P: Drugs for Pain Management - Week 9 Flashcards
Provide 3 examples of how pain can cause profound changes in autonomic function
- heart rate
- blood pressure
- micturition
How does pain experience vary from person to person?
pain is uniquely individual and subjective
Define Acute Pain
Pain that has a recent onset and limited duration, usually due to an identifiable cause relatingto injury or disease
How can you classify acute pain. Provide and explain 2 classifications
- Somatic - sharp pain that is well localised
2. Visceral - dull pain that is poorly localised
What percentage of people with chronic non-cancer pain gain access to effective care?
less than 10%
NAme the 3 broad groups of chronic persistent pain (classified based on cause)
- Define nociceptive basis - e.g. cancer
- Well-defined neurophathological basis- e.g. postherpetic neuralgia
- Idiopathic - e.g. chronic musculoskeletal pain
How long should pain be ongoing to be considered chronic persistent pain?
more than 3 months
In regards to nociceptive superficial somatic pain, describe:
- stimulus origin (4)
skin, subcutaneous tissue, mucosa of mouth
In regards to nociceptive superficial somatic pain, name an example
malignant ulcers
In regards to nociceptive superficial somatic pain, describe: symptoms (3)
- hot, burning, stinging
In regards to nociceptive superficial somatic pain:
- does it have sudomotor/vasomotor effects?
No
In regards to nociceptive deep somatic pain:
- describe stimulus origin (6)
bones, muscles, joints; organ capsules, pleura
In regards to nociceptive deep somatic pain:
- provide 2 examples
- bone metastases
- liver capsule distension or inflammation
In regards to nociceptive deep somatic pain:
- describe symptoms (2)
- does it have sudomotor/vasomotor effects?
dull, aching
sudomotor/vasomotor effects may occur
In regards to nociceptive visceral pain:
- describe stimulus orgin (2)
- solid or hollow organs
- deep tumour masses
In regards to nociceptive visceral pain:
provide 2 examples
- deep abdominal or chest masses
- intestinal, biliary colic
In regards to nociceptive visceral pain:
- describe symptoms (2)
- dull, deep
In regards to nociceptive visceral pain:
- does it have sudomotor/vasomotor effects? (4)
Yes. Nausea, vomiting, sweating, BP/HR changes
In regards to neuropathic pain:
- describe stimulus origin (1)
damage to nociceptive pathways
In regards to neuropathic pain:
- provide 2 examples
- tumour-related
- spinal cord compression
In regards to neuropathic pain:
- describe symptoms (6)
- “pins and needles”
- tingling
- burning
- shooting
- allodynia
- phantom pain
In regards to neuropathic pain:
- describe sudomotor/vasomotor effects
sudomotor/vasomotor instability: warmth, sweating, pallor, cold, cyanosis
Describe in 5 steps the pathway of the nociceptive circuit
- activation of the peripheral terminal by a noxious stimulus leads to action potentials
- conducted to the dorsal horn of the spinal cord
- the dorsal horn relays the signal to cns regions
- signal passes through brainstem areas, the thalamus and to the cortex of the brain, to action
- descending modulatory control pathway
Describe the activation of nociceptive neurons (3)
- a thermal, chemical or mechanical sensory event activates a specific peripheral receptor, leading to ion influx and depolarisation of the peripheral terminal
- the generator potential induced by the nociceptive signal leads to AP production if the threshold for activation of the voltage sensitive sodium channel is reached
- frequency and duration of APs in activated fibre transfer information to CNS re onset, intensity and duration of stimulus
In regards to neurotransmission in the spinal cord dorsal horn, what does the incoming AP from the periphery activate?
activates presynaptic voltage sensitive calcium channels leading to calcium influx and subsequent synaptic vesicle release
In regards to neurotransmission in the spinal cord dorsal horn: What do the released neurotransmitters act on?
postsynaptic receptors
In regards to neurotransmission in the spinal cord dorsal horn: what does stimulation of ionotropic glutamate R lead to?
fast postsynaptic depolarization
In regards to neurotransmission in the spinal cord dorsal horn: what does activation of other modulatory R lead to?
slower postsynaptic depolarization
In regards to neurotransmission in the spinal cord dorsal horn: what happens when postsynaptic depolarization is sufficient?
it leads to AP production (signal generation) in secondary relay neuron and pain signal continues to higher centres
What regulates synaptic transmission in the spinal cord? (2)
actions of both:
- local inhibitory interneurons
- and projections that descend from the brainstem to the dorsal horn
T/F: the regulatory systems for synaptic transmission are a good site for pharmacological intervention
True
Name the 5 major inhibitory neurotransmitters in the dorsal horn
- opioid peptides
- noradrenaline
- 5-HT (serotonin)
- Glycine
- Gaba
In regards to pain severity based on pain score, how would you treat the following?
A) 1-3, Mild pain
B) 4-6, Moderate pain
C) 7-10, Severe pain
A: paracetamol
B: paracetamol + NSAID + oral opioid
C: Same as B but wiht increased dosage of oral opioid or with fentanyl patch (transdermal)
How many alkaloids does opium contain? Which alkaloid is most abundant in the opium?
More than 40 alkaloids. Most abundant is morphine (9-17%)
Provide one example of a naturally occurring opioid compound and a synthetic opioid compound
natural: morphine
synthetic: methadone
What is another name for endogenous opioid peptides?
Endorphins
How are endorphins synthesised and where? (2)
snythesised and released from nerves
- brain and spinal cord
- GI tract
Describe the physiological roles of endorphins (2)
- Analgesia: inhibit pain neurotransmission and perception of pain
- Regulation of intestinal motility
Where do endorphins act? (1) Are they useful as therapeutic agents? (1) Why? (3)
Act at opioid recetpros (several GPCRs)
- the are not absorbed from the gut, are rapidly metabolised, and do not pass BBB, therefore not useful as therapeutic agents
Where are u opioid Gi-coupled GPCRs found? (3)
- dense in brain and spinal cord
- peripheral tissues (vascular, cardiac, airway/lung, gut, immune/infl.cells)
Where do u-opioid Gi-coupled GPCRs act? (2) What do they achieve? (1)
act at primary sensory, local-circuit interneurons and descending inhibitory fibres to inhibit central relaying of nociceptive stimuli
Describe where in the nociceptive circuit (what step) do u-opioids act? (3)
- u-opioid agonists inhibit peripheral nerve transmission
- u-opioid agonists inhibit activity of relay neurons in dorsal horn
- u-opioid agonists enhance descending inhibition
What is the presynaptic action of u-opioid agonists? (1). What does this result in?
inhibition of calcium influx of action potential
- results in decreased NT release
What is the postsynaptic action of u-opioid agonists? (1) What does this result in?
u-opioid receptor activation increases K+ conductance (i.e. hyperpolarizing)
- results in decreased postsynaptic response to excitatory neurotransmission
What is the overall affect of opioid agonists acting at both presynaptic and postsynaptic sites?
jointly attenuates afferent neuron-evoked excitation of secondary neuron
Name 7 effects of the action of morphine u agonists
- analgesia
- euphoria
- less emotional response to pain
- sedation and respiratory depression (at therapeutic dose)
- nausea and vomiting
- pupillary constriction (miosis)
- antitussive (cough suppression)
Where does morphine act in the periphery?
GI tract
Kidneys
CV system
Mast Cells
What effects does morphine have on the GI tract? (2)
- constipation
- decreased ACh release + decreased motility
What effect does morphine have on the kidneys? (1)
- urinary retention
What effects does morphine have on the cardiovascular system? (3)
- reduce sympathetic tone, which
- causes orthostatic hypotension and bradycardia
How does morphine influence mast cells and what does this result in?
Histamine release from mast cells
- bronchoconstriction (may trigger asthma)
- vasodilation (decreases BP)
- itching
Describe the following pharmacokinetics of Morphine:
A: How is it usually administered?
B: What is the bioavailability when administered orally?
C: Which forms of morphine have the longer duration of action. Why?
A: Usually given either I.V (intravenous), I.M (intramuscular) or S.C (subcutaneously)
B: 25%
C: I.t. or epidural: there is a longer duration of action because the hydrophilic morphine takes time to diffuse out of the CNS to systemic circulation
Describe the hepatic metabolism of morphine: How much hepatic metabolism does morphine undergo and what does morphine metabolise into?
Morphine undergoes significant hepatic metabolism
- is metabolised to morphine 6-glucuronide (& 3-glucuronide)
How does morphine 6-glucuronide differ from morphine in terms of its action?
morphine 6-glucuronide is a more potent analgesic
Why is morphine dose reduction needed with people who have renal failure?
Because morphine glucuronides are excreted in the urine: this excretion will be difficult if there is renal failure so the drug could accumulate
Name 5 morphine tolerance effects
- analgesia
- euphoria
- sedation
- respiratory depression
- nausea and emesis
What 2 effects are NOT morphine tolerance effects?
- constipation
- miosis
In regards to morphine, how long does dependence last:
A: Physical dependence
B: Psychological dependence
A: physical dependence lasts for days
B: psychological dependence lasts for months or years
Why is heroin so addictive? Explain why in 4 points (4)
- heroin is a highly lipid soluble prodrug
- and so has more rapid entry to CNS than morphine
- is metabolized rapidly in brain to produce 3 and 6-acetylmorphine and then morphine
- results in fast, strong activation of pleasure centre and euphoria
List 4 general medical conditions that Diamorphine is prescribed for
- myocardial infarction
- palliative pain
- pulmonary oedema (to cause systemic vasodilation and sedation)
- post-operative pain
T/F: Diamorphine is prescribed for opiate addicts
True. However this practice is becoming increasingly uncommon
In regards to Methadone, describe the following:
A: route of administration
B: speed of onset
C: duration of half life
D: withdrawal reaction compared to heroin and morphine
E: what is it used for?
A: oral B: slow onset C: long half life (over 24 hours) D: withdrawal reaction less intense but prolonged E: tx of opioid dependence
In regards to Naloxone, describe the following:
A: what receptor does it act on, and in what way?
B: speed of hepatic metabolism, and consequence of this on administration
C: withdrawal reaction level
D: what is it used for?
A: opioid receptor antagonist
B: rapid, therefore usually given intravenously
C: normally no effect, but induces withdrawal in an opioid tolerant patient
D: used to treat opioid overdose
How does Naloxone treat opioid overdose?
By reversing sedation and respiratory depression
In regards to codeine, describe the following:
A: potency vs morphine
B: Form of administration
C: Level of euphoria and respiratory depression
D: Does it cause constipation?
A: less potent
B: oral
C: little to none
D: yes
What effect does codeine have at sub-analgesic doses?
antitussive effect (i.e. prevents/relieves cough)
In regards to Fentanyl, describe the following:
A: duration of action and what type of drug it is
B: level of potency
C: duration of half life
D: are active metabolites present?
E: constipation effects compared to other opioids
A: short-acting synthetic opioid B: potent (75-100 x morphine) C: short half life (1-2 hours) D: no active metabolites and less CNS adverse effects that morphine E: least constipating opioid
Describe the lipid solubility and lipophilicity of fentanyl and the consequence of this
Highly lipid soluble and liphophilic. HIgh lipophilicity allows biovailability via various routes
How can we administer Fentanyl to provide a long-acting effect?
Use a transdermal patch. This releases the drug slowly for long-acting systemic analgesia
Which drugs are used as an analgesic for the following:
A: Burns (2)
B: Chronic pain (e.g. cancer) (1)
C: Myocardial infarction (1)
A: morphine or fentanyl
B: morphine 1st choice
C: morphine
In what proportion of patients does opioid therapy work?
1/3rd
