Physiology of pain 2 Flashcards
When is pain classified as acute
Pain<3months
When is pain classified as chronic
Pain>3months
Examples of acute pain
- Following surgery
- MSK injury
- Burn
Examples of substances released by mast cells, macrophages and neutrophil granulocytes that activate or modulate nociceptors
- Histamine
- Serotonin
- Bradykinin
- Prostaglandins
- ATP
What is peripheral sensitisation
- AKA primary hyperalgesia
- Peripheral sensitization is an increased sensitivity to an afferent nerve stimuli
Mechanism for peripheral sensitisation
- Occurs after there has been an injury or cell damage to the area
- Produces a flare response due to nociceptors producing lots of neuropeptides
- This then results in an increased sensitivity to heat and touch stimuli which is referred to as primary hyperalgesia or primary allodynia if the stimulus was not a painful one prior to the injury
Which channels undergo a reduction in threshold potential during peripheral sensitisation
- Reduction in threshold of TRPV1 channels(by bradykinin, nerve growth factor)
- Reduction in threshold of sodium channels(prostaglandins)
Sites of action for acute pain treatments
- PNS(i.e at the site of injury)
- CNS
- Or both
Action of lidocaine/lignocaine
- Local anaesthetic
- Sodium channel blocker
- Prevents nociceptor firing
- Apply topically to skin
What is topical capsaicin treatment
- Component of chilli peppers
- Repeated use reduces nociceptor firing
Mechanism of topical capsaicin treatment
- TRPV1 channel agonist
- Depletes substance P
- Causes peripheral terminals to die back
- Calcium overload causing mitochondrial dysfunction
Examples of non-steroidal anti-inflammatory drugs
- Aspirin
- Ibuprofen
Mechanism of action of non-steroidal anti-inflammatory drugs
- Reduces the inflammatory response by inhibiting prostaglandin synthesis
- Prevents peripheral sensitisation
- Cyclooxygenase(COX) inhibited
- Prostaglandin synthesis reduced
- Prevents decrease in Na+ channel threshold
What is the believed mechanism of action of paracetamol/acetoaminophen
- Not NSAID
- Inhibits cyclooxygenase(COX) enzymes but does not reduce inflammation
- Acts on descending serotonergic pathways
Mechanism of opioids
- Most effective pain relief but numerous side effects
- Agonists of the endogenous opioid system
Multiple sites of action: - Brainstem(disinhibition)
- Spinal cord
- Peripheral(inhibit channels on nociceptors)
What is the gate control theory
- Modulation evoked by nociceptors can be reduced by simultaneous activation of low threshold mechanoreceptors(A-beta fibres)
- Simply put: rubbing/blowing on the painful area can reduce the pain sensation
- C fibres inhibit inhibitory interneurons - opens gate
- Alpha beta fibres activate inhibitory interneurons - closes gate
Approximately what percentage of population are affected by chronic pain
- 20-50% of population
What is neuropathic pain
- Neuropathic pain is pain caused by damage or disease affecting the somatosensory nervous system
Symptoms of neuropathic pain
- Stabbing, aching, burning, electricity/shooting, spontaneous
- Hypersensitivity(allodynia and hyperalgesia)
What is spontaneous firing of nociceptors(part of main peripheral mechanisms along with peripheral sensitization)
- Following a peripheral nerve injury, there is an increase in axonal firing at the injury site, due to
- Accumulation of ion channels at generating tip of axon after being severed
- Responsible for spontaneous pain
- Underlies central neuropathic pain mechanisms
Main central mechanisms of pain
- central sensitisation - within spinal cord
2. Changes in activation patterns/cortical remapping - within brain
Why is there an increase in the responsiveness of nociceptive neurons within the CNS after an injury
- Due to the reduced threshold for activation of 2nd order neurons(similar to LTP)
What causes the reduced threshold for activation of nociceptors in CNS
1) Constant firing of axons from the periphery(following injury)
2) Sustained release of glutamate
3) Prolonged depolarisation of the postsynaptic membrane
4) Massive influx of Ca2+ through NMDA receptors
5) Activation of kinases
6) Phosphorylation of NMDA/AMPA receptors + channel protein synthesis
- Alters kinetics of channels and causes insertion of more channels
What is the central hyperalgesia mechanism
Following central sensitisation
- Activation of nociceptors results in amplified spinal cord activation
What is the central allodynia mechanism
- Non-noxious A-beta fibres also synapse onto 2nd order spinothalamic neurons(normally these are non-functional)
- Following central sensitisation, non-noxious afferents activate sensitised 2nd order neurons –> allodynia
Other likely mechanisms for central allodynia
- A-beta fibres form new sprouts that synapse onto 2nd order spinothalamic tract neurons
or
- Loss of inhibitory interneurons(eg GABA and glycine)
Main issue with central changes
- They are not easily reversible
What are some other associated symptoms that may need to be managed with chronic pain
- Depression
- Sleep disturbances
- Fatigue
Examples of drug classes used in the treatment of chronic pain
- Tricyclic antidepressants
- Anticonvulsants
- NMDA antagonists
all have analgesic properties
Other ways of treating chronic pain
- Physiotherapy - eg manipulation of tissues, pacing
- Psychological therapies - eg cognitive behavioural therapy
- Surgery - eg spinal cord stimulator
Example of a tricyclic antidepressant
- Amitriptyline
Possible mechanism of amitriptyline
- Act on descending pathways
- Inhibits reuptake of serotonin(and noradrenalin)
- Longer activation of GABAergic inhibitory interneurons
Examples of anticonvulsants
- Pregablin/gabapentin, cabamazepine
Possible mechanism of anticonvulsant action
- Act in spinal cord to reduce excitability
- Blocks calcium(pregablin/gabapentin) and sodium(carbamazepine) channels
Does pregablin/gabapentin act on GABAergic interneurons
- No
- Blocks presynaptic voltage-gated Ca2+ channels
- Prevent release of glutamate from nociceptors
Action of ketamine
- NMDA antagonist
- Reduces glutamate influx
- Prevents depolarization of second order neuron
- Adverse side effects(hallucinations/bad dreams)
First line drugs for chronic pain
- Amitriptyline or pregablin
Second line of treatment for chronic pain
- Switch drugs or combine
Third-line of treatment for chronic pain
- Refer patient to a specialist pain service and consider oral tramadol(opioid) or in combination with the second-line treatment, consider topical lidocaine
Placebo effect therapy
- Placebo analgesia has been demonstrated for the treatment of neuropathic pain
- Due to activation of descending inhibitory pathways
Examples of other complementary alternative therapies
- Acupuncture
- Massage therapy
- Homeopathy
- Herbal medicine
- Hypnosis
Why is it important to consider peripheral mechanisms as well when treating chronic pain
- Peripheral firing drives central changes
- Therefore, also think about the periphery
