulum is swinging back - maybe pain is in old brain parts - maybe posterior insula
30
Congenital Insensitivity to Pain (with Anhidrosis) (CIPA, HSN IV/V)?
 Insensitivity to acute tissue damaging stimuli  No pain with chronic injury  No sweating  Variable cognitive impairment  Recurrent episodic fever  Normal touch, motor function, special senses TrkA mutations in Congenital Insensitivity to Pain and Anhidrosis Most patients with HSN IV show a loss of small diameter sensory neurones in peripheral nerves Congenital insensitivity to pain maps to SCN9A (Nav1.7) in some families (Can sweat with HSN but not smell?)
31
Which neurones are lost in trkA or NGF null mutant mice and what is NGF important for?
Most small sensory neurones NGF promotes the survival of developing symapthetic and sensory neurones NGF is a pain mediator in the adult
32
Why is there so much interest in trying to block Nav 1.7?
If you could block this sodium channel then you would have blocking from all this pain Mice with a deletion of Nav 1.7 in nociceptors show no inflammatory pain behaviour Point Mutations in SCN9A (Nav1.7) lead to primary Erythromelalgia and Paroxysmal Extreme Pain Disorder
33
Genetic influences on pain from twin studies?
More correlation in monozygotic than dizygotic twins
34
What mediates and causes dysfunctional pain?
Not known
35
What factors activate peripheral sensitisation mechanisms?
Heat/H+/Capsaicin Mechanical H+ ATP PGE2 Bradykinin NGF
36
What are the mechanisms of peripheral sensitisation?
1. Receptor modulation - phosphorylation of receptor 2. Channel modulation - cAMP - PKA - PLC - DAG + IP3 - PKA + Ca2+ in 3. Gene expression - Ras - MEK - ERK1,2
37
How does central sensitisation work?
Altered CNS processing 1. Central sensitization 2. Anatomical reorganization 3. Reduced inhibition 4. Glial activation Repeated nociceptor activation facilitates spinal processing of nociceptor activity
38
What is neuropathic pain and what are its causes?
* Infectious e.g. HIV, Post-herpetic neuralgia * Metabolic/Nutritional e.g. Diabetic, alcoholic neuropathy * Neurotoxity e.g. Cisplatin, taxol, vincristine * Truamatic e.g. entrapment, transection, surgical damage * Central lesions e.g. spinal cord injury, stroke
39
What are the mechanisms of neuropathic pain?
Retrograde transport of trophic factors. Injury factors Altered gene expression Ectopic activity Iron channel expression Altered CNS Processing: Central glia contribute to Chronic pain. (Altered CNS processing 1. Central sensitization 2. Anatomical reorganization 3. Reduced inhibition 4. Microglial activation)
40
What does electrical stimulation of the periaqueductal gray or several medullary sites show?
Endogenous opioids involved in pain control since, in animals, electrical stimulation of the periaqueductal gray or several medullary sites can produce antinociception. This effect is partially blocked by naloxone.
41
What are the different types of analgesic drugs and what can they be used for?
1. Local anaesthetics - lidocaine 2. Non-steroidal anti-inflammatory drugs - (NSAIDs) aspirin, ibuprofen, paracetamol 3. Opioids morphine, codeine 4. Miscellaneous drugs (To prevent what is causing the pain stimulation) -nitrates: angina - triptans: migraine carbamazepine: trigeminal neuralgia tri-cyclic antidepressants (TCA): neuropathic pain
42
Are opioids effective in the treatment of neuropathic pain?
Long duration - opioids are not good at neuropathic pain treatment - tricyclics etc - used more
43
Which analgesics do acute and chronic pain respond well to?
acute pain responds well to all three types of analgesic chronic pain usually defined as pain of more than 3-6 months duration 1. due to chronic nociceptive activation responds well to opioids 2. neuropathic pain due to adaptive changes responds poorly to opioids
44
How do local anaesthetics work?
Local anaesthetics are Na channel blockers Weak bases. At pH 7.4, fairly lipid soluble drugs and the non-ionised form can cross the neuronal membrane Inside the neuron, local anaesthetic dissociates and the free base binds to Na channel Local anaesthetics have highest affinity for inactivated or closed state of the Na channel, they slow the rate at which channels revert to resting state Local anaesthetics block action potential generation by decreasing the number of Na channels available to open They have greatest effect in rapidly firing neurons (See page 6 of control of pain lecture)
45
How are local anaesthetics administered?
Local anaesthetics are given topically or infused near to the nerve to be blocked Can be administered locally to spinal cord to produce regional block - epidurally - intrathecally ie during child birth (spinal block)
46
What are NSAIDs and what are their effects?
Non-Steroidal Anti-inflammatory Drugs (NSAIDs) NSAIDs inhibit cyclo-oxygenase (COX) COX produces eicosanoids eg prostaglandin E2 (PGE2) from arachidonic acid NSAIDs have three effects: - anti-inflammatory - anti-pyretic ie anti-fever analgesic
47
How are NSAIDs antipyretic?
Prevent prostaglandins to prevent the resetting of the temperature thermostat in the hypothalamus
48
How do NSAIDs produce analgesia?
Prostaglandins do not stimulate nociceptors - sensitise nociceptors to other mediators NSAIDs produce analgesia by preventing this sensitization NSAIDs are peripherally active analgesics
49
What are the main NSAIDs used as analgesics?
aspirin - irrevesible inhibitor ibuprofen - reversible inhibitor paracetamol - indirect inhibitor of COX often combined with a weak opioid eg codeine in OTC medicines (No anti inflammatory action - mops up intermediates needed for activate of COX and it can be converted to canabanoids which cause analgesia at there receptors )
50
What are opioid analgesics and what are the types of opioid receptor?
Opioid analgesics (eg morphine) produce analgesia by activation of the endogenous opioid system. Morphine acts on specific receptors termed opioid receptors. Opioid receptors defines by stereospecific blockade by NALOXONE Three types of opioid receptor μ, δ, κ Most of the clinically used opioids act on the μ receptor
51
What do you know about the Mu opioid receptors?
μ - Mu - morphine - increase K+ conductance - inhibit adenylate cyclase - inhibit voltage gated Ca2+ channels
52
What do you know about the Delta opioid receptors?
δ - Delta - [Leu5]enkephalin - [Met5]enkephalin - increase K+ conductance - inhibit adenylate cyclase - inhibit voltage gated Ca2+ channels
53
What do you know about the Kappa opioid receptors?
κ - Kappa - Dynorphin - increase K+ conductance - inhibit adenylate cyclase - inhibit voltage gated Ca2+ channels
54
Where a most opioid receptors located and how would you broadly describe their mechanism of action?
Activation of opioid receptors cause neuronal hyperpolarization. Most opioid receptors are located on nerve terminals and inhibit neurotransmitter release
55
What are endogenous opioid peptides?
Endogenous ligands for opioid receptors are peptides First ones isolated were: [Leu5]enkephalin Tyr-Gly-Gly-Phe-Leu [Met5]enkephalin Tyr-Gly-Gly-Phe-Met Proenkephalin - [Leu5]enkephalin Tyr-Gly-Gly-Phe-Leu - [Met5]enkephalin Tyr-Gly-Gly-Phe-Met Prodynorphin gives peptides containing Tyr-Gly-Gly-Phe-Leu Dynorphin A 17 amino acids Dynorphin B 13 amino acids Large molecular weight precursors identified Three families of opioid peptides endorphins, enkephalins, dynorphins All mammalian opioid peptides have Tyr-Gly-Gly-Phe-Met or Tyr-Gly-Gly-Phe-Leu as their first 5 amino acids
56
What does Pro-opiomelanocortin (POMC) give rise to?
- β-endorphin 31 amino acids with Tyr-Gly-Gly-Phe-Met. - melanocyte stimulating hormone (MSH) - adrenocorticotropic hormone (ACTH)
57
What areas of the CNS have high levels of opioid receptors?
High concentrations throughout the brain. Areas involved in pain control have high levels of receptors and peptides periaqueductal gray (PAG) nucleus raphe magnus (NRM) nucleus reticularis paragigantocellularis (NRPG) (DLF dorsolateral funiculus LC locus coeruleus) dorsal horn of the spinal cord especially lamina II (substantia gelatinosa
58
What is the effects do opioids on the ascending pain pathways?
If one records firing of dorsal horn neurones, opioids inhibit firing and stop transduction of the signal to the brain. Inhibit release of glutamate and substance P from primary afferents
59
What effect of opioids on the brain that inhibit pain pathways do you know?
Activation of PAG and NRM by morphine causes increase firing of descending pathway to dorsal horn. This involves mainly serotonergic neurons and depletion of 5HT or 5HT antagonists decrease anti-nociceptive effect of morphine. Effect in PAG and NRM is due to inhibition of release of GABA from local interneurons. This leads to dis-inhibition of the descending serotonergic pathway which decreases transmission of nociceptive information through the dorsal horn
60
In the gate control pain theory what are the inhibitory factors?
Descending inhibitory pathways | Mechanoreceptors (A-Beta)
61
What are the effects of morphine?
Morphine is a selective agonist at μ-receptors. ANALGESIA All kinds of acute & severe pain Reduces sensation of pain (nociception) and the emotional response EUPHORIA Depends on circumstances, varies with different opioids RESPIRATORY DEPRESSION Selective depression of sensitivity to PCO2 MIOSIS Pin-point pupils, diagnostic for opioid overdose EMESIS Due to stimulation of chemical trigger zone in area postrema CONSTIPATION Increase in gut tone, decreased gut transit, due to high level of receptors on enteric neurons Kaolin and morphine used to treat diarrhoea Loperamide (Imodium) COUGH SUPPRESSION All opioids suppress cough reflex, not an opioid effect, possibly due to stimulation of dextromethorphan receptor codeine more potent than morphine most cough mixtures contain codeine CONTRACTS GALL BLADDER AND CONSTRICTS BILIARY SPHINCTER do not use in biliary colic HYPOTENSION TOLERANCE Decrease response with repeated administration High analgesia, emesis Low miosis, constipation DEPENDENCE Psychological dependence - drug seeking behaviour Physical dependence - withdrawal syndrome
62
How can opioids be given?
``` ORALLY (po) INTRAVENOUSLY (iv) INTRAMUSCULARLY (im) INTRATHECALLY (it) EPIDURALLY SUBLINGUALLY buprenorphine TRANSDERMALLY fentanyl ```
63
What strong opioids do you know?
μ-agonists DIAMORPHINE (diacetylmorphine) – more lipophilic and more potent than morphine BUPRENORPHINE – very lipophilic, given sublingually, partial agonist OXYCODONE – cancer pain FENTANYL - very lipophilic, very short acting, used as part of pre-medication for surgery. Fentanyl patches used for long term relief in cancer patients. PETHIDINE – labour, minor surgery. No pin-point pupils (Morphine in childbirth - foetus cant cope. But this is metabolised by MAO so it is ok.) METHADONE – long acting, once daily dosing, used for maintenance of addicts
64
What weak opioids do you know?
``` CODEINE DIHYDROCODEINE DEXTROPROPOXYPHENE - u often combined with a NSAID ``` OTHERS TRAMADOL & TAPENTADOL opioid and non-opioid effects (blocks noradrenaline uptake (+seratonin) ) Less respiratory depression
65
What antagonists to opioids do you know?
Used to treat opioid overdose NALOXONE NALTREXONE has longer duration of action Peripherally active antagonist ALVIMOPAM paralytic ileus counter constipation
66
What drugs are used to treat opioid addicts
METHADONE - μ-agonist BUPRENORPHINE - partial μ-agonist NALTREXONE - μ-antagonist LOFEXIDINE - α2-agonist
67
What miscellaneous analgesics do you know?
Nitrates - eg glycerol trinitrate - angina - cause venodilation and decrease cardiac O2 demand Triptans - eg sumatriptan - migraine - 5HT1b/d agonists, - inhibits release of mediators during inflammation carbamazepine - trigeminal neuralgia - Na channel blocker used to treat epilepsy - Inhibits repetitive firing of neurons Tricyclic antidepressants (TCA) - eg amitryptiline - neuropathic pain - blocks noradrenaline, 5HT and dopamine uptake - used to treat depression - mechanism of action in neuropathic pain is unclear
68
How does the placebo effect work?
The psychosocial context tells the patient's brain to expect a therapeutic effect. As a result, neurobiological events occur in the brain via unconscious and / or conscious mechanisms, bringing about the release of effector molecules. These cause physiological changes in the brain and other organs that can generate a therapeutic effect
69
How does expectation of pain relief relieve pain?
1) Expectation of clinical benefit › Expectation has a role in placebo-induced analgesia  Expectation of reward (less pain) results in enhanced release of dopamine in nucleus accumbens  Increased mu opioid activity and descending pain inhibition (PAG)  Anxiety modulation (orbitofrontal region): expect less pain and anxiety decreases
70
How might conditioning be involved in the placebo effect?
› After repeated associations between a conditioned stimulus (CS), the environment around the patient (e.g. color of pill or the injection) and an unconditioned stimulus (the active drug, e.g.morphine) the CS alone is able to elicit a conditioned response (CR) similar to that induced by the drug. › Dorsolateral prefrontal cortex might be involved
71
Which parts of the brain are thought to be involved in the conditioning reponse in the placebo effect and in the Edward and anxiety response?
conditioning response: - dorsolateral prefrontal cortex reward and anxiety response: - nucleus accumbens - orbitofrontal cortex,
72
The CB1 cannabinoid receptor antagonist rimonabant blocks what type of analgesia?
The CB1 cannabinoid receptor antagonist rimonabant blocks non-opioid placebo analgesia
73
Is the placebo effective in Alzheimer's?
No