Physiological Analgesia + Analgesic Drugs Flashcards
What is the decending pain pathway?
Brain regions involved in pain perception (e.g. cortex, amygdala) and the spinomesencephalic pathway project to the periaqueductal grey (PAG) in the midbrain.
The PAG projects to brainstem nuclei that project to the spinal cord, modifying nociceptive transmission. These include:
- the locus coeruleus (in pons), which sends noradrenergic projections
- the nucleus raphe magnus (in medulla) that sends serotonergic projections
What does stimulation of the PAG do?
Excitation produces profound analgesia
Excitation can also be caused by enkaphalins (enogenous opioids), morphine
This is through inhibition of inhibitory GABA (aka disinhibition)
How does suppression of descending nociceptive transmission work?
- Direct presynaptic inhibition - inhibition of presynaptic neurotransmitter release from nociceptors (via GPCRs supressing VGCCs)
- Direct postsynaptic inhibition - GPCRS open K+ channels -> hyperpolarisation
- Indirect inhibition - activation of inhibitory interneurons (enkephalinergic, GABAergic) that suppress transmission pre- and post-synaptically (opioid agonists mimic enkaphalinergic neuron actions) (enkephalin acts on mu receptors presynaptically -> blocks VGCCs -> prevents neurotransmitter release OR acts on mu receptors post-synaptically -> activates K+ channels -> hyperpolarisation)
How do analgesics reduce nociception/pain?
- NSAIDs (decrease nociceptor sensitisation in inflammation)
- Block nerve conduction
- Suppress nociception signals in dorsal horn
- Activate descending inhibitory pathways
- Target ion channels upregulated in nerve damage
Describe the analgesic ladder by The WHO
Analgesics are placed on rungs according to clinical efficacy. Rungs:
- Strong opioids (morphine, fentanyl, heroin)
- Weak opioids (codeine, tramadol)
- NSAID (aspirin, diclofenac, ibuprofen, naproxen)
What neurotransmitter do neurons from the nucleus raphe magnus use?
Noradrenaline
Noradrenergic pathway
What neurotransmitter do neurons from the locus coeruleus use?
Serotonin (5HT)
Serotonergic pathway
What are the 3 types of opioid receptors?
Mu - analgesic, rewarding
Delta - analgesic, proconvulsant
Kappa - analgesic at spine/periphery, sedation, dysphoria, hallucinations
Why are opioids rewarding?
Presynaptic mechanims -> blocks GABA release at interneurons that project onto VTA dopaminergic cells -> disinhibition + increased excitation of dopamine neurons -> DA released into nucleus accumbens -> rewarding plus addictive
What systems can be affected by opioid use?
- Respiratory (nausea)
- Cardiovascular (orthostatic hypotension - like when you stand up suddenly)
- Gastrointestinal (nausea, vomiting, constipation)
- CNS (confusion, euphoria, dysphoria, hallucinations, dizziness, myoclonus, hyperalgesia)
Morphine
Mu agonist
For acute severe and chronic pain
Metabolised by liver
Can be given IV, IM, SC, and orally
Oral most appropriate in chronic pain
Epidural provides profound analgesia
Diamorphine
More lipophilic than morphine
IV works rapidly
For severe post-operative pain
Codeine
Weaker opioid for milf/moderate pain
Metabolised in liver by demethylation to morphine by CYP2D6 + CYP3A4
Orally
Reduces gut motility (anti diarrhoea)
Semi-synthetic derivatives with higher potency (oxycodone + hydrocodone)
Fentanyl
75-100 fold more potent than morphine
IV as maintenance anaesthesia (can reduce amount of anaesthetic needed)
Okay for chronic, not acute
Pethidine (meperidine)
Acute pain, like labour
Given IV, SC, IM - rapid but short duration of action, not for chronic pain
Not used with MOA inhibitors (excitement, convulsion, hyperthermia)
Norpethidine is neurotoxic metabolite (seizures)
Buprenophine
Partial agonist (competitive)
Chronic pain
Slow onset, long duration of action
Can be used to wean off addicts - lower abuse potential
Tramadol
Weak agonist for mu
Analgesic action through potentiation of serotonergic pathway from NRM and adrenergic from LC
Orally
Methadone
Weak agonist
Acts on K+ channels, NMDARs and 5-HT receptors as well
Long duration of action - decent for chronic pain
Orally
Can help with withdrawal from ‘strong’ opioids
Etorphine (immobilon)
For animals not humans
1000-fold more potent than morphine
Diprenorphine is weak partial agonist that reverses action of etorphine
Naloxone
Competitive antagonist at mu (less at kappa + delta)
Reverse opioid toxicity
IV preferred
Short half-life
Naltrexone
Similiar to naloxone (antagonist)
Longer half-life
Oral availability
Alvimopan and methylnatrexone
Do not enter CNS, do not cross BBB
Reduce G.I. effects of surgical and chronic opioid agonist use
What do NSAIDs do?
Reduce mild/moderate anti-inflammatory pain
Analgesic, antipyretic, anti-inflammatory actions by inhibiting synthesis + accumulation of prostaglandins by cyclo-oxygenase (COX) enzymes COX-1 (constitutively active) and COX-2 (locally induced by cytokines)
Decreases recruitment of leukocytes that produce inflammatory mediators
If cross BBB -> suppress production of prostaglandins in dorsal horn (may reduce action of glycine)
Multiple signalling pathways -> several do not involve arachidonic acid metabolism
Long-term may cause GI problems (PGE2 protects against stomach acid for instance)
COX-2 inhibitors may be prothrmbotic
What are COX-2 selective NSAIDs?
Etoricoxib
Celecoxib
Parecoxib
What are prostaglandins?
Molecules that modulate activation of nociceptor neurons + responses
Preventing this prevents pain
Decrease activation threshold of peripheral terminals of nociceptors (suppressed by NSAIDs)
What are instances of neuropathic pain?
Traumatic nerve, spinal cord, brain damage
Trigeminal neuralgia
Diabetic neuropathy
HIV/AIDS neuropathy
Post-herpetic neuralgia
Multiple sclerosis
Phantom limb pain
Doesn’t respond to NSAIDs + relatively insensitive to opioids (maybe due to down regulation of mu receptors or reduced sigalling via mu)
What are drugs for neuropathic pain?
Gabapentin (GBP) and pregabalin (PGB) (antiepileptics)
First line treatments (works in <35%)
GBP does NOT act via GABA
GBP reduces expression of alpha2delta1 subunits of VGCCs which are upregulated in damaged sensory neurons
Decreases enhanced neurotransmitter release
PGB useful for diabetic neuropathy
Carbamazepine
Blocks subtypes of voltage-activated sodium channels upregulated in damaged nerve cells
Used to control frequency of attacks in trigeminal neuralgia
Amitryptaline, nortryptaline, desipramine (tricyclic antidpressants)
First line treatments
Decrease noradrenaline reuptake
Duloxetine + venlafaxine can also decrease reuptake of serotonin
