PHARM - Drugs for Pain Management - Week 9 Flashcards
Define pain.
Unpleasant sensory and emotional experience associated with actual or potential tissue damage
What is the vital purpose of pain?
Serves as a defence function
Is pain objective or subjective?
It is a uniquely individual and subjective exerience
List the two kinds of acute pain and list two properties for each.
Somatic
-sharp
-well localised
Visceral
-dull
-poorly localised
Do a significant number of individuals live with constant chronic pain or is it rare?
Common - 1 in 5 for Australia
Are current evidence-based treatments of chronic pain under- or over-utilised? Explain.
Under-utilised.
<10% of people with chronic non-cancer pain gain access to care that could allow up to 80% to be treated effectively.
What period of time is chronic persistent pain considered to be?
> 3 months
List the three broad groups of chronic persistent pain and give an example of each.
Defined nociceptive basis
-cancer
Well-defined neuropathological basis
-peripheral neuropathy
Idiopathic
-chronic musculoskeletal pain
Describe the kind of pain felt by the following classifications:
Superficial somatic (3)
Deep somatic (2)
Visceral (2)
Neuropathic (5)
Superficial somatic - hot, burning, stinging
Deep somatic - dull, aching
Visceral - dull, deep
Neuropathic - pins/needles, tingling, burning, shooting, phantom pain
Briefly describe, in 5 steps, the nociceptive curcuit for pain.
Activation of the peripheral terminal by a noxious stimulus
It is conducted to the dorsal horn of the spinal cord
Dorsal horn relays the signal to the CNS
Signal passes through brainstem areas, the thalamus, to the cortex of the brain
Signal descends along a modulatory control pathway
What are the three kinds of sensory events that can activate a nociceptive neuron? Can all the receptors be activated by a single event or are there specific receptors for specific events?
Thermal, chemical, and mechanical
Each one activates a specific peripheral receptor
What three pieces of information can frequency and duration of an action potential by a nociceptor transfer to the CNS?
Onset
Intensity
Duration
Describe the two inhibitory regulations that can occur to the spinal cord.
Local inhibitory interneurons
Projections that descend from the brainstem to the dorsal horn
Name 5 major inhibitory neurotransmitters in the dorsal horn.
Opioid peptides
Noradrenaline
5-HT
Glycine
GABA
Consider acute pain severity. Describe the pharmacological treatment for mild (1), moderate (3), and severe (4) score ratings.
Mild - paracetamol
Moderate - paracetamol ± an NSAID ± oral opioid
Severe - as in moderate with an increased dose of oral opioid ± i.v./s.c. opioid or fentanyl patch
What are opiate substances derived from?
Opium poppy
What are the two naturally occuring opioid compounds in opium poppy?
Morphine and codeine
What are endogenous opioid peptides called?
Endorphins
What are endorphins, where are they made, and what molecule does it have similar activity to?
Neurotransmitter and hormone peptides made in the brain that acts similar to morphine
Aside from the brain, where else are endorphins made and released?
Gastrointestinal tract
List two roles of endorphins.
Analgaesia - inhibit pain neurotransmission/perception of pain
Regulation of intestinal motility
Can endorphins be absorbed from the gut? What happens to them? Do they pass the blood-brain barrier? Are they useful therapeutic agents?
Not absorbed by the gut.
Rapidly metabolised and cannot pass the blood-brain barrier.
Not useful as therapeutic agents.
What are the receptors for opioids, what effect do they elicit, and in what two areas of the body are they dense?
Can they be found in peripheral tissues or na?
μ Opioid Gi-coupled GPCRs
They elicit analgaesia
Dense in the brain and spinal cord
Can also be found in peripheral tissues
Consider peripheral nerve transmission for pain. Keeping whether opioid receptors are present peripherally or not, describe the effect μ-opioid agonists would have on this transmission.
Opioid receptors are found peripherally, and so agonists to these receptors would inhibit peripheral pain transmission.
Consider a peripheral pain signal being conducted to the dorsal horn of the spinal cord. What effect would a μ-opioid receptor agonist have on this process?
No effect.
Consider a pain signal at the dorsal horn. What effect would a μ-opioid receptor agonist have here?
An agonist would inhibit the activity of relay neurons.
Consider a pain signal passing through brainstem areas, the thalamus, and to the cortex of the brain. What effect would a μ-opioid receptor agonist have here?
No effect.
Consider the descending modulatory control pathway. What effect would a μ-opioid receptor agonist have here?
They enhance descending inhibition
Describe the pre-synaptic mechanism of action of a μ-opioid receptor agonist (2).
Inhibits Ca2+ influx
-decreases neurotransmitter release
Describe the post-synaptic mechanism of action of a μ-opioid receptor agonist (3).
Increases K+ conductance, leading to hyperpolarisation, and decreased post-synaptic response to excitatory neurotransmission
Name three effects of morphine.
Analgaesia
Euphoria
Less emotional response to pain
List 8 adverse effects of morphine in the CNS.
Sedation
Respiratory depression
Nausea/vomiting
Miosis
Antitussive
Constipation
Urinary retention
Orthostatic hypertension
Histamine release from mast cells
What is miosis an important diagnostic feature of regarding morphine?
Overdose
What may morphine administration trigger?
Athsma
How is morphine usually administered (3)?
IV, intramuscularly, or subcutaneously
Can morphine be administered orally?
Yes but absorption is variable
Where is morphine mostly metabolised?
Liver
What is the duration of action for morphine?
Plasma half life is 3-6h
Does tolerance occur for morphine? Explain.
Yes, an increased dose is needed for the equivalent effect due to gradual loss of effectiveness
What does the level of tolerance typically depend on (2)?
Potency of the agonist
Route/frequency of administration
What is typically done when tolerance levels increase (3)?
A change of analgaesic drug
Higher dose
Higher frequency
Name 6 effects of tolerance to morphine.
Analgaesia
Euphoria
Sedation
Respiratory depression
Nausea
Emesis
Do constipation and miosis occur as a result of morphine tolerance?
No
Describe physical and psychological dependence on morphine.
Physical - withdrawal symptoms that occur when morphine use stops
Psychological - craving for morphine
How long can psychological dependence on morphine last?
Months or years
How long can physical dependence on morphine last?
Days
What is the physical dependence reaction to morphine proportional to?
The level of tolerance
What kind of drug is heroin (aside from being an opiate)?
A prodrug
Is heroin highly lipid or water soluble?
Lipid
Which gains more rapid entry to the CNS, heroin or morphine?
Heroin
What happens to morphine in the brain?
Rapidly metabolised into morphine
What is the result of taking heroin (2)?
Results in a fast, strong activation of the pleasure centre and euphoria
Briefly explain what diamorphine was used for and whether it is common practice to use it.
Typically prescribed for opiate addicts as well as some general medical conditions like paliative or post-op care.
Generally only used in the UK, not well understood outside the UK, and specifically prohibited in most countries.
Can methadone be taken orally? What is its onset like? Does it have a quick or long half-life?
Orally active
Slow onset
Long half life >24h
Compare the withdrawal reaction of methadone to other opiates like morphine.
Reaction is less intense but prolonged
What may occur due to methadones half-life?
Accumulation
What can methadone be used to treat aside from pain management?
Opioid dependence
What is the mechanism of action for naloxone? Does it have an affinity for all opioid receptors?
Opioid receptor antagonist
Affinity for all opioid receptors
What kind of metabolism does naloxone undergo and how is it normally administered?
Rapid hepatic metabolism, sousually given i.v.
What is the normal effect of naloxone and what does it induce in an opioid-tolerant patient? What is it used to treat? What two symptoms does it reverse?
Normally has no effect
In opioid-tolerant patients, it will induce withdrawal
Used to treat opioid overdose
Can be used to reverse sedation and respiratory depression
What is more potent, codeine or morphine?
Morphine
Is codeine orally active?
Yesd
In what population (percentage) can codeine cause no analgaesia and why?
In 10% of caucasians, they lack the metabolising enzyme for codeine to morphine (hepatic) so no analgaesia
Which of the following are induced by codeine (4):
Euphoria
Respiratory depression
Constipation
Antitussive
Little to no euphoria
Little respiratory depression
Causes constipation
Antitussive only at sub-analgaesic doses
What is fetanyl?
Short acting synthetic opioid
What is more potent, fetanyl or morphine?
Fetanyl, 75-100x more than morphine
Is fetanyl highly lipid- or water-soluble?
Lipid
Does fetanyl have a long or short half-life?
Short
What is fetanyl suitable for given its half-life (2)?
Incident or procedure-related pain
What is the analgaesic effect of fetanyl limited by?
Redistribution to inactive tissue stores
Does fetanyl have active metabolites?
Noh
What is the least constipating opioid?
Fetanyl
Which has more CNS adverse effects, fetanyl or morphine?
Morphine
What does the high lipophilicity of fetanyl allow for?
Bioavailability via various routes, including oral
What is fetanyl typically used for and how? Why is it administered this way? How often is it readministered?
Used for ongoing severe pain as a transdermal patch
Changed every three days
This releases the drug slowly for long acting systemic analgaesia
Consider the administration of fetanyl. What is the half-life like after one administration cycle and why?
Half-life is 15-20h
This is due to the redistribution of fetanyl out of inactive stores to active sites
What is the first choice opiate for chronic pain (like cancer)?
Morphine
What is the first choice opiate for myocardial infarction?
Morphine
What two drugs can be used as anaesthesia and how is it administered (3)?
What is the benefit of doing it this way?
Fetanyl - epidural or transdermal patch
Morphine - epidural
Decreases the need for IV/inhaled anaesthetics, less circulatory depression
