Nervous system and Pain
non-pharmacological treatment of migraines
Avoid triggers Encourage diary to document headaches for minimum of 8 weeks Discontinue meds that exacerbate headaches e.g. -reduce HRT dose - modify oral contraceptive -medication overuse headaches
how many people with migraine experience auras?
20-30%
explain the connectivity at the superficial dorsal horn
3 main neuronal types: • projection neurons • excitatory interneurones • inhibitory interneurons • Each neuronal type can receive inputs from Aδ- and/or C-fibers. • Descending & propriospinal axons connect to these neurons. • Extensive synaptic connections exist between the 3 neuronal types. • Gives strong potential for modulation of information transfer.
The trigeminal nerve is which number cranial nerve
5
how many lumbar spinal nerves are there?
5
how many sacral spinal nerves are there?
5
5-HT (5-hydroxytryptamine) breakdown
5-HT is taken back into pre-synaptic terminal where monoamine oxidase degrades it
how many cervical spinal nerves are there?
8
CGRP antagonists
A number of small-molecule CGRP receptor antagonists (Telcagepant, MK- 3207) were shown to be effective in (acute) treatment of migraine. Liver toxicity with other agents.--> may have to be injected to avoid liver problems
Microglia
Act as phagocytes, eating damaged cells and bacteria, act as the brains immune system
Gabapentin and pregabalin MOA in pain
Act via binding to the α2δ1-subunit of the voltage-gated Ca2+ channel
What is the key trigger for sensitization, hyperalgesia and allodynia - CHRONIC PAIN!?!
Activation of the NMDARs
Amitriptyline moa
Amitriptyline is in the tricyclic antidepressant (TCA) drug classification and acts by blocking the reuptake of both serotonin and norepinephrine neurotransmitters
6 main classes of neuroglia
Astrocytes: form the blood brain barrier. • Microglia: phagocytosis to fight infection. • Oligodendrocytes: bind the CNS neurons together and insulate the axons. • Schwann cells: myelin sheath • Non ciliated ependymal cells: secrete cerebro spinal fluid. • Ciliated ependymal cells: move cerebro spinal fluid around to keep it homogenous
why is the perception of pain is associated with an autonomic response.
Because the cortex, thalamus and brainstem are interconnected with the hypothalamus and autonomic nervous system
Congenital analgesia
Congenital insensitivity to pain (CIP) -when loss of function = no pain; a rare condition, < 60 cases known worldwide. due to mutations in SCN9A coding for Nav 1.7 (sodium channel)
Aδ
D-hair and AM (A-mechanonociceptor) Respond to both: Touch (via d hair) and (nociceptor via AM)--> crucial for the fast signalling of injury) medium myelin sheath
excitatory receptors
glutamate (AMPA) and SP (NK1R) receptors More prolonged afferent inputs from A-δ and C-afferents activate NMDA receptors.
Schwann cells
myelin sheath in PNS
dorsal root
nerves go into spinal cord via this root
ventral root
nerves go out of the spinal cord via the ventral root
Enteroceptors/visceroreceptors
from internal viscera
Ciliated ependymal cells
move cerebrous spinal fluid around to keep it homogenous
acute pharmacological migraine management
*analgesics should be taken as soon as aura arises:* - ibuprofen (400mg to 600mg) -aspirin (900mg) -paracetamol 1g -AVOID opioids *triptans should be taken when the headache actually starts* -first choice 50mg-100mg oral sumatriptan -if vomiting then intranasal or subcutaneous and consider adding antiemetic e.g. 10mg metaclopramide or prochlorperazine--> Avoid metoclopramide as an antiemetic in young women due to risk of extrapydimidal crisis overall, evidence says NSAIDS and triptan is the best
name 5 regions where opioid receptors are
- CNS: cortex, thalamus, periaquaductal gray, spinal cord - Peripheral neurons - Inflammed tissue - Immune cells - Respiratory and GI tract
When should you consider preventative treatment for migraines?
- Migraine attacks are causing frequent disability • for example, if there are two or more attacks per month that produce disability lasting for 3 days or more. - The person is at risk of medication overuse headache (MOH) due to frequent use of acute drugs e.g. triptans
Pure menstrual and menstrual-related migraine. non-hormonal prevention.
- NSAID if menorrhagia or dysmenorrhea is present. • e.g. Mefenamic acid is the NSAID of choice (off-label indication) - If this is not effective, and where migraine is predictable, consider treatment with frovatriptan or zolmitriptan starting 2 days before the expected onset of migraine (not licensed).
preventative migraine treatment
- Propranolol (80-160 mg daily, in divided doses) - Topiramate (50-100 mg daily, in divided doses [contraindicated in pregnancy — highly effective contraception is required prior to initiation])--> only prescribed by specialists as its very teratogenic or - Amitriptyline (25-75 mg at night). • *Do NOT offer gabapentin for migraine prophylaxis.* - Other drugs: pizotifen (antagonist of 5HT2- and histamine H1 receptors), calcium channel blockers, α2-adrenoceptor agonist
what generally increases pain tolerance?
- alcohol consumption, - medication, hypnosis, - warmth, distracting activities, - strong beliefs or faith.
symptoms of neuropathic pain
- allodynia - hyperalgesia - dysaesthesia - hyperpathia
preventative migraine treatment
- beta blockers: Antimigraine action related to the reflex vasoconstriction -antiepiletptic drugs: • Not well understood! • Multiple mechanisms including GABA-mediated suppression of neurotransmission in the brainstem. -Amitryptyline: • Not well understood! • Multiple receptor-neurotransmitter interactions that modulate nociception. -• Pizotifen • Methysergide
sensations of neuropathic pain
- numbness - tingling - burning - paresthetic (numbness/tingling) - paroxysmal (spasm/seizure) - lancinating - electriclike (piercing and spasm) - raw skin - shooting - deep, dull, bonelike ache
what generally decreases pain tolerance?
- repeated exposure to pain, - fatigue, anger, boredom, apprehension, - sleep deprivation.
Episodic Tension-Type Headache characteristics
- usually less than 15 days/ month for acyte -chronic pain for months -lasts 30mins to 7 days -bilateral location -mild or moderate intensity -pressing/tightening quality -not aggregated by rouite physical activity -no N/V and photophobia - at least 10 previous episodes fulfilling the criteria for full diagnosis SO SPECIFIC TYPICAL PATIENT NOT MIGRAINE
Resting membrane potential
-60 to -90mV (mainly said to be -70mv then threshold potential tends to be -55mV)
ectopic activity in neuropathic pain after nerve injury
-Increased sodium currents -Decreased of potassium currents The accumulation of sodium channels at sites of ectopic impulse generation may be one of the mechanisms responsible for lowering action potential threshold and for spontaneous activity in damaged primary afferents.
Aspirin/NSAIDs and renal impairment and drugs which increase sodium
-bad because aspirin can increase sodium retention -can caused reduced GFR -->Patients (particularly elderly and volume depleted) are at risk of renal ischemia with NSAIDs.
symptoms of fibromyalgia
-chronic widespread pain, -fatigue, -sleep disturbance, -heightened pain in response to tactile pressure (allodynia).
How does inflammation cause pain
-damaged tissues (and tumor cells) release chemical mediators -Inflammatory mediators cause peripheral sensitisation- they sensitise: 1. The small silent C fibres which then fire and cause pain 2. A-delta fibres sensitised? sensitisation: reduce afferent firing threshold, increase response to stimuli and increase spontaneous activity
Causes of trigeminal neuralgia
-demyelination so is often associated with late stages of MS -pressure of blood vessel or tumor on trigeminal nerve - damage to the nerve e.g. by surgery
Migraine characteristics
-moderate- severe pulsating/throbbing pain -4hrs-3days -onset most commonly as child/teen/young adults -aggravated by physical activity -more common in women -usually one sided (but can swap side between attacks) - symptoms include aura, nausea, vomiting, photophobia, sound and smells (migraines can occur with/without aura) post drone symptoms may include allodynia - might hurt to wash hair
Role of serotonin in migraine
-serotonin (acting on 5HT1 d and b receptors) may be low during migraine. -as serotonin is a vasoconstrictor it may lead to vasodilation Also -low serotonin leads to low blood PH also -low serotonin may cause the release of pro-inlammatory mediators
2nd afferent neurons from the spinal cord
-transmit the impulse from the substantia gelatinosa (SG) and laminae--> through the ventral and lateral horn-->crossing in the same or adjacent spinal segment, to the other side of the cord---> From there the impulse is carried through the spinothalamic tract to the brain. The two divisions of spinothalamic tract are known: 1. the neospinothalamic tract - it carries information to the mid brain, thalamus and post central gyrus (where pain is perceived). 2. the paleospinothalamic tract - it carries information to the reticular formation, pons, limbic system, and mid brain (more synapses to different structures of brain).
6 types of exteroceptors
1. Free nerve endings (pain and temp) 2. Merkel discs (light touch) 3. Root hair plexuses - entwine hair follicles (light touch) 4.Encapsulated Meissner's corpuscles (light touch in hairless skin) 5. Ruffini's corpuscles (deep pressure and stretch) 6. Pacinian corpuscles (deep pressure, vibration, visceral: pain, nausea, hunger, fullness)
Forebrain: Telencephalon consists of...
1. Frontal lobe: planning, emotion, problem solving, some parts of speech and movement 2. Parietal Lobe: touch, pressure, temperature, PAIN 3. Occipital lobe: vision 4. Temporal lobe: auditory stimuli (hearing) and MEMORY (hippocampus here)
Aspirin effect on respiration
1. Low doses: uncoupling phosphorylation → ↑ CO2 → stimulates respiration. 2. Direct stimulation of respiratory center → Hyperventilation → resp. alkalosis → renal compensation. 3. Depression of respiratory center and cardiovascular center → ↓ BP, respiratory acidosis, no compensation + metabolic acidosis also.
Functions of the cerebrospinal fluid (CSF)
1. Protection: shock absorbency 2. Provides a medium for the exchange of nutrients and wastes between blood and nervous tissue Formed in the choroid plexus by ependymal cells , maintains a stable pressure, channels through ventricles
8 Pharmacological effects of opioids
1. Sedation and anxiolysis 2. Respiratory depression (avoid alcohol) 3. Cough suppression 4. Pupillary constriction 5. Nausea and vomiting 6. Reduced peristalsis (loperamide) 7. Itching (histamine relase) 8. Affects WBC
what metabolic effects can aspirin cause?
1. Uncoupling of Oxidative Phosphorylation. 2. Hyperglycemia and depletion of muscle and hepatic glycogen.
Mechanisms of pharmacological tolerance to opioids
1. drug of administration causes desensitization, internalization, down-regulation and phosphorylation of opioid receptor 2. drug of administration causes the opposite effects by activating different neuronal circuits which increase/engage NMDAr this is by... MOR receptor activated--> leads to removal of mg2+ block of NMDAr
Pathophysiology of migraine
1. migraine originates deeps within the brain 2. cortical spreading depression (a slow propagating wave of depolarisation followed by a wave of inhibition) which spreads to other regions of the brain and may be a contributing factor to the aura symptoms pre-migraine 3. the trigeminal nerve system is activated and becomes sensitised 4. Inflammatory mediators are released such as neurokinin A substance P and CGRP and blood vessels dilate 5. central sensitisation may occur as the signal travles to the thalamus and cortex 6. pain occurs Also Serotonin ( 5- hydroxytryptamine) is thought to be an important mediator of migraine as during a migraine serotonin may be low--> serotonin is a vasocontristcor so vasodilation may occur
2 divisions of the spinothalamic tract
1. neospinothalamic tract 2. paleospinothalamic tract
2 types of somatogenic pain
1. nociceptive (stimulation of nociceptors common in acute pain) 2. neuropathic (damage of the NS)
4 stages of migraine
1. prodrome --> some people may experience craving, tiredness, light and sound sensitivity, depression ect. 2. aura--> tingling sensation, scotoma (blind spots), scintilla (flashing lights), unilateral weakness, hemianopsia (blindness is one half of the visual filed) 3. headache--> photophobia, vomiting, worse on movement, unilateral, osmophobia (fear of odours) 4. post drone --> low feeling, tiredness
Three locations of peripheral sensory receptors
1.Exteroceptors: Peripheral sensory receptors- Sensitive to stimuli arising from outside body 2. Enteroceptors: Or visceroreceptors, from internal viscera 3. Proprioceptors: Monitor degree of stretch in skeletal muscles, tendons, joints and ligaments
3 main regions of the brain and their subsections
1.Hindbrain: cerebellum, pons, medulla oblongata, reticular formation • 2.Midbrain: Tectum: Superior colliculi and Inferior colliculi Tegmentum: Periaqueductal gray, Substantia Nigra and red nucleus+++ • 3. Forebrain Telencephalon: cerebral cortex; corpus callosum; Limbic system (hippocampus; anterior cingulate cortex; amygdala; olfactory bulb) Diencephalon: thalamus; hypothalamus; pituitary gland; pineal gland
Common adverse effects of NSAIDS
1.Platelet dysfunction--> increase bleeding time 2. Gastritis and peptic ulcers 3. Acute renal failure in susceptible (as blocks PGs such as PGI2 which dilate afferent arteriole) 4. Sodium/water retention and edema 5. Prolonged gestation and inhibition of labor 6. hypersensitivity (asthma??)
how many thoracic spinal nerves are there?
12
Describe the trigeminal system
1st order afferents project from the face and to the pars interpolaris and pars caudalis of medulla 2nd order neurones ascend (controlaterally) to the thalamus 3rd order neurons project to the cortex
BBB function and structure
Blood-brain barrier • a highly selective permeability barrier that separates the circulating blood from the brain--> allows passage of water and some small molecules and lipid molecules passively, and active transport of f molecules such as glucose and amino acids that are crucial to neural function prevent the entry of potential neurotoxins (and drugs) by way of an active transport mechanism mediated by P- glycoproteins •formed by capillary endothelial cells, which are connected by tight junctions astrocytes promote tight junctions
why doesnt CGRP antagonists need to penetrate the BBB to act?
CGRP and CGRP receptors are expressed in the trigeminal ganglion. As the trigeminal ganglion is expressed outside the blood-brain barrier (BBB),
What type of pain are opioids used for
Cancer pain Acute pain (e.g. post-op)
Mechanisms of touch-evoked pain (allodynia)
Capsaicin-insensitive A-nociceptors are essential for secondary hyperalgesia
Women who have migraine *with aura* should not have what type of pill?
Combined. It contains oestrogen and can increase the risk of ischeamic stroke. They should opt for a progesterone only pill.
Dopamine termination
DA is taken back into pre-synaptic terminal where monoamine oxidase degrades it
Two mechanisms by which opioids work
Decrease conduction Prevent centralization
when can you give sumatriptan as a P med?
For OTC supply: • 18-65 years old • Must have had migraine diagnosed by doctor (or pharmacist) • Established history of migraine >5 previous attacks Must refer if - 4 or more attacks per month or requests for 4 or more packs per month • Increased risk of stroke in women on COCs • History of CVD, renal impairment • Worsening symptoms and migraine with aura • Motor weakness, reduced level of conciousness
Glutamate synthesis
Glutamine---Glutaminase--->Glutamate
GABA (Gamma-Aminobutyric acid) synthesis
Glutamine---Glutaminase--->Glutamate----GAD--->GABA
substantia gelatinosa
In the dorsal horn, Superficial laminae I and II (substantia gelatinosa) receive nociceptive inputs
peripheral sensitization
Increased responsiveness and reduced threshold of nociceptive neurons in the periphery
Atherosclerosis and aspirin/NSAIDs
Inhibition of COX-2 can destabilize atherosclerotic plaques (due to its anti-inflammatory actions).
chronic pain
Is persistent or intermittent usually defined as lasting at least 3-6 months. • Extends beyond the the usual course of acute illness or injury. • The cause is often unknown, often develops insidiously, very often is associated with a sense of hopelessness and helplessness. • Depression often results.
What might aspirin generate as an antiinflammatory mediator
Lipoxins
NA termination
NA is taken back into pre-synaptic terminal where monoamine oxidase degrades it
what may be given to reduce opioid tolerance?
NMDAr antagonists (ketamine)
NSAIDs and Renal Function
NSAIDS constrict the AFFERENT arteriole = decreased blood flow to glomerulus and decreased renal perfusion. Be careful in renally impaired, one kidney
at resting membrane potential which ions are outside the cell
Na+ and Cl-
Neurons vs. Neuroglia
Neurons - excitable cells that transmit electrical signals Neuroglia - supporting cells and so much more
What causes neuropathic pain?
Neuropathic pain often seems to have no obvious cause; but, some common causes of neuropathic pain include: alcoholism, amputation, back, leg and hip problems, chemotherapy, diabetes mellitus, facial nerve problems, HIV infection or AIDS, multiple sclerosis, shingles (Herpes zoster), spine surgery.
paracetamol key use
No significant anti-inflammatory effect, but used for its mild analgesic effect.
Do all responses involve integrations at the CNS?
No, reflex responses don't
NOP
Nociceptin/Orphanin peptide receptor
Mechanism of opioid
Normally: Activation of peripheral nociceptive fibers causes release of substance P and other pain-signaling neurotransmitters from nerve terminals in the dorsal horn of the spinal cord Gi coupled receptor... causes decreased cAMP by inhibiting adenylyl cyclase. Pre-synaptically inhibits calcium influx and NT (e.g. substance P) neurotransmission. Post synaptically causes k+out flux and so hyperpolarisation occurs
Somatic efferent NS organisation
One fibre which releases Ach at the neuromuscular junction.
How can aspirin/NSAIDs? raise BP?
PGI2 normally can antagonise the effect of angiotensin 2 induced vasoconstriction. If PGs and PGI2 is isnt made by blocking COX-2 then vasoconstriction --> higher BP ALSO: NSAIDs tend to promote Na+ retention and can therefore increase bp.
How might NSAIDs prolong labour?
PGs (generated from COX-2) are involved in the initiation and progression of labor and delivery. Therefore, inhibition of their production by NSAIDs can prolong gestation.
Dopamine synthesis
Tyrosine (AT into the neurone)--tyrosine hydroxylase-->DOPA---DOPA decarboxylase --->DA
NSAIDS and GI effects mode of action
PGs (generated via COX-1) 1) inhibit stomach acid secretion, 2) stimulate mucus and HCO3- secretion, vasodilation and therefore, 3) are cytoprotective for the gastric mucosa. • Therefore, NSAIDs with COX-1 inhibitory activity will produce opposite effects, leading to: gastric distress, gastric bleeding, sudden acute hemorrhage (effects are dose-dependent).
Neuropathic pain
Pain initiated or caused by a primary lesion or dysfunction in the nervous system.
acute pain
Pain up to 3 months Sudden onset Protective mechanisms Often stimulates sympathetic NS
who should not be supplied sumatriptan as a P?
Patients with 3 or more risk factors for CVD should not be supplied: • Obesity (BMI>30) • Diabetes • Men >40years and postmenopausal women • Hypercholesterolaemia • Smoker (10+ per day) • Family history of heart disease <55 years for men and <65 years for women Must refer if - 4 or more attacks per month or requests for 4 or more packs per month • Increased risk of stroke in women on COCs • History of CVD, renal impairment • Worsening symptoms and migraine with aura • Motor weakness, reduced level of conciousness
Exteroceptors
Peripheral sensory receptors: Sensitive to stimuli arising from outside body
SYMPATHETIC pre and post ganglion fibres (long/short or Ach and NA?)
Pre ganglionic fibre: short and Ach Post ganglionic fibre is long and Na exceptions - sweat glads where both NTs are Ach despite being sympathetic -adrenaline (NOT NA)release from adrenal gland is a single fibre where ach is released and the adrenal gland releases adrenaline
PARASYMPATHETIC pre and post ganglionic fibres (long/short or Ach and NA?)
Preganglionic: long and Ach Post ganglionic: Short and Ach
AB fibres
RAM and SAM (rapidly/slowly adapting mechano receptors) Respond to touch sensation (not nociception) Thickest myelin sheath, fast
Acute pain first and second response
Rapid first pain Via A fibres (delta) Second pain follows, slower onset as by C-fibres
cell body
Receives inputs (e.g. from sense organs, other neurones) and encodes these inputs
Why is the effectiveness of opioids reduced in neuropathic pain?
Reduced number of mu opioid receptors Reduced binding to mu opioid receptors
some brain changes associated with chronic pain
Reduction in grey matter Reduction in white matter integrity Reduction in neurotransmitter concentration
Innervation of muscles and glands via the autonomic NS
Release of neurotransmitters are different: in the automatic NS there are swellings/boutons where the nts are released, which is abit slower
reviewing migraines
Review after the first pack of triptans (typically three to six doses), enquire about the effectiveness of treatment - 2-8weeks
Why can't you give aspirin to children under 16?
Reye's syndrome
Noradrenaline synthesis
Tyrosine (AT into the neurone)--tyrosine hydroxylase-->DOPA---DOPA decarboxylase --->DA---DA beta hydroxylase-->NA
Tricyclic antidepressants (TCAs) mode of action for pian
Serotonin reuptake inhibitors (e.g. amitryptyline). Probably by increasing serotonin levels, engaging the descending pain inhibitory circuitry. Off-target effect include inhibition of voltage-gated Na+ channels and NMDA receptors.
if over 3 weeks post migraine weakness is still present then what might it be
TIA or nerve damage If inadequate, or poorly tolerated, reconfirm diagnosis, reassess lifestyle advice, check that usage of treatment is correct, and rule out medication-overuse headache. - Consider prescribing a triptan that is more suitable for the person - If the person has tried two or more triptans unsuccessfully, or treatment is successful but attacks are frequent, consider preventive treatment
potential future treatment for migraines
Targeting CGRP or CGRP receptor with monoclonal antibodies
Describe the PNS
The peripheral nervous system (PNS) consists of nerves and scattered groups of neuronal cell bodies (ganglia) found outside the CNS. There are two main divisions of the PNS: 1. somatic NS (voluntary control) 2. autonomic NS
Name 3 painful conditions of the trigeminal system
Tigeminal neuralgia Headache Migraine
Menthol activates
Trpm8
capsaicin activates
Trpv1
Fibromyalgia definition
a disorder of pain processing due to abnormalities in how pain signals are processed in the CNS 50% less stimulus is needed to evoke pain in those with fibromyalgia
The CGRP receptor
a heterotrimer: composed of calcitonin-like receptor (CLR), a 7 transmembrane Gs protein-coupled structure, and the receptor activity-modifying protein (RAMP1). • The receptor component protein (RCP) is important for signaling.
central sensitization
a key central mechanism of chronic and neuropathic pain; the abnormal hyperexcitability of central neurons in the CNS, which results from complex changes induced by the incoming afferent barrages of nociceptors. Central sensitization also occurs independent of peripheral injury or inflammation.
dorsal root ganglion
a nodule on a dorsal root that contains cell bodies of afferent (sensory) spinal nerve neurons
opioid induced hyperalgesia
a phenomenon in which exposure to an opioid induces increased sensitivity, or a lowered threshold, to the neural activity conducting pain perception Occurs when administration is terminated or reversed (naloxone)
hyperpathia
abnormally painful reaction to a stimulus, especially a repetitive stimulus
Acetylcholine Degradation
acetylcholinesterase in the synaptic cleft breaks down Ach into choline and acetate
CGRP (calcitonin gene-related peptide) role in migrains
aids release of nueroinflammatory mediatiors and vasodilation
MDEG
an amiloride-sensitive sodium channel
Ergotamine and dihydroergotamine
antimigraine with affinity for 5HT1b/d receptor although not offered by nice guidelines
rebound headache
associated with triptan frequent use In high proportion of patients taking triptans, the migraine can recur within 12h Frequent use may lead to chronic daily headache or exacerbation of migraine
Endogenous ligands of the delta opioid receptor
b- endorphins enkephalins
Endogenous ligands of the mu opioid receptor
b- endorphins enkephalins endomorphin 1 and 2
Oligodendrocytes
bind the CNS neurons together and insulate the axons
autonomic NS
branch of the PNS which is outside of voluntry control (flight or flight)
white matter
bundles of axons each coated with a sheath of myelin
Chronic pain pathology (multiple cellular changes which can occur)
changes in trafficking, threshold/activation kinetics of AMPA and NMDA receptors. --> leads to increase membrane excitability Alterations in ion channels to increase inward currents and reduce outward currents. Reduction in the release or activity of GABA and glycine --> leads to disinhibition Longer term changes of cellular and molecular events in the spinal cord may lead to irreversible chronic pain All can lead to central sensitisation which may result in increased spontaneous activity, reduced threshold for activation by peripheral stimuli, ect.
trigeminal neuralgia
characterized by severe lightning-like pain due to an inflammation of the fifth cranial nerve - more common in women -more common >40 years
Acetylcholine synthesis
choline is taken up into the neurone. choline + acetyl-coenzyme A----cholineacetyl transferase--->Ach
Why might opioids not be used to treat chronic pain
chronic pain is associated with reduced opioid responsiveness opioid tolerance addiction? although studies have shown Chronic pain inhibits seeking behaviour
TREK
co-expressed with TRPs, K+ channel, activity reduced by heat,
Cluster headache characteristics
commonly happens at same time each year/ season/ time of day then free -excruciating stabbing pain in one eye -ALWAYS THE SAME SIDE -symptoms include: watery eyes, red eye, swollen eyelid, sweating, runny nose Typical patient: middle aged smoker
if vomiting is stopping the person from taking the triptan what should you do?
consider a non-oral formulation (such as intra-nasal or subcutaneous). consider antiemetic
COX 1
constitutively expressed, associated with gastro-protective effects
what causes phantom pain?
cortical re-organization in 'body maps' of thalamus & cortex
Primary hyperalgesia
describes pain sensitivity that occurs directly in the damaged tissues • can be accounted for by peripheral mechanisms • Strong contribution from nociceptor sensitization
ASICS & DRASICS
detect H+,cation selective, DRASICs also detect mechanical stimuli
sensory division: proprioceptive sensors
detect stretch in tendons and muscles.. help position and movement of body in space
Gabapentin and pregabalin are used for which types of pain?
diabetic neuropathy, fibromylalgia, postherpetic neuralgia (often caused by shingles).
Endogenous ligands of the kappa opioid receptor
dynorphin A and B
hyperalgesia
exaggerated response to a normally painful stimulus
Astrocytes
form BBB
pharmacological tolerance
increased drug conc. to have the same efficacy/effect as before
Inherited erythromelalgia
inherited Erythromelalgia, , is a rare vascular peripheral pain disorder in which blood vessels due to mutations in SCN9A coding for Nav 1.7 (sodium channel)
Efferent analgesic system role
inhibition of afferent pain signals!
neospinothalamic tract -
it carries information to the mid brain, thalamus and post central gyrus (where pain is perceived).
paleospinothalamic tract
it carries information to the reticular formation, pons, limbic system, and mid brain (more synapses to different structures of brain).
Ephapses in neuropathic pain
like wires touching. axons may touch and cause neuropathic pain.
C fibres
loads: C-mechanonociceptor(CM) • C-mechanoheatnociceptor (CMH) • C-mechanocoldnociceptor (CMC) • C-heatnociceptor (CH) • some C's are 'silent' (15%) but 'awake' following injury • C-low threshold (CLT) Respond to pain (nociception) not myelinated, slow response
gray matter
masses of the cell bodies and dendrites - each covered with synapses
Subclasses of nociceptors
mechanical, thermal & polymodal nociceptors
Proprioceptors
monitor the position and movement of skeletal muscles and joints by monitoring degree of stretch in skeletal muscles, tendons, joints and ligaments Skeletal muscles, joints, tendons, ligaments ● Degree of stretch, therefore information on body movement: ● to cerebrum, ● cerebellum and ● spinal reflex arcs Include: -Muscle spindles -Golgi tendon organs -Joint kinesthetic receptors
most likely mechanism for opioid induced hyperalgesia
morphine and its metabolites activate the NMDAr receptor and glutaminergic system
sensory (afferent) neurons
neurons that carry incoming information from the sensory receptors to the brain and spinal cord e.g. general: touch, pain pressure, proprioception or sepecial e.g. hearing vision, smells
Tricyclic antidepressants (TCAs) used for what type of pain?
neuropathic
Chemical signaling
neurotransmission
can teeth get allodynia?
no, they do not have a beta fibres
COX 2
occurs at the site of inflammation
Pure menstrual and menstrual-related migraine
occurs within 1-2 days of period onset occurs in 60% of cycles often is not associated with aura • Consider co-morbidities and need for contraception before prescribing non-hormonal or hormonal migraine prevention. • Preventive drugs should be tried for at least three cycles, at the maximum tolerated dose, whilst effectiveness is established.
A drop in what on the controlled oral contraceptive may cause a migraine when on the break days?
oestrogen
Aspirin causes increased risk of bleeding how?
on platelets--> Inhibition of platelet COX-1-derived TxA2 with the net effect of increasing bleeding time (inhibition of platelet aggregation). irreversibly inhibits platelet COX. The enzyme is inhibited for the lifetime of the platelet (~8 -11 days). Effect achieved at very low dose.
what drug should not be used for migraines?
opioids
psychogenic pain
pain for which no physical cause can be identified but processing of sensitive information in CNS is disturbed.
allodynia
pain from a stimulus that does not normally evoke pain
Secondary hyperalgesia
pain sensitivity that occurs in surrounding undamaged tissues • not easily accounted for by peripheral mechanisms • central mechanisms implicated
insular cortex and pain
receives input from the autonomic nervous system (ANS),
sensory division: visceral sensory
receives sensory information from viscera General visceral senses - stretch, pain, temperature, nausea, and hunger • Widely felt in digestive and urinary tracts, and reproductive organs - Special visceral sense = taste Sens
Parts of the brain which control the emotional and affective response to pain.
reticular formation limbic system
non ciliated ependymal cells
secrete cerebro spinal fluid
what drug class are the triptans?
selective serotonin receptor agonists
TRPM8 nociceptors
senses 'cool' stimuli
3 systems which interact to produce pain
sensory motivational cognitive
3 types of distractors from pain
sensory motivational cognitive
name a special visceral sense
taste
Mode of action of Carbamazepine for pain
technically an anticonvulsant but is also a Na+ channel blocker.
Parts of the brain which identify dull longer-lasting, and diffuse pain.
thalamus reticular formation brainstem
Electrical signaling
the action potential
TRP (VR) classes
thermal sensitivity in the warm-hot range mediated by multiple TRP channels e.g. TRPV1, TRPV2, TRPV3 & TRPV4, cation selective (Ca2+)
Selective COX-2 inhibitors risk
thrombotic events and MI
what drug class is amitryptyline
tricyclic antidepressant
Carbamazepine is first line to treat which type of pain?
trigeminal neuralgi
Chemoreceptors are a type of polymodal nociceptor. true or false?
true
Pain threshold tends to increase with ageing. true or false?
true
Tolerance and opioid-induced hyperalgesia (OIH) are pharmacologically distinct phenomena that share the same net effect on dose requirements. true or false.
true
• Nociceptors anatomically exist as free nerve endings. true or false?
true
Pure menstrual and menstrual-related migraine. hormonal contraception..
try and give progesterone?? - If contraception is desired. Consider: • Combined hormonal contraceptives (CHC), such as the combined oral contraceptive pill, patch or vaginal ring. • An oestrogen supplement during the pill-free interval with the combined oral contraceptive pill. • Oral desogestrel (Cerazette®, the only progesterone pill to inhibit ovulation), sub- dermally implanted etonogestrel (Nexplanon®), or injectable depot progestogens. - Oestrogen supplements are an option but are not licensed for pure menstrual or menstrual-related migraine. - *Do not offer combined hormonal contraceptives to women who have migraine with aura as increased risk of stroke.*
5-HT (5-hydroxytryptamine) synthesis
tryptophan AT into the neuron, tryptophan---tryptophan hydroxylase--> 5-HTP---aromatic aminoacid decarboxylase)--5-HT
Paracetamol analgesia MOA
unclear but -associated with both central and peripheral mechanisms underlying its analgesia effect • results from inhibition of PG synthesis in inflamed tissues. • PGs cause little pain relief themselves, but potentiate the pain caused by other mediators of inflammation (e.g., histamine, bradykinin).
causes of fibromyalgia
unknown! • Central sensitization? Neuropathic pain and major depressive disorder often co-occur with fibromyalgia.
dysaesthesia
unpleasant abnormal sensation, (spontaneous or provoked)
side effects of triptans
warm-sensations, tightness, tingling, flushing, some nausea, dry mouth and drowsiness
can women with migraines be on combined oral contraceptives?
yes, unless they have aura where it should be avoided due to ischeamic stroke risk and progesterone only should be used. If a drop in oestrogen on the off days triggers migraine then consider a progesterone only, or oestrogen on off days
Triptans for migraine mode of action
• *Serotonin 5HT1B/1D receptor agonists*, with additional activity at 5HT1F receptor. work on peripheral pathways Mechanisms include: • Intracranial vasoconstriction, • Inhibition of neurotransmission in the trigeminocervical complex, • Inhibition of release of pro-inflammatory and vasoactive mediators • Relieve from pain and the nausea associated with migraine. we now also know that Sumatriptan acts via presynaptic 5-HT1B/D receptors to suppress CGRP release from trigeminal nerves
Summary of neuropathic pain mechanisms- central NS changes
• Central Sensitisation in the cord - 2ary to peripheral inputs - 2ary to central changes • Reduced inhibition • Functional (neurotransmitter) & anatomical (sprouting) changes in Aβ fibres--> tactile allodynia (pain induced by light touch) • Increased synaptic efficacy (increased glutamate release, co- release of glutamate and a peptide, activation of novel receptors e.g. NMDA or mGluRs • Reduced inhibition/altered GABA receptor expression • Up-regulation of postsynaptic receptors (e.g for substance P) • Gene expression and altered phenotype of central neurones • Unmasking of silent synapses • Re-wiring of spinal or brain circuitry
what are Lipoxins
• During inflammation, cells die by apoptosis. • Lipoxins signal macrophages to clean up. • During the acute inflammatory process, cytokines can induce the expression of anti-inflammatory mediators (lipoxins), which promote the resolution phase of inflammation.
Paracetamol Antipyretic MOA
• Fever release of endogenous pyrogens (e.g., interleukin-1) released from leucocytes acts directly on the thermoregulatory centers in hypothalamus increase body temperature. • This is associated with increase in brain PGs (pyrogenic). • Aspirin prevents the T°-rising effects of interleukin-1 by preventing the increase in brain PGs.
NSAIDs (mainly aspirin) effect on respiratory system
• High doses (salicylates) cause partial uncoupling of oxidative phosphorylation with increased CO2 production (COX-independent effects). Increase in plasma CO2 hyperventilation. Even higher doses cause depression of respiration. • Other uses of NSAIDs (mechanisms less understood) - Decreased risk of fatal colon carcinoma.
Summary of neuropathic pain mechanisms- peripheral NS changes
• Threshold for activation of injured 1o afferents is lowered: sensitization of peripheral afferents by inflammatory mediators and/or modification of afferent phenotype (altered peptide expression, altered ion channel expression etc.) • Ectopic discharges may arise from the injury site or the DRG - 2o to changes in Na+ channel expression
Medication overuse headaches
• Using acute pain-relief > 2-3 three times a week or >10 days out of the month can set off a cycle called 'medication-overuse headaches' (MOH). • As each dose of medicine wears off, the pain comes back, leading them to take even more. Causes medicine to stop helping pain and actually start causing headaches. • MOH can occur with both OTC and prescription pain-relief medicines. They can also occur whether you take them for headache or for another type of pain.
migraine triggers
• foods : spices, wine , chocolate, citrus • food additives : monosodium glutamate • sleep : both too much and too little • stress : mainly offset and fatigue • female hormones : fluctuating or falling oestrogen • family history of migraine headaches (70-80%) • medications (ie, birth control pills, vasodilators) • noise, light • exertion
Efferent analgesic system mechanism
• pain afferents stimulates the neurons in periaqueductal gray (PAG) - gray matter surrounding the cerebral aqueduct in the midbrain results in activation of efferent (descendent) anti-nociceptive pathways. • from there the impulses are transmitted through the spinal cord to the dorsal horn. • there they inhibit or block transmission of nociceptive signals at the level of dorsal horn!
3 major neuronal types in Superficial Dorsal Horn
• projection neurons • excitatory interneurones • inhibitory interneurons
