Adjunct Analgesics Flashcards
4 steps in the pain pathway
- Nociception (Adelta and C fibers)
- Neurotransmission (up ascending pathways in spinothalamic path)
- Sensation, cognition, emotion (somatosensory cortex, limbic system, amygdala)
- Neuromodulation (descending pathways can turn the signal up or down)
A delta fibers
1-5 micrometers 5-30 m/s Myelinated Mechanosensation Nociception
C fibers
<1.5 um <2 m/s Unmyelinated Temperature Nociception
Crude way of analyzing pain
Visual analog scale
7+ is severe
5-6 is moderate
1-4 is mild
3 types of pain
Nociceptive
Inflammatory
Neuropathic
5 things that can activate nociceptors
Mechanical Heat Cold Pathogens Chemicals
4 causes of neuropathic pain in the periphery
Trauma
Metabolic disorders
Infection
Chemotherapy-induced neuropathy
3 causes of neuropathic pain in the CNS
Spinal cord injury
Stroke
Multiple sclerosis
Tricyclic Antidepressants (TCAs)
Very effective for chronic neuropathic pain
Ex: Amitriptyline
Analgesic effect occurs separately from mood change
Blocks neuronal uptake of NA and Serotonin in the spinal cord (increases descending inhibition)
Also blocks NMDA receptors and some ion channels
Side effects: dry mouth and drowsiness
Serotonin-noradreniline reuptake inhibitors (SNRIs)
Ex: duloxetine, venlafaxine
Not as effective as TCAs at reducing pain
Side effect profile decreases
Fewer side effects than amitriptyline because it doesn’t block NMDA receptors
Selective serotonin reuptake inhibitors (SSRIs)
Ex: Fluoxetine, fluvoxamine
Fewer side-effects due to high selectivity
But low efficacy for diabetic neuropathic pain
Antidepressant order for
- Efficacy
- Side effects
- TCAs> SNRIs > SSRIs
2. TCAs > SNRIs > SSRIs
Anticonvulsants
Developed for use in epilepsy
Interferes with neuronal excitability
Effective for postherpetic neuralgia, diabetic neuralgia, fibromyalgia
Side effects: drowsiness, dry mouth, weight gain, dizziness
Ex: gabapentin, pregabalin
Gabapentinoids
Binds to alpha 2 delta subunit of Ca channel
Inhibits release of excitatory NTs
Also modulates Na, K activity (altered neuronal excitability)
Gabapentin and Joint Pain study
Gabapentin given locally into joint
The drug reduced mechanosensitivity in normal and inflamed joints
Effect greater in normal than arthritic joints
Inflammation may alter gabapentin binding to the alpha 2 delta subunit of Ca channel
Not ideal for inflammatory pain
4 states of a voltage-gates sodium channel
Closed (primed) - gate is open, pore is shut
Open (activated) - both are open
Open inactivated (fast) - pore is open, gate is shut
Closed inactivated (slow)- both are closed
Where are
- TTX sensitive channels
- TTX resistant channels
- Muscle, CNS
2. Some sensory neurones
Gain of Function Mutation in Na V1.7
Mutation in SCN9A gene Familial erythromelagia (tissues look very red) Burning and intense pain Higher than normal levels of Na V1.7 channels
Loss of Function Mutation in Na V1.7
Loss of function in SCN9A gene
Congenital insensitivity to pain
Self harm, unknown injuries
The patients suffer acute mental illness – crave feeling of pain and do self-harm
Lidocaine
Local anaesthetic
Binds to intracellular pore (channel inactivation)
Can be delivered as a patch to control neuropathic pain
Can be administered in IV
Not selective so 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 so can affect cardiac and skeletal muscle activity
Carbamazepine
Anticonvulsant
Preferentially binds to inactivated channels and keeps them in the inactive state
Inhibits both TTX sensitive and resistant Na channels
Used to treat trigeminal neuralgia and migraine
Non-selective for Na channel subtypes so can effect cardiac and skeletal muscle activity
Effect of Na V1.8 blockade on joint pain
The number of APs decrease when administered locally
Can tell the pain is decreasing because they start to shift their weight back to the osteoarthritic joint
Voltage-gated Ca channels
Open in response to changes in membrane potential
Classified based on type of voltage required to activate them (low or high threshold)
Subclassified based on the alpha 1 pore forming subunit structure and pharmacological properties
L-type Ca channel
- Examples (2)
- Results (2)
“Long lasting”
- Nifedipine, verpamil (channel blockers)
- decrease substance P release and decrease pain
N-type Ca channel
“Neuronal”
omega conotoxin causes decreased substance P release and decreased pain
Knockout animals have decreased inflammatory and neuropathic pain
P/Q type Ca channel
“Purkinje”
omega agatoxin causes decreased substance P release and decreased migraine
R-Type Ca channel
“Residual”
SNX-482 from tarantula causes decreased substance P release
T-Type Ca channel
- Example
- Results in
“Transient”
- Mibefradil (partial channel blocker)
- Decreased pain
Proteinases
Enzymes that hydrolyse peptide bonds in proteins
Generally physiologically active peptides
Coagulation cascade
Inflammation
Tissue destruction/remodelling
Signal pain
Which class of proteinases signal pain?
Serine proteinases
How do proteinase activated receptors work?
A proteinase has to cleave off a sequence at the N terminal, and leave the tethered ligand sequence exposed
This can then bind to the extracellular ligand binding domain on the receptor
From an inactive receptor, you can get cleavage and what 3 resultant forms?
Activated receptor
Disarmed receptor
Antagonist blockade
PAR 1
- Proteinase
- Physiological functions (2)
- Thrombin
2. Vasorelaxation, decreases pain
PAR 2
- Proteinases (3)
- Physiological functions (2)
- Trypsin, Tryptase, Elastase
2. Vasorelaxation, increases pain
PAR 3
- Proteinase
- Physiological function
- Thrombin
2. Unknown
PAR 4
- Proteinase (2)
- Physiological functions (2)
- Thrombin, Cathepsin G
2. Vasorelaxation, increases or decreases pain depending on the tissue
Osteoarthritis
Most common form of arthritis
Degenerative disease
Destruction elicited by serine proteinases
Loss of articular cartilage and remodelling of subchondral bone
2 ways to measure pain in rats
Weight bearing
vo Frey Hair Algesiometer
Neutrophil elastase
Will see rats move their weight to the other leg if you give this
It’s signalling pain
Mast cell tryptase
Caused pain when injected into knee joint
Can see it in reduced hindlimb weight bearing and reduction in paw touch sensitivity
Effect reduced in TRPV1 knockout mice
How does PAR2 signalling work?
Neutrophils and mast cells release elastase and tryptase respectively
They act on the PAR2 receptor on the afferent nerve terminal
PAR2 activates TRPV1
Releases substance P
Acts on NK1 to cause pain
How does PAR1 signalling work?
Release of thrombin can act on PAR 1
Activation of par 1 causes release of endogenous opioids
They act on mu opioid receptors present on sensory receptors
Get analgesic effect
How does PAR4 signalling work?
Cathespin G and thrombin can act on mast cells (where PAR4 is expressed)
Mast cells release bradykinin
Acts on afferent nerve terminals
Also are PAR4 receptors directly on the nerve terminal
If its in the GI tract, causes analgesia
If its in the joint, causes pain
Cytokines
Extracellular signalling molecules
Mostly water soluble
Synthesis is activated by mitogen-activated protein kinase
When do interleukins increase?
During inflammation and injury
Antagonists can block pain
IL-6
Requires receptor alpha and gp130 signal transducing subunit of cytokine class 1 receptor superfamily
Needs both receptor, and subunit to signal
Increases pain
IL-10
Inhibits cytokine production from activated T cells
Used Jak/Stat pathway
Decreases pain
TNF-alpha
Cytokine producing inflammation, pain, joint erosion
Can be membrane bound or soluble
2 receptors
2 main classes of TNF-alpha blockers
Soluble receptors
Monoclonal antibodies
3 TNF-alpha blocker drugs
Etanercept
Infliximab
Adalimumab
TNF-alpha blocker drugs
Decrease acute flares and pain Can reverse disease Some patients go into complete remission Usually taken with methotrexate Works in 2/3 patients Efficacy decreases over time Side effects: fever, infection, cost
Biosimilar
Antibodies that are highly similar to an originator, but are not the exact same
Genetic drift and evolution occurs
Where can biosimilars go different? (6)
Different genetic sequence Different DNA vector Different recombinant cell system Different in-process controls Different purification protocol Different formulation
4 problems with biosimilars
Immunogenicity (people can have poor efficacy from antibodies neutralizing the biosimilar)
Variable manufacture of reagent
Extrapolation of indication (can bypass phase III clinical trials)
Substitution (by prescribers or non-prescribers)
