Pain week 1 Flashcards
describe nociception and its transmission to the spinal chord and brain
- the physical process of detection and transmission of damaging or potentially damaging stimuli.
- nociception by peripheral activation and release of pain mediators.
-pain gating at the dorsal horn of the spinal cord. - pain perception within the brain (thalamus, limbic and cortical systems)
describe the mechanisms of sensitisation of nociceptors
can be stimulated by high mechanical stim, thermal stim, low pH, chemicals (inflammatory response). Bradykinin + Histamine
Channels affected by bradykinin, prostaglandins and opioids. (opioids reduce sensitivity of channels)
stimuli –> channel opening–> change in membrane voltage–> depolarisation and action potential generation–> transmitter released –> second order ascending neurone response in spinal cord dorsal horn.
describe the modulation of pain pathways at the spinal cord and descending pain pathway
ascending pathway - goes upwards carrying sensory information from body via spinal cord to the brain.
Spinothalamic tract:
Sensory input from first order neurone –> spinal cord (dorsal horn) –> joins second order neurone through medulla –> synapse with neurone in Thalamus –> third order neuron extends to primary somatosensory cortex
descending pathway - neural pathways that go downwards from the brain to reflex organs via spinal cord. Neurones can affect neuronal signals in ascending pathway.
explain the role of opioids, NSAIDS and other agents in analgesia
-either inhibit ascending pain pathway or enhance descending pain pathway to relieve pain
which fibres are responsible for each type of pain
A delta fibber (myelinated) - first pain (sharp)
C fibber (non-myelinated) - second pain (dull burning)
what is allodynia and hyperalgesia in chronic pain development?
Allodynia - pain to non -noxious stimulus
Hyperalgesia - increased pain to mildly noxious stimulus.
where can sensitisation occur?
in the peripheral - increased sensitisation of nociceptors
centrally - transmission to second order neurone in the dorsal horn
how does peripheral sensitisation occur?
- stim by release of bradykinin and prostaglandins increase sensitivity of nociceptors
- allow more depolarisation and generation of action potentials
how does central transmission occur at the spinal cord?
- first order neurone synapsing second order neurone at dorsal horn.
- neurotransmitters e.g. glutamate, CGRP and substance P.
-Bind to NMDA and AMPA receptors. - substance P binds to NK-1 receptors.
-synaptic strengthening - actively repeating activation of fibers causes stronger signal to spine.
how is central wind - up prevented?
reduction of peripheral stimulation NMDA receptor antagonist
how does afferent pain gating at the spinal cord work?(Gate theory of Pain)
non-pain sensory fibres (second order neurones) can synapse with the first order neurone at the dorsal horn. Also connected via inhibitory interneuron, inhibits second order neurone –> reduces pain message travelling up afferent pathways/ascending.
How does the descending pain pathway modulate the ascending pain messages?
- PAG receives input from different brain areas (HUB)
- neurones descend through the medulla to spinal cord (inhibit pain pathway)
-neurones from Locus coeruleus (pons) to spinal cord also inhibit ascending pain pathway.
-when descending pathway is active it inhibits the ascending pathway.
how does peripheral analgesia work with NSAIDS and Aspirin?
non - opioid: Aspirin and NSAIDs inhibit COX/COX2 (catalyses generation of PGE2 from arachidonic acid). Paracetamol unclear.
NSAIDS: Acts on prostanoid receptor. Prostaglandins cause other channels to open. By inhibiting COX enzymes –> prostaglandins aren’t produced–> prostanoid receptor isn’t activated–> other channels don’t open–> no action potential generated in nociceptor.
what are the three main types of opioid receptors and say some key points about them?
mew, kappa, delta (natural ligands are endorphins).
GPCRs, inhibitory of Ca2+ or promote opening of K+ channels. (decreasing excitability leading to hyperpolarisation).
Act peripherally and centrally
centrally they activate pathways by acting on inhibitory interneurons causing disinhibition.
how do opioids act on the descending pain pathway?
- inhibits excitation in periphery (inhibits ascending pathway)
- inhibit transmission in dorsal horn(inhibits ascending pathway)
-activates descending pathway which inhibits the ascending pathway (receptors located in midbrain and medulla)
what are the classes of opioid drugs?
-opiates e.g. morphine and codeine
- synthetic e.g. heroin, oxycodone, methadone, fentanyl
-antagonists e.g. Naloxone/naltrexone
what receptor causes the analgesia effect mostly and where are they located in the CNS?
mu receptor
-forebrain (cerebral hemispheres)
-limbic system (amygdala)
-mid-brain
-spinal (dorsal horn)
which receptors when activated give the feeling of euphoria v dysphoria?
mu - euphoria
kappa - dysphoria
key side effects of opioids
respiratory centre - resp depression even at therapeutic dose
GI tract - reduced motility (constipation)
Cough - depression of cough reflex
chemoreceptive zone - N+V
pupillary constriction -pinpoint pupils
what are the pharmacokinetics of opioids?
most undergo first pass metabolism so less potent orally
codeine has good oral bioavailability
most morphine like drugs have a half life 3-6h
methadone has a half life of 15-30h so easy to use in drug addiction clinics
fentanyl = very potent in transdermal patch form pain relief of 12-24h. May leave a build up of drug even when patch is removed
morphine like drugs inactivated by hepatic metabolism and excreted via kidneys
interactions with benzodiazepines potential resp depression
how do non-opioid drugs work on noradrenaline within the pain pathways?
NA is transmitter of inhib pathway linking locus coeruleus to the dorsal horn. TCAs inhibit NA reuptake so more signalling. SNRIs and tramadol have the same effects
how do anti-seizure medications work e.g. gabapentin and pregabalin as a CCB
reduce primary afferent transmission used for neuropathic pain
how do cannabinoid drugs work for analgesic effects?
- central and peripheral effects
- act on CB1 and CB2 receptors
-help with neuropathic pain
what are the common paediatric dosage forms used for analgesics and examples?
suspensions - solid particles dispersed in aq vehicle e.g. paracetamol (calpol) and ibuprofen (Nurofen) (shake well)
Solutions - drug and excipients and completely dissolved in a liquid solvent e.g. paracetamol elixir BP for mild to mod pain (high ethanol content)
Suppositories - drug is incorporated in water soluble base which melts at body temp usually used for local effect, but can be systemic delivery of paracetamol, diclofenac and aspirin. Paracetamol usually available as 60mg,125mg,250mg,500mg of drug.
Tablets/capsules - older children
what is a orodispersible dosage form and give classifications and how they are manufactured?
formulated to dissolve rapidly in the mouth so that drugs + excipients can be swallowed.
orodispersible tablets - disintegrate within 3 min, using water as liquid medium. Formulated through direct compression and require incorporation of superdisintegrants e.g. croscarmellose Na, crospovidone. Can be formulated from sublimation using volatile substances e.g. methol, camphor. Phase transition method of manufacture - compression of high/low mpt sugar alcohols, heated to leave pores in the tablet.
oral lyophilisates - produced using lyophilisation/freeze-drying. Dosage forms are soft. A solid single dose preparation made by freeze-drying tended to be placed in the mouth before being dissolved. Need to understand phase diagrams.
orodispersible films - single/multi-layer sheets that dissolve in the mouth produced using solvent casting method e.g. Setofilm for nausea and vomiting
granules
four main stages of freeze-drying to create an oral lyophilisates
Freezing stage - carefully controlled to make ice crystals, blister packs exposed to -10 - -30 degrees cel in large drying units using liquid nitrogen.
Vacuum application stage - vacuum is applied to bring pressure down below the triple point.
Sublimation stage - heat of sublimation applied (increased temp/primary drying) Solid phase to gas phase. Vapour continually removed
secondary drying - temp raised to 50 - 60 degrees cel to remove final moisture present.
what dosage forms are used for chronic + moderate to severe pain in paediatrics?
- Parenteral dosage forms e.g. IV paracetamol or morphine
-Buccal route e.g. fentanyl lozenges
-Transdermal route e.g. fentanyl patches
-Intranasal route for specialised delivery of fentanyl using a MAD (mucosal atomization device)
-Medicinal gases e.g. Entonox (mixture of NO and O) short term analgesia administered using mask or mouthpiece
what is PEGylation?
Process of hiding peptide drugs “stealth” in order to avoid processes within the body
