Pharmacology of Pain Flashcards
How can pain occur within seconds to minutes?
Activation of nociceptive/specific wide dynamic range neurons proportional to intensity of stimulus
How can pain occur within minutes to days?
Sensitisation of nerve terminals at the injury site and delayed central sensitisation
How can pain occur within days to months?
Changes in supply of trophic growth factors, sprouting of fibres, abnormal innervation and trans-synaptic degeneration
What are the 3 types of pain?
- nociceptive (acute noxious mechanical/thermal/electrical stimuli)
- inflammatory (semi-acute or chronic ischaemia/infection/local degeneration)
- neuropathy (chronic maladaptive plasticity/disease affecting somatosensory nervous system)
What is the formation of the local circuits in the dorsal horn?
- first synapse between C fibre and dorsal neuron releases multiple transmitters which bind to various receptors
- NO, PG, glutamate
- interneuron modulates neuron so multitude of possible targets even just at first synpase
What is the role of opoids?
In the efferent pathway:
- activate PAG
- inhibits transmission directly at first synapse
- activates NRPG
- inhibits transmission at secondary neuron in periphery
Which parts of the brain do nociceptive stimuli activate?
- spinal cord
- thalamus
- somatosensory cortex
- anterior cingulate cortex
- insula
- amygdala
- prefrontal cortex
- hippocampus
What factors influence pain perception?
- cognition (attention/distraction/control/hypervigilance)
- mood (depression/anxiety)
- context (beliefs/expectations/placebo)
- chemical and structures (atrophy/dopaminergic dysfunction)
- injury (peripheral and central sensitisation)
- genetics
Which factors modulate the risk of developing chronic pain?
- hardware at birth (gender, genotype, epigenetic profile)
- environmental influences (acute injury/disease at critical developmental periods, stressful life events)
- gene + environment interactions (personality and psychology - pessimism/anxiety)
What are the 3 main families of opoids?
Proopiomelanocortin
Proenkephalin
Prodynorphin
What are the main receptors which opoids act on?
- Mu (1 and 2, widespread)
- Delta (1 and 2)
- Kappa (1,2,3)
- also pro-nociceptive endogenous systems such as CCK
What explains the broad spectrum of effects of opoids?
- Mu receptors being widely distributed
What are the problems of direct administration of opoids?
Very short half-lives so rapidly inactivated in circulation
Why can Mu receptors be negative?
- when opoids bind react most intensely which can cause adverse effects:
- increased dependence, respiratory depression, pupillary constriction
How can receptors to opoids be targeted in different patients?
- cause difference is responses
What are the 3 types of analgesia?
Supraspinal
Spinal
Peripheral
Which opoid receptors cause supraspinal analgesia?
Mu receptors
Which opoid receptors cause spinal analgesia?
Mu receptors
Delta receptors
Kappa receptors may
Which opoid receptors cause peripheral analgesia?
Mu receptors
Kappa receptors
Which opoid receptors cause pupillary depression?
Mu receptors highly
Delta receptors
Kappa receptors may
Which opoid receptors cause pupillary constriction?
Mu
Which opoid receptors cause reduced GI motility?
Mu
Delta
kappa may
Which opoid receptors cause sedation?
Mu
Kappa
Which opoid receptors cause euphoria?
Mu
Which opoid receptors cause dysphoria?
KAPPA!!!
Which opoid receptors cause dependence?
Mu!!!
What effects may opoids have on the CNS?
Analgesia, nausea & vomiting Respiratory depression Drowsiness/lethargy Miosis
What effects may opoids have on the CV system?
Hypotension
What effects may opoids have on the GI system?
Delayed gastric emptying
What are some examples of opoids?
- morphine
- heroin
- dextromoramide
- methadone
- meptazinol
- pethidine
What is the mechanism of morphine?
Forms active metabolite M6G
- decreased excitability and release of neurotransmitters
- activation of K+ conductance and decreased Ca2+ conductance
What is the mechanism of heroin?
High solubility compared to morphine
- cachexia is drug of choice
What is the mechanism of dextromoramide?
Active sublingually
What is the mechanism of methadone?
Half life increases on repeated dosing
What is the mechanism of meptazinol?
U1 receptor agonist
What is the mechanism of pethidine?
Forms metabolite
What is the significance of tolerance?
- not equivalent to development of addiction
- not important in terms of chronic pain
- natural neurobiological adaptation
What is the significance of personalised analgesia?
Patient variability
Affects different backgrounds
Possible to switch opoid when patient is becoming tolerant
What are the main non-opoids?
- paracetamol
- NSAIDs
- anticonvulsants
- tricyclic antidepressants
How does paracetamol work?
Reduces active oxidised form of COX2
Analgesic, antipyretic, little anti-inflammatory effect
How do NSAIDs work?
Inhibit COX2
What are examples of NSAIDs? What do they do?
- aspirin (COX1 and 2 inhibitor and anti-inflammatory
- ibuprofen/diclofenac/ketoprofen (COX1 and 2 inhibitiors)
- rofecoxib (selective COX2 inhibitors)
What are some indications for non-opoids?
Rheumatoid arthiritis Osetoarthiritis Dysmenorrhea Gout Muscle Spasms
What are the side effects of non-opoids?
Nausea
GI bleeding
What are anticonvulsant used for?
- neuropathic pain and trigeminal neuralgia
What are some examples of anticonvulsants and what do they act on?
- carbamazepine (Na+ channels)
- sodium valproate (Na+ channels)
- pregabalin (Alpha2delta subunit)
What is an example of a tricyclic anti-depressant and how does it work?
- amitriptyline
- inhibit reuptake of amine, block Na+ and Ca2+ channels
What is the WHO analgesics ladder for pain management?
1) Non-opoids and adjuvant
2) Moderate efficacy opoids - codeine (+1)
3) High efficacy opoids - morphine (+1)
Which drugs should be used for complex pain types?
- antidepressants
- anticonvulsants
- calcium channel ligands (gabapentin)
- vanilloid receptor agonists (capsaicin)
- NMDA glutamate receptor antagonists
- GABA receptor agonists
- opoid agonists (tramadol)
- local anaesthetics
How should you manage neuropathic pain?
1) offer convulsant or TCA + calcium channel ligands
2) try switching if initial drug is not tolerant
3) consider tramadol if acute rescue therapy needed
4) capsaicin cream if oral treatment not tolerated
How do local anaesthetics work?
- block sodium channels (risk of systemic toxicity = hypotension/respiratory depression)
- administered through surface/infiltration/epidural
What are examples of local anaesthetics?
Lignocaine
Prilocaine
How do general anaesthetics work?
Activation of inhibitory receptors/inhibition of excitatory receptors
- induce CV depression so monitored in surgery
