Lecture 3- Adjunct Analgesics 1 Flashcards
Pain
- sensory interface with our environment
Chronic pain
- > 3 months
- maladaptive
- leads to plasticity changes in NS
Acute pain
- warning system for harmful stimuli
the pain pathway
Two main neuronal pathways for transmission of pain:
1) Spinothalamic pathway
2) Spinoreticular pathway
sensation portion of pain: somatosensory cortex
cognition: hypothalamus
emotional aspect of pain: limbic system
Classification of Sensory Nerves
- Sensory nerve classification —> depends on diameter
- large diameter + myelination = fast signalling
- proprioception: sensation of body in 3D
- mechanosensation: feelings of touch
red table= slow conducting fibres, they have very thin myelin and small diameter
- a delta: twist ankle
- c fibres: when things too hot or too cold
Pain classification based on time
- Acute: < 3 months
- Intermittent
- Chronic: > 3 months
Pain classification based on intensity
- Visual Analogue Scale (VAS)
- very rudimentary
- scale 1-10
- mild: 1-4
- moderate: 5-6
- severe: 7-10
3 types of pain
- Nociceptive: touching hot plate
- Inflammatory: rheumatoid arthritis
- Neuropathic: postherpetic neuralgia (damage to NS)
Nociceptive pain
Inflammatory pain
- TRPV1= activated by acidity
- VIP and SP (substance P)= made in DRG and stored, transported to peripheral nerve ending where can be stored in vesicles, ready to rapid release in response to noxious stimulus
- VIP= VPAC 1 receptor
- substance p —> on NK1 receptor
- Mast cells release histamine —> H1 receptors on nerve terminals —> itchy
- Leukocytes —> release proteases —> act on PAR (proteinase activating receptors)
- Prostaglandins
- whole family of inflammatory cytokines
Neuropathic pain
- damage to the nervous system
Damage to peripheral NS
- Trauma: ex- post surgery
- Metabolic: diabetic neuropathy
- Infection: postherpetic neuralgia
- Chemotherapy-induced neuropathy
Damage to central NS
- Spinal cord injury
- Stroke
- Multiple sclerosis
Classes of Analgesics
Non-opioid analgesics
- Acetaminophen, NSAIDs, Coxibs
Opioid analgesics
- Morphine, oxycodone, fetanyl
Adjunct analgesics
- Anti-convulsants
- Anti-depressants
- Biologics
Types of anti-depressants
- TCAs / tricyclic antidepressants
- SNRIs / serotonin-norepinephrine reuptake inhibitors
- SSRIs/ selective-serotonin reuptake inhbitors
Amitriptyline
- tricyclic anti-depressant
- blocks re-uptake of NA and 5-HT in spinal cord
- increased descending inhibition
- analagesic effect independent of mood change
- good for neuropathic pain
Side effects
- messy
- blocks calcium channels by stabalizing the inactive state
- also blocks NMDA, Na+, K+ channels in heart and skeletal muscle
- dry mouth and drowsiness
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Duloxetine
- SNRI
- blocks reuptake of 5-HT and NA
- not as effective for treating neuropathic pain as TCAs, but fewer side effects (doesn’t block NMDA receptors)
Venlafaxine
SNRI
blocks reuptake of 5-HT and NA
not as effective for treating neuropathic pain as TCAs, but fewer side effects (doesn’t block NMDA receptors)
TCAs
- tricyclic antidepressants
- highly effective for chronic neuropathic pain
- Amitriptyline
BUT
- analgesic effect occurs independently of mood change
- amitriptyline blocks the neuronal uptake of noradrenaline and 5-HT in spinal cord: increases descending inhibition (impulses from brain to 2nd neurons in SC, dampening down the neurotransmission of pain info to brain)
- messy: blocks NMDA receptors, Na+, K+, Ca2+ channels
Side effects
- dry mouth
- drowsiness
Gabapentinoids
- anti-convulsant
Mechanism of action
- binds a2d (alpha2delta) subunit of Ca2+ channel
- inhibits the release of excitatory NTs
- also modulates Na+, K+ activity –> altered neuronal excitability
- given dose= decrease in firing of AP = decreased pain
- in acute inflammation —> does not reduce pain
- very effective at reducing mechanosensation, but if in inflammatory pain, not as effective
- why? alpha2delta subunit has been altered, no longer able to bind
- not ideal for inflammatory pain
- however is effective for neuropathic pain
Voltage-gated sodium channels (VGSC) Blockers
- Na+ channels activated in response to cell depolarization
- voltage-dependent conformational change in ion channel –> open state
- inactivation result of conformational change in ion channel sub-units
4 different shapes of sodium channel
open inactivated; pore still open, sodium wont flow cuz trapped door
closed inactivated: double blockage
Types of VGSC
NaV1.7
Gain of function
- mutation in SCN9A gene
- familial erythromelalgia
- burning, intense pain
Loss of funtion
- loss of function in SCN9A gene
- congenital insensitivity to pain
- self harm, unknown injuries
Lidocaine
- local anaesthetic
- binds to intracellular pore –> channel inactivation
- can be delivered as a patch to control neuropathic pain
- can be administered i.v
- not selective –> can inhibit cardiac Na+ channels at high concentration
Amitriptyline
- antidepressant
- preferentially binds to inactivated channels keeping them in the inactive state
- interacts with the local anaesthetic binding site
- effective in treating neuropathic pain
- non-selective for Na+ channel subtypes –> can affect cardiac and skeletal muscle activity
Carbamazepine
- anti-convulsant
- preferentially binds to inactivated channels keeping them in the inactive state
- inhibit both TTX-sensitive and TTX-resistant Na+ channels
- used to treat trigeminal neuralgia and migraine
- non-selective for Na+ channel subtypes so can affect cardiac and skeletal muscle activity
Effect of Nav1.8 Blockade on joint pain
-give same amount of rotation to joint, firing of sensory nerves reduced, less pain
Voltage-gated calcium channels table
L type calcium channels = current maintained for a longer period of time
PQ= Purkinje
R= residual, initial depolarization, slowly tapers down to baseline
T type= current is transient, not maintained, high threshold activation
Voltage-gated calcium channels (VGCC)
- open in response to changes in membrane potential
- classified based on type of voltage required to activate them
- Low threshold (T-Type)
- High threshold (L, N, P/Q, R Type)
- sub-classified based on the a1 pore forming subunit structure and pharmacologic properties
