L5.3 Drug for control of chronic and severe pain

Question 1

What is chronic pain characterised by

Answer 1

Pain > 3 months

1. Defined nociceptive basis (e.g. chronic arthritis)
2. Well-defined neuropathology
3. Idiopathic

• Pathogenesis not well accepted (e.g. musculoskeletal pain)

Question 2

Neuropathic pain

Answer 2

• Pain generated & perpetuated by NS
• Initiated by trivial injury central/peripheral NS (e.g. shingles)
• Pain becomes independent of initial triggering injury
• Poor response to analgesics (<50%)

Question 3

Nociceptive circuit overview

Answer 3

1. Activation of peripheral stimuli → AP
   
   • μ-opioid agonist inhibits activation
2. Conducted to dorsal horn of spinal cord
3. Dorsal horn relays signal to CNS
   
   • μ-opioid agaonist inhibit activating relay neurons
4. Signal pass through brainstem, thalamus → cortex of the brain
5. Descending modulatory control
   
   • μ-opioid agonist enhance inhibitory descending signals

Question 4

Features of the nociceptive neurons (receiving peripheral stimuli)

Answer 4

• Thermal/mechanical/chemical R activated → causes ion influx/depol → AP

Question 5

Neurotransmission in Dorsal horn

Answer 5

• AP activates N-type Ca channels → Ca influx → synaptic vesicle release
• NT release (glutamate – the main one in CNS) → co-released with other neuropeptides (CGRP & Substance P)
  
  • Co-release occurs after strong pains signals
• Ionotropic glutamate R → fast depolarisation
• CGRP R modulatory R → slow depolarisation

Question 6

Inhibitory regulation of NT

Answer 6

• NA, GABA, opioids released by descending &/or local-circuit ibhibitory neurons (in dorsal horn)
  
  • Acts at pre & post synaptic
• Presynaptic inhibition → Inhibition via ↓activating of voltage sensitive Ca channels
  
  • μ-opioid agonist acts like a2 → inhibits Ca influx
• Post-synaptic inhibition ↑Cl influx & K efflux
  
  • Hyperpolarised

Question 7

Pharmacological treatments: Acute

Answer 7

• Pain 1-3 = paracetamol
• Pain 4-6 = paracetamol ± NSAID ± oral opioids
• Pain 7-10 = ↑dose or stronger opioids

Question 8

Pharmacological treatment: Chronic

Answer 8

• Opioid therapy
• Limited, ↓intensity by 30-50%
• 80% patients have adverse effects
• May improve function & quality of life

Question 9

Where are opiate substances and opioid compounds from?

Answer 9

• Opiate substrates: From opium poppy
• Opioid compounds:
  
  • naturally occurring: Morphine, Codeine
  • Synthetic: Methadone & fentanyl

Question 10

μ-opioid Gi-coupled GPCR

Answer 10

• Dense in brain & spinal cord & peripheral tissues
• Acts at primary sensory
• Could act to inhibit control relaying of nociceptive stimuli

Question 11

Morphine

Answer 11

• 1st choice for chronic pain (i.e. in cancer)
• Analgesia, euphoria, Sedation, anti-tussive

Question 12

SE of morphine

Answer 12

• Resp depression (at therapeutic dose)
• Nausea & vomiting
• Miosis (pupil constriction) → diagnostic feature of overdose

Question 13

Peripheral SE of morphine

Answer 13

• GIT
  
  • Constipation
  • ↓ACh release & gut motility
• CV
  
  • ↓sympathetic tone → orthostatic hypotension
• Airways
  
  • Histamine release from mast cells → constrict bronchi → trigger asthma

Question 14

Pharmacokinetics of morphine

Answer 14

• Given iv or im (oral abs variable ~25% bioavailability)
  
  • Oral prep used for slow release (chronic pain)
• Significant hepatic metabolism → morphine-6-glucuronide (more potent)
  
  • Poor CNS entry
  • Excreted in urine
• Plasma ½ life = 3-6h
• Oral = 12-24h

Question 15

Tolerance of morphine

Answer 15

• ↑dose for equivalent effect
• depends on:
  
  • Potency of agonist
  • Route & freq of admin
• Morphine tolerance does not affect GIT & miosis (diagnosis of overdose) SE

Question 16

Naloxone

Answer 16

• Rapid metab → therefore given iv (1/2 life ~1h)
• Reverses sedation & resp depression
• opioid R antagonist
• Has affinity for all opioid R

Question 17

What is targeted in the circumstance that there is opioid resistant pain

Answer 17

• targets Voltage gated Ca channels instead

Question 18

Features of the VG Ca channels

Answer 18

• 4 subunits, a1 = pore forming subunit allowing Ca entry
• a2ζ protein (a2 attached to ζ subunit)
  
  • Accessory subunit of VG Ca channels
  • Predominant on CNS → involved in VG channels associated with pain)
• Modifies channel functional properties when present
  
  • ↑inactivation → therefore ↑ca current (more Ca entry)
  • Causes hyperexcitation

Question 19

Gabapentinoids

Answer 19

• Gabapentinoids designed to mimick GABA but not related
• Gabapentin & pregabalin

Question 20

Features of pregabalin

Answer 20

• AA which readily crosses BBB (via L-AA transporter)
• Ca channel modulator
• ↓SE and drug interactions

Question 21

Mechanism of pregabalin

Answer 21

1. Binds to a2ζ → ↓Ca influx in hyperexcited neurons, PRESYNAPTIC
2. ↓ time in open state
3. ↓ release of excitatory NT → ↓transition of pain signals

Question 22

What is used during neuropathic pain

Answer 22

• Gabapentin + morphine → ↑effectiveness at ↓dose , compared to ↑dose of individuals
  
  • ↓SE

Question 23

N-type Ca channel inhibitors

Answer 23

• Ziconotide (Synthetic w-conotoxin)
• w-conotoxin targets N-type Ca channels (selective antagonist)
  
  • Channels upregulated in dorsal horn after peripheral tissues inflammation/N damage

Question 24

Mechanism of ziconotide

Answer 24

• Ziconotide binds to N-type channels (disrupt Ca influ into presynaptic terminals)
• i.t. ziconotide effectively inhibits pain transmission in spinal cord

Question 25

When are N-type Ca channels inhibitors used?

Answer 25

Used when intolerant to other treatments

Question 26

Features of ziconotide (Admin, SE, potency)

Answer 26

• Intrathecal catheter into spinal cord to reduce SE
  
  • Sig peripheral implications with peripheral admin
  • Sympatholytic action → Major CV SE (hypotension, bradycardia)
• If supraspinal dose too high → CNS SE (abnormal gait, confusion…)
• No tolerance/addiction
• 10x more potent than morphine
  
  • Additive effects with morphine