Pain Flashcards
What are the 4 types of pain?
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
What are the 7 classes of pain?
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
See diagram in intro lecture on first page for the pathogens is of pain
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Is the PAG important in pain pathways?
Very
Page 2 of intro lecture for mood and state of mind diagram
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Summarise how pain is managed?
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
Summarise specialised pain management
TENS
Acupuncture
Physical therapies
Psychological therapies
Pharmacotherapies
Tricyclic antidepressants, gabapentinoids,
Analgesics, opioids
Topical agents
Combinations
Injections
Trigger point, nerve blocks, epidurals, facet joint injections
Can we test for pain?
No
Read notes on final page of intro lecture
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What is the intensity theory of pain?
Intensity theory (pain not a unique modality but emotional state produced by stronger than normal stimuli)
What is today’s pain definition?
An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage
How does nociception work?
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.
What are the 4 main modalities of nociception and what type of fibres carry them?
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
Where do pain pain pathways from the periphery end up?
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
What are the main 2 ascending pain pathways?
Spinothalamic: Discriminative aspect of nociception. Fast pain
Spinoreticular: Responsible for arousal and affective (unpleasantness) aspects. Dull pain
Where is pain processed in the brain? (L02)
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)
What is the Gate Control theory?
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.
What factors regulate the gate control mechanism?
- Amount of activity in pain fibres
- Amount of activity in other peripheral fibres (activation of mechanoreceptors Aß fibres)
- Messages descending from brain, e.g. emotions (anxiety, relaxation), mental conditions (boredom, learning)
Thus: psychological factors influence pain perception by regulating the gate mechanism
What do you know about the PAG?
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
What do you know about the RVM?
RVM: rostro ventromedial medulla: important area both for inhibition and facilitation of nociceptive processing; bidirectional central control of nociception
Pain is a subjective experience and has what three components?
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
Are pain pathways rigidly hardwired?
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
How can we divide up types of pain?
Nociceptive
Clinical
- inflammatory
- neuropathic
- functional
What are the 2 forms of pain hypersensitivity?
◦ 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
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)
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
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
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)
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
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?)
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
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
Genetic influences on pain from twin studies?
More correlation in monozygotic than dizygotic twins
What mediates and causes dysfunctional pain?
Not known
What factors activate peripheral sensitisation mechanisms?
Heat/H+/Capsaicin
Mechanical
H+
ATP
PGE2
Bradykinin
NGF
What are the mechanisms of peripheral sensitisation?
- Receptor modulation
- phosphorylation of receptor - Channel modulation
- cAMP - PKA
- PLC - DAG + IP3 - PKA + Ca2+ in - Gene expression
- Ras - MEK - ERK1,2
How does central sensitisation work?
Altered CNS processing
- Central sensitization
- Anatomical reorganization
- Reduced inhibition
- Glial activation
Repeated nociceptor activation facilitates spinal processing of nociceptor activity
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
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)
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.
What are the different types of analgesic drugs and what can they be used for?
- Local anaesthetics - lidocaine
- Non-steroidal anti-inflammatory drugs
- (NSAIDs) aspirin, ibuprofen, paracetamol - Opioids morphine, codeine
- Miscellaneous drugs
(To prevent what is causing the pain stimulation)
-nitrates: angina
- triptans: migraine
carbamazepine: trigeminal neuralgia
tri-cyclic antidepressants (TCA): neuropathic pain
Are opioids effective in the treatment of neuropathic pain?
Long duration - opioids are not good at neuropathic pain treatment
- tricyclics etc - used more
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
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)
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)
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
How are NSAIDs antipyretic?
Prevent prostaglandins to prevent the resetting of the temperature thermostat in the hypothalamus
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
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 )
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
What do you know about the Mu opioid receptors?
μ - Mu
- morphine
- increase K+ conductance
- inhibit adenylate cyclase
- inhibit voltage gated Ca2+ channels
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
What do you know about the Kappa opioid receptors?
κ - Kappa
- Dynorphin
- increase K+ conductance
- inhibit adenylate cyclase
- inhibit voltage gated Ca2+
channels
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
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
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)
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
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
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
In the gate control pain theory what are the inhibitory factors?
Descending inhibitory pathways
Mechanoreceptors (A-Beta)
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
How can opioids be given?
ORALLY (po) INTRAVENOUSLY (iv) INTRAMUSCULARLY (im) INTRATHECALLY (it) EPIDURALLY SUBLINGUALLY buprenorphine TRANSDERMALLY fentanyl
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
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
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
What drugs are used to treat opioid addicts
METHADONE - μ-agonist
BUPRENORPHINE - partial μ-agonist
NALTREXONE - μ-antagonist
LOFEXIDINE - α2-agonist
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
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
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
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
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,
The CB1 cannabinoid receptor antagonist rimonabant blocks what type of analgesia?
The CB1 cannabinoid receptor antagonist rimonabant blocks non-opioid placebo analgesia
Is the placebo effective in Alzheimer’s?
No
