L5.3 Drug for control of chronic and severe pain Flashcards Preview

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Flashcards in L5.3 Drug for control of chronic and severe pain Deck (26)
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1

What is chronic pain characterised by

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)

2

Neuropathic pain

  • 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%)

3

Nociceptive circuit overview

  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

4

Features of the nociceptive neurons (receiving peripheral stimuli)

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

5

Neurotransmission in Dorsal horn

  • 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

6

Inhibitory regulation of NT

  • 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

7

Pharmacological treatments: Acute

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

8

Pharmacological treatment: Chronic

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

9

Where are opiate substances and opioid compounds from?

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

10

μ-opioid Gi-coupled GPCR

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

11

Morphine

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

12

SE of morphine

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

13

Peripheral SE of morphine

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

14

Pharmacokinetics of morphine

  • 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

15

Tolerance of morphine

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

16

Naloxone

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

17

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

  • targets Voltage gated Ca channels instead

18

Features of the VG Ca channels

  • 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

19

Gabapentinoids

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

20

Features of pregabalin

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

21

Mechanism of pregabalin

 

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

 

22

What is used during neuropathic pain

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

23

N-type Ca channel inhibitors

 

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

 

24

Mechanism of ziconotide

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

25

When are N-type Ca channels inhibitors used?

Used when intolerant to other treatments

26

Features of ziconotide (Admin, SE, potency)

  • 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