Lecture 12. Pain and Opioid Analgesics Flashcards
(78 cards)
1
Q
What is the definition of pain?
A
An unpleasant sensory and emotional experience associated with real or potential tissue damage or described in terms of tissue damage
2
Q
What is pain coloured by?
A
Context, previous experience, expectation, culture, attention, anxiety
3
Q
What are the two components of pain pathways?
A
Peripheral nociceptive afferent neurons activated by noxious stimuli
Central mechanisms by which the afferent input generates a pain sensation
4
Q
What fibres are responsible for fast pain (sharp, short duration, well localised, pricking pain) in the peripheral pain pathways?
A
Aδ
5
Q
What are the features of Aδ fibres?
A
Myelinated
1-5 μm diameter
Fast conductance (5-30 m/s)
6
Q
What fibres are responsible for slower pain (dull, diffuse, long lasting, poorly localised, burning pain) in the peripheral pain pathways?
A
C fibres
7
Q
What are the features of C fibres?
A
Unmyelinated
0.1-1.5 μm diameter
Slow onductance (<1 m/s)
8
Q
What stops Aδ fibres from functioning?
A
Anoxia
9
Q
What stops C fibres from functioning?
A
Local anaesthetics
10
Q
What happens when both Aδ and C fibres are knocked out?
A
Patient feels no pain
11
Q
What activates Aδ fibres?
A
Mechanosensitive (eg tissue damage)
Temperature sensitive
12
Q
What activates C fibres?
A
Mechanosensitive (eg tissue damage)
Temperature sensitive
Chemical (capsaicin) etc
13
Q
What do both Aδ and C fibres release?
A
Glutamate and neuropeptides (such as substance P)
14
Q
Why is there a fast pain and a slow pain?
A
Don’t know
Theory is that fast pain exists to limit tissue damage and slow pain exists to tell you to immobilise area allowing healing.
15
Q
What is the main pain pathway?
A
Spinothalamic tract
16
Q
How does pain from the head and neck enter the CNS?
A
Via trigeminal nerve
17
Q
Where do sensory neurones have their cell bodies?
A
Not in the spinal cord, in the dorsal root ganglia
18
Q
Where do the pain pathways enter the spinal cord?
A
The dorsal horn of the spinal cord
19
Q
What part of the brain controls pain from the right hand side of the body?
A
Left brain
20
Q
Where is the synapse located that connects the spinothalamic tract to the sensory cortex?
A
In the thalamus
21
Q
What types of afferents carry pain?
A
Small afferents
22
Q
What lamina do the afferents that carry pain synapse into?
A
Lamina II - substantia gelatinosa
23
Q
How many segments can fibres ascend before crossing over?
A
1-2 segments
24
Q
Besides from pain sensation, what other effects are caused by pain?
A
Emotional (affective) effects of pain
25
What do the descending pathways from the brain modulate?
Pain sensation
26
What is Gate Theory?
That activating other fibres (distracting stimulus) prevents pain signals from entering the brain
27
What do parallel pathways modulate?
Affective dimensions of pain and control of autonomic activity
28
What is the periaqueductal gray (PAG)?
Region of cells around the aqueduct (central canal of the spinal cord) and connects to many different pathways (including the ascending pain pathway). The PAG can cause inhibition/reduction of the pain by acting with certain nuclei, analgesic pathway
29
What are examples of analgesics (pain killers)?
Local anaesthetics (block nerve conduction)
General anaesthetics
Non-steroidal anti-inflammatory drugs (NSAIDS like aspirin, ibuprofen)
Opioids (morphine etc.)
30
What does opiate mean?
Opiate is used to describe drugs derived from the opium poppy Papaver somniferum
31
What does opiod mean?
Opioid refers to both opiates and synthetic substances
32
What effects do opioids have on the CNS?
Profound analgesia (without loss of consciousness) - Good for acute and chronic pain, not so good for neuropathic pain
Respiratory depression - Reduces PCO₂ sensitivity of respiratory centre in medulla, most problematic of the side effects
Nausea and vomiting - Occurs in up to 40% of patients, activation of chemotrigger zone (medulla), disappears with repeated administration (tolerance)
33
What is the most common cause of death in an opiate overdose?
Respiratory depression
34
What do opioid drugs reduce sensitivity to and what does this mean?
Reduced sensitivity to the partial pressure of CO₂, meaning a much larger increase in CO₂ is required to stimulate breathing
35
What are the further CNS effects caused by opioids?
Euphoria, contentment and well being
Dry mouth
Drowsiness/lethargy
Depression of cough reflex (Pholcodeine)
Pupillary constriction (stimulation of occulomotor nucleus)
36
What are an important diagnostic feature of an opiate overdose?
Pinpoint pupils
37
What effects do opioid analgesics have on the GI tract?
Increases tone and reduces motility of gut
Constipation
Delays gastric emptying (slowing drug absorption)
38
What effects do opioid analgesics have on the direct release of histamine (from mast cells)?
Urticaria (hives)
Bronchoconstriction (bronchospasm), hypotension
39
What do opioid antagonists do?
Reverse the effect of opioid analgesics
40
When were opioid antagonists developed and why?
As early as 1915 when a derivative of morphine woke dogs that were asleep due to morphine injection
41
What do opioid antagonists imply the existence of?
Specific receptors for opioid analgesics (although could be functional antagonist)
42
What is a key difference between opioids and anaesthetics?
Opioids have a strict structure-activity relationship
43
How were opioid receptors first recognised?
Through binding studies utilising opiates labelled with radioisotopes that bound to brain membrane homogenates
44
Who were credited as the discovered of opioid receptors, when were they discovered and how?
Candace Pert and Solomon H. Snyder
1973
Published the first binding study of what would turn out to be the μ opioid receptor, using ³H-naloxone
45
What endogenous opioid peptides triggers contractions of the ileum and is antagonised by Naloxone?
Enkephalins
46
What are enkephalins?
Endogenous opioid peptides, analgesic and makes us feel good by triggering the release of dopamine
47
What are endogenous opioid peptides derived from?
Derived by cleavage of large precursors such as Proenkephalin by enzymes called peptidases
48
Where are opioid peptides found?
In areas associated with nociception (PAG, rostral ventral medulla and substantia gelantosa)
49
Why is it thought that enkephalins play a role in many processes?
Diffuse distribution
50
Where is β endorphin located and what role does it have?
Found in hypothalamus which send projections to PAG also to noradrenergic nuclei in brain stem, also found in the periphery in adrenal medulla, heart, kidney etc
Role unclear
51
What is the role of endogenous opioid peptides?
Modulate pain perception
Reward
Stress response
Autonomic control
52
What system do opioid analgesics work through?
Opioid analgesics essentially work through the endogenous opioid system replacing or supplementing the endogenous ligands
53
What is the evidence for multiple opiate receptors?
Many different opioid analogs
Nalorphine and morphine: N and M receptors
Studies using cross tolerance and withdrawal suggested at least 3 different receptor subtypes
54
What is more effective in inhibiting electrical-induced contractions within guinea pig ileum, morphine or enkephalins?
Morphine, potently blocked by naloxone
55
What is more effective in inhibiting electrical-induced contractions within the vas deferens, morphine or enkephalins?
Enkephalins, weakly blocked by naloxone
56
Where are μ opioid receptors (MOP) distributed?
Widely distributed in CNS and periphery
Cortex, thalamus, PAG, RVM, substantia gelatinosa
57
Where are κ opioid receptors (KOP) distributed?
Hypothalamus, PAG, substantia gelatinosa
58
Where are δ opioid receptors (DOP) distributed?
Pontine nuclei, amygdala, olfactory bulb, cortex
59
What do all opioid receptors produce?
Analgesia but other effects depends on receptor subtypes Kappa produces the most dysphoria (unease, opposite of euphoria)
60
What receptor subtype does morphine and diamorphine act on as an agonist?
MOP
61
What happens when the opioid receptors are activated?
Ca²⁺ channels inhibited
K⁺ channels activated
cAMP inhibited
62
What is tolerance?
Increase in the dose required to produce a pharmacological effect
63
How long does it tale for tolerance to develop?
Occurs within a few days
64
What causes tolerance to occur?
analgesia, emesis, euphoria, respiratory depression
65
How many times over the normal analgesic dose do addicts take in order to get high?
Can be up to 50
66
What has no/little tolerance?
Constipation and pupil dilation
67
What is dependence?
Compulsive craving that develops as a result of repeated administration of the drug
Psychological dependence outlasts physical withdrawal syndrome
68
What are the pharmacokinetics of opioids?
Morphine analogues - half-life of 3-6 hours
Erratic absorption orally
Hepatic metabolism (conjugation with glucoronide), some metabolites still active
Most excreted in urine, a proportion via the gut (entero-hepatic cycling)
Used on demand (infusion pump, PCA)
69
What are the properties of morphine and what is it used for?
Used for acute and chronic pain (palliative care)
Premedication, postoperative pain, PCA, myocardial infarction
Injected, rectal and oral formulation (including sustained release)
Half-life 3-4 hours (dose every 4 hours)
Many unwanted effects with tolerance and withdrawal not seen with analgesic use
70
What is diamorphine?
Heorin - powerful analgesic
Less nausea than morphine. Greater water solubility means smaller injections useful in palliative care when patient emaciated
71
What are the properties of fentanyl and what is it used for?
Acute pain and anaesthesia
Patient controlled infusion systems for chronic pain
Highly potent (about 100x morphine)
Rapid onset and short duration
Led to 50,000 death in USA during 2016 alone
72
What is carfentanil?
Extremely potent fentanyl derivative (10,000x morphine)
Used as a large animal tranquilliser
73
What are the properties of codeine and what is it used for?
Methyl ester of morphine
Naturally occurring in opium
Weaker analgesic than morphine (1/6 to 1/15 strength of morphine)
Less respiratory depression than morphine
Less liable to produce constipation
Combined with paracetamol (co-codamol)
74
What are the properties of oxycodone and what is it used for?
Acute and chronic pain
Oral (sustained release)
Half-life 3-4 hours
Claims for less abuse potential are unfounded
75
What are the properties of pethidine and what is it used for?
Prompt, short lasting analgesia, less potent than morphine
Anti-muscarinic (dry mouth, blurring of vision)
Duration similar to morphine
Less constipating than morphine
Analgesia during labour: does not reduce force of uterine contractions
Only slowly eliminated in neonate so may need naloxone (antagonist)
76
What are the properties of methadone and what is it used for?
Chronic pain and maintenance of addicts
Oral or injection
Long half-life (greater than 24 hours)
Little euphoria and less sedation (than morphine)
Slow recovery attenuates withdrawal
77
What are examples of opioid antagonists and what are they used to treat?
Nalorphine*, Naloxone, Naltrexone
Competitive antagonists (not *)
Useful for treating opioid overdose
For respiratory depression in babies
Precipitates withdrawal in addicts
78
What is an example of a partial opioid agonist and what is it used for?
Buprenorphine (Temgesic)
Partial agonist at MOP receptors
Sublingual, injection, intrathecal
Inactive orally as high first pass metabolism
Half-life ~ 12 Hours
Similar effects to morphine but less respiratory depression
Useful for chronic pain and dependence (USA)
Will precipitate withdrawal in patients dependent on morphine
