Physiology of pain 2 Flashcards
Acute pain
<3 months
Inflammatory (and nocioceptive)
- due to tissue injury or inflammation
e.g. following surgery, musculoskeletal injury, burn
Chronic pain
> 3 months
Affects 20-50% population
e.g. chronic back pain, cancer, carpal tunnel syndrome, arthritis, fibromyalgia, diabetes, migraine, post surgery, multiple sclerosis
Due to injury to nervous system
Peripheral sensitisation
Major mechanism of acute pain
Leads to pain hypersensitivity
Acute pain treatments sites of action
PNS (site of injury)
CNS
Both
Local anaesthetics
e. g. lidocaine, lignocaine
- topically applied to skin
Mechanism of action
- sodium channel blockers
Topical capsaicin treatment
TRPV1 channel agonist
Mechanism of action
- depletes substance P
- causes peripheral terminal to die back
Non-steroidal anti-inflammatory drugs
e.g. aspirin, ibuprofen
Mechanism of action
- reduces the inflammatory response by inhibiting prostaglandin synthesis
- prevents peripheral sensitisation
Cyclooxygenase inhibited ->
Prostaglandin synthesis reduced ->
Prevents decrease in Na+ channel threshold
Paracetamol/ acetominophen
Not NSAID
Mechanism of action
- inhibits cyclooxygenase enzymes
- acts on descending serotonergic pathways
Opioids
e.g. morphine, codeine, tramadol
Most effective pain relief but numerous side effects
Mechanisms of action
- agonists of the endogenous opioid system
- multiple sites of action (brainstem, spinal cord, peripheral)
Gate control theory
Modulation of pain at the spinal cord level
Pain evoked by nocioceptors can be reduced by simultaneous activation of low threshold mechanoreceptors
Rubbing/ blowing on the painful area can reduce the pain sensation
Stimulation of Aβ fibres in vicinity of injury activates interneurones in dorsal horn which inhibits spinothalamic neurones
Neuropathic pain mechanisms
Mechanisms are complex and involve both peripheral and central nervous systems
Spontaneous firing of nocioceptors
Following a peripheral nerve injury increase in axonal firing at the site of injury
Due to accumulation of ion channels at regenerating tip of axon
Responsible for spontaneous pain
Underlies central neuropathic pain mechanisms
Main peripheral mechanisms
Peripheral sensitisation
Spontaneous firing of nocioceptors
Central mechanisms
Central sensitisation
- with spinal cord
Changes in activation patterns/ cortical remapping
- within brain
Central sensitisation
Increase in the responsiveness of nocioceptive neurones within the CNS
Normal inputs begin to produce abnormal responses
Due to reduced threshold for activation of 2nd order neurones
Reduced threshold for activation
Constant firing of axons from the periphery (following injury)
Sustained release of glutamate
Prolonged depolarisation of the postsynaptic membrane
Massive influx of Ca2+ through NMDA receptors
Activation of kianses
Phosphorylation of NDMA/ AMPA receptors
Channel protein synthesis
Alters kinetics of channels and causes insertion of more channels
Central hyperalgesia mechanism
Following central sensitisation
Activation of nocioceptors results in amplified spinal cord activation
Central allodynia mechanism
Non-noxious Aβ fibres also synapse onto 2nd order spinothalamic neurones (normally non-functional)
Following central sensitisation
Non- noxious afferents activate sensitised 2nd order neurones
Altered synaptic connections
Aβ fibres form new sprouts that synapse onto spinothalamic tract neurones
Loss of inhibitory interneurones
e.g. GABA and glycine
Chronic pain treatments
Difficult to treat
Acute pain treatments do not work
Good individual patient management is critical
Important to manage primary condition and other associated symptoms
- depression
- sleep disturbances
- fatigue
Current treatments for chronic pain
Drugs
- tricyclic antidepressants
- anticonvulsants
- NMDA antagonists
Physiotherapy
Psychological therapies
Surgery
Tricyclic antidepressants
e.g. amitriptyline
Mechanism of actions
- unclear
- act on descending inhibitory pathways
- inhibits reuptake of serotonin
Anticonvulsants
Pregabalin/ gabapentin, carbamazepine
Mechanism of action
- unclear
- act in spinal cord to reduce excitability
- blocks calcium and sodium channels
Pregabalin/ gabapentin
Do not act on GABAergic interneurones
Blocks presynaptic voltage gated Ca2+ channels
Prevents release of glutamate from nocioceptors
NMDA antagonists
Ketamine
Mechanism of action
- NMDA receptor antagonist
- prevents depolarisation of second order neurone
- adverse side effects
NICE guideline neuropathic pain
First line
- amitriptyline or pregabalin
Second line
- switch drugs or combine
Third line
- refer to specialist pain serve and consider oral tramadol or in combination with second line consider topical lidocaine
Placebo effect
Placebo analgesia has been demonstrated for the treatment of neuropathic pain
Due to activation of descending inhibitory pathways
What’s gone wrong in chronic pain?
Peripheral terminals
- peripheral sensitisation
Axon
- spontaneous firing of nocioceptors
Dorsal root ganglia
- synthesis of new ion channels
Dorsal horn/ spinal cord
- central sensitisation
Brain
- changes in brain activation patterns
