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PCOL3922 > Drugs and afflictions > Flashcards

Drugs and afflictions Flashcards

1
Q

Describe the spectrum of opoid effects on the body and their consequences

A 
•	Analgesia
o	For acute, severe pain 
o	Used in anaesthesia 
•	Nausea, vomiting
•	Respiratory depression
o	Major cause of death by opioid overdose
•	Constipation
•	Reward
o	Cause euphoria
•	Tolerance
o	Development of tolerance to opioid 
•	Addiction
o	Opioid dispensing episodes increased 15-fold in the last 20 years
o	Now the leading cause of accidental death in the USA
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2
Q

What are specific nerve pathways that are activated by noxious stimuli?

A

• Specific nerve pathways are activated by noxious stimuli
o Specific sensory nerve pathways
o Specific parallel pathways from spinal cord
o Descending modulatory pathways to spinal cord

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3
Q

Describe how noxious stimuli is transported to and regulated by the brain

A

• Nociceptors are responsive to noxious stimuli and transmit information into the spinal dorsal horn, which ascends into the brain
o Brain asserts descending control to determine how effective the pain transmission is going to be
 There are environmental conditions that are counteractive to experiencing pain

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4
Q

What are the two main pes of fibres for pain?

A

• Two main types of fibres for pain
o C fibres-
o Aδ fibres

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5
Q

Describe the speed, myelination and role of C fibres

A

o C fibres-
 1.5 m/s APs
 Unmyelinated fibres
 Second pain

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6
Q

Describe the speed, myelination and role of Adelta fibres

A

o Aδ fibres
 6-25 m/s APs
 Myelinated fibres
 First pain

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7
Q

Where are opioid receptors generally located and where do opioids act?

A

• Opioids act primarily on C-fibre synapses (central terminals of the fibres, but there are some in the periphery)
o Opioids act mostly on C-fibres that transmit noxious information in sensory neurons
 Act on Aδ fibres a bit as well
o μ opioid receptors are located on nociceptive nerve terminals (main actions are in the central nervous system
o Opioids act at all levels of pain pathways
 Forebrain- lateral sensory system (thalamus, cortex), medial system emotional responses (limbic system)
 Midbrain and brainstem- descending systems (PAG, raphe nuclei)
 Spinal cord- sensory modulation (dorsal horn)

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8
Q

Describe the physiological actions of opioids

A

 Presynaptic inhibition
• Opioids close calcium channels
 Postsynaptic inhibition
• Opioids open potassium channels
• Opioids act to block neurotransmitter release and action potential activity
o Alpha and betagamma subunit release from G receptor:
 Opens potassium channels that reduce excitability of the cell
 Shut voltage gated calcium channels in the synapses that allow calcium into the nerve terminal that triggers sequences of events that releases neurotransmitters
• Inhibits N-type calcium channels
 Inhibit cyclicAMP formation
 Inhibits synaptic potentials
• Opening GIRK blocks action potentials and hyperpolarize the cell membrane (locus coeruleus neuron)

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9
Q

How does the brain modulate pain signals (descending pathways) and the consequences of this on drug design to relieve pain

A

o Opioid action and descending inhibition
 Descending NA and 5HT modulate sensory synapses (filled terminals are inhibitory, open terminals are excitatory)
• Predominantly utilise norepinephrine and serotonin
 NA and 5HT excite enkephalin (ENK) neurons and inhibit projection neurons (synergism). Enkephalin inhibits sensory synapses
• Inhibit projection neurons to C fibres, (which contains opioid receptors)
• Safer because the enkephalin neurons which release enkephalin are target to pain system and don’t reach respiratory system
 Noradrenaline and serotonin transport inhibitors relieve pain
• Important in chronic pain
 Mixed function drugs (tramadol, tapentadol) act directly on both opioid and monoamine systems synergistically
• Tramadol μ-receptor and SERT
• Tapentadol μ-receptor and NET
 Mixed function drugs are dose sparing, so safer
• Don’t have to stimulate μ opioid receptor as much if the other receptors are already being stimulated

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10
Q

What are the 3 main families of endogenous opioids? Describe their features and location

A 
main families-
o	Proenkephalin (nerve cells, adrenal)
	Tyr-gly-gly-phe-leu
	Tyr-gly-gly-phe-met 
	Enkephalin immunoreactivity in periaqueductal grey 
o	Prodynorphin (nerve cells)
	Alpha-neoendorphin 
	Dynorphin A and B 
	Predominantly on the kappa receptors 
o	Pro-opiomelanocortin (pituitary, brain-restricted)
	ACTH
	B-endorphin
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11
Q

What are the 3 main opioid receptor types and what are their actions when activated?

A

o μ (mu)- strong analgesia, constipation, nausea, respiratory depression, cough reflex, tolerance and dependence
 Nearly all clinically used opioids are very μ-receptor selective
o δ (delta)-mild spinal analgesia (convulsions, cardiovascular complications)
o κ (kappa)- moderate analgesia, diuresis, hallucinations (dysphoria)

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12
Q

What is the main structure of opioid receptors and what is their structural change when they become activated?

A

o G-protein coupled receptor
o Ligand sticks in barrel of helices
o Active state crystal has small shift in orientation of intracellular domains of the receptor that switch on the G protein

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13
Q

What are the physiological consequences of mu opioid receptor activation?

A

• Inhibition of adenylyl cyclase
o Inhibition of voltage-dependent pacemaker Ih- cation non-selective current activated at hyperpolarised potentials to depolarise membrane (sensory nerve)
• Increase in potassium conductance
o All three ORs activate GIRK potassium conductance through membrane delimited beta/gamma subunits, inhibits action potentials
• Decrease in calcium conductance
o Similar to potassium channels, beta/gamma subunits, directly inhibit neurotransmitter release

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14
Q

What are the main types of opioid drugs?

A 
•	From opium (poppy)
o	Morphine 
	Analgesics 
o	Codeine (methyl morphine)
o	Heroin (diacylmorphine)
o	Hydromorphone
o	Oxycodone 
•	Agonists (duration of action varies)
o	Methadone
o	Fentanyl 
•	Partial agonist
o	Buprenorphine 
•	Mixed actions
o	Tramadol 
o	Tapenntadol
•	Antagonists
o	Naloxone 
o	Naltrexone
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15
Q

What opioid started the opioid crisis and why?

A

o Oxycodone

 Root cause of opioid crisis-> overpromotion of oxycodone

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16
Q

What is the use of buprenorphine?

A

 Good drug in dependency management

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17
Q

What is the use of naloxone?

A

o Naloxone

 Used to reverse overdose

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18
Q

What is the use of naltrexone?

A

o Naltrexone

 Used to combat alcoholism

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19
Q

Why are heroin and codeine inactive forms of morphine and how do they become active forms?

A

 Inactive form of morphine= reason
o Heroin= diacetyl (3,6)
o Codeine= CH3 (methyl) and glucuronide (M3G)
 What makes the opioid active
o Heroin to 6-Acetyl Morphine
o Codeine to Morphine-6-Glucuronide (M6G)
 How an opioid goes from inactive to active state-
o From heroin -> 6-Acetyl Morphine
 Esterases strip off acetyl group
o From codeine -> Morphine-6-Glucuronide
 CYP2D6 strips off methyl group
• Up to 10% of individuals are deficient in CYP2D6
• Up to 10% have excessive activity in CYP2D6

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20
Q

What does the strength of G-protein signalling (due to morphine binding) depend on?

A

 Strength of G-protein signalling (due to morphine binding) depends on:
o Intrinsic efficacy of agonist (not the same as potency)
o Capacity of receptors to signal
o Capacity of cell to translate signal
o Tolerance modifies capacity of receptor and cell to signal

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21
Q

Why does buprenorphine give a weak G-protein signal and how does it behave when the person is tolerant to opioids?

A

 If there is a weak G-protein signal (such as due to buprenorphine(partial agonist)) depends on:
o Buprenorphine binds very tightly so other agonists and antagonists cannot compete
o Problem when there is a weak G-protein signal in the first place as well as when tolerance decreases signal, there may be no signal from this drug in the first place
o When tolerance has developed there may be no signal- that is buprenorphine behaves almost as an antagonist

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22
Q

Does high or low G-protein efficacy improve opioid drug safety? Why?

A

 Low G-protein efficacy improves safety
o Don’t have to get a lot of receptor occupancy to get maximum pain relief
o Get to more severe levels of respiratory depression at higher levels of occupancy

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23
Q

Could safer opioids be developed using signalling bias? Why/why not?

A

• Safer opioids could be developed using property of signalling bias
o The consequences are still uncertain. Category B (moderate intrinsic efficacy, unbiased) were thought to produce less side effects only if extended to no arrestin signal and would thus be very safe in overdose
o But all studied very biased drugs developed so far actually have very low intrinsic efficacy (like buprenorphine)
o Structural basis of bias or low efficacy is still not understood

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24
Q

How can safer opioid drugs be developed?

A

• In summary, safer opioids can be developed by:
o Reducing the intrinsic efficacy of μ-opioids
 Mu receptor has to be stimulated enough to relieve pain but not stimulated enough to induce respiratory depression
o Using mixed function drugs for dose sparing (e.g. tapentadol for NET or tramadol for SERT)
 Tapentadol and tramadol have low intrinsic efficacy at the μ-opioids
o Using drug mixtures (e.g. NSAIDs with opioids) for dose sparing
 NSAIDs alone not effective for all human pain, but good experimentally

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25
Q

What are the major types of drugs used for pain?

A

• Opioids (e.g. codeine, oxycodone,morphine,heroin)
• Non-steroidal anti-inflammatory drugs (NSAIDs) (e.g. aspirin, ibuprofen and diclofenac)
• Antidepressants (inhibitors of noradrenaline [NET] and serotonin [SERT] transport)
o Important for chronic pain relief
• Gabapentanoids (e.g. pregabalin) and anticonvulsants

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26
Q

When was morphine discovered and when were endogenous opioids implicated for pain relief?

A

o Morphine was discovered in early 19th century: first plant alkaloid ever isolated and purified
 With the advent of hypodermic syringe, became widely used
o 1970s- electrical stimulation produced analgesia (periaqueductal grey) reversed by opioid antagonists implicating endogenous opioids

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27
Q

What mediators are relleased in injury and inflammation? (Give the stimulus and its representative receptor)

A 
Stimulus on the left, representative receptor on the right
Stimulus	Representative receptor
NGF=TrkA
Bradykinin=BK2
Serotonin=5-HT3
ATP=P2X3
H+=ASIC3/TRPV1
Lipids=PGE2/CB1/TRPV1
Heat=TRPV1/VRL-1
Cold=TRPM8
Pressure=DEG/ENaC
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28
Q

What peripheral pain pathway for NSAIDs inhibit?

A 
o	The other major class of pain-relieving drugs (e.g. aspirin) act on the prostaglandin pathway
	Prostaglandins sensitise nociceptive sensory nerves (C-fibres) and non-steroidal anti-inflammatory drugs (NSAIDs) inhibit this
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29
Q

What is the process of the prostaglandin pathway and what part of this pathway does NSAIDs inhibit?

A 
o	Stimulus-> phospholipase A2 activation->breakdown of  arachidonic acid-> either lipoxygenase or cyclo-oxygenase (COX)
	Lipoxygenase
•	HETE’s
•	Leukotrienes
•	Lipoxins
	Cyclo-oxygenase (COX) (inhibited by NSAIDs)
•	Prostaglandins
•	Prostacyclin
•	Thromboxane
o	Prostaglandins (PGE2) excite and sensitive nociceptive nerve endings (Gs coupled receptor)
	Gs coupled receptors activate adenyl cycle, phosphorylate protein kinase A, and that phosphorylation turns up the activity of certain ion channels 
o	NSAIDs block synthesis from amino acids 
	Block PGE (prostaglandin signal) arachidonic acid pathway
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30
Q

What drugs can be used in conjuction with opioids to enhance opioid actions on nerve endings

A

• Non-steroidal anti-inflammatory drugs (NSAIDs) can synergise and enhance opioid actions on nerve endings

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31
Q

What is tolerance and when can it develop?

A

• Tolerance- an increase in the dose needed to produce a given pharmacological effect
o Tolerance can develop rapidly (days) following repeated administration

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32
Q

What are the effects of opioid tolerance and what is the pharmacological consequences of it (physiological and physical effects)

A

o For morphine, tolerance extends to most of the pharmacological effects including analgesia, euphoria, respiratory depression etc.
o Less tolerance is observed for constipating and pupil-constricting actions
 Therefore an addict may take large doses and still have marked constipation and constricted pupils
o Usual dose escalations are 10-30 fold clinically. Up to 1000 fold has been documented
• Tolerance reduces signalling efficacy
o Receptor is phosphorylated, arrestin binds-> weaker G-protein signal
• Receptor regulation differs for different agonists (contributes to tolerance)
 Phosphorylation of receptor-> binding of arrestin-> formation of encoded pit->internalisation of receptor

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33
Q

How is acute pain treated?

A

• Treatment of acute pain is of great concern, but it is generally served by current analgesics, e.g. opioids, NSAID, etc

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34
Q

What is chronic pain? Why is it a problem?

A

• A major clinical presentation is chronic pain
o Pain persisting beyond the acute phase- following wound healing and recovery
o The definition- beyond 3 months pain= chronic
o It is highly prevalent and costly

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35
Q

What are the two main types of chronic pain?

A

o Inflammatory pain

o Neuropathic pain

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36
Q

What is inflammatory chronic pain caused by?

A

 Tissue injury and inflammation processes, e.g. arthritis

 Often ongoing nociceptor activity-> maintains the pain

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37
Q

What is neuropathic chronic pain caused by?

A

o Neuropathic pain
 Lesion or disease affecting the somatosensory system
 Peripheral and central lesions
 Caused by:
• Trauma to peripheral nerves- accidents, surgery
• Central injury- spinal cord injury, stroke
• Disease (post-herpetic neuralgia, diabetes, HIV, MS, etc.)
• Chemotherapy induced

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38
Q

Why is neuropathic chronic pain a problem?

A

 Particularly difficult to treat

 The pain can persist even after the injury resolves

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39
Q

What is neuropathic chronic pain characterised by? Which of these factors is most distressing for patients?

A

 Abnormal pain syndrome characterised by:
• Spontaneous pain-pain/burning sensations in the absence of stimulation
• Allodynia- normally innocuous stimuli perceived as painful, such as light touch, brushing, cool/cold
• Hyperalgesia- painful stimuli more painful, reduced threshold to pain response
 Spontaneous pain and allodynia are particularly distressing for patients

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40
Q

In addition to pain, what can chronic pain cause?

A

• Chronic pain is a multi-dimensional experience and can also include:
o Disturbances of familial and social relationships
o Sleep disruptions
o Metabolic and endocrine disturbances
o Reduced movement
o Loss of interest in external events
o Depression
o Viscious cycle: Pain leads to anxiety which leads to disturbed sleep which leads to increased anxiety and more pain

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41
Q

What are current medications used for neuropathic chronic pain?

A

o Anticonvulsants, e.g. gabapentin (Neurotin) and pregabalin (Lyrica)
o Voltage gated calcium channel blockers (VGCCs) e.g. Ziconotide (prialt)
o Antidepressants
o Opioid agonists (have ben include as first-line, but opioid crisis)
o Tramadol (partial opioid agonist + SNRI)
o Topical drugs, e.g. capsaicin, local anaesthetics

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42
Q

What are anticonvulsant drugs for chronic neuropathic pain based on and what channel do they target?

A

 These are GABA analogues
 Best current practice for chronic pain
 Similar end-target to VGCCs, but different mechanism

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43
Q

Describe the original use, current use, common name, pharmacokinetic profile and side effects of gabapentin and pregabalin

A

 Gabapentin and pregabalin-
• Originally used as anti-convulsants
• Proven efficacy vs placebo in several neuropathic pain conditions. The current best practice neuropathic pain medication
• Pregabalin (lyrica-pfizer) and gabapentin (Neurontin)
• Pregablin has better pharmacokinetic profile (better, more reliable absorption)
• Side effects- dose-dependent dizziness, sedation, incoordination, memory…
o And recent controversy about abuse potential

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44
Q

How do anticovulsants alleviate neuropathic pain? How/why does this work?

A

• Analogue of the neurotransmitter GABA- crosses the blood-brain barrier. Thus gets into brain and spinal cord
• Unlike GABA, gabapentin does not bind to GABAA or GABAB receptors, or the benzodiazepine site
o Don’t act through GABA receptors
• Gabapentin- binds to the α2δ subunit of some VGCCs, e.g. L, N and P-type
o VGCCs are made up of subunits. One of these, the α2δ, helps:
 Trafficking and tethering of VGCC to the membrane
 Channel activation
o When gabapentin binds to the α2δ subunit it:
 Reduces VGCC trafficking to the membrane and tethering
 Also reduces VGCC activation
• The end effect is reduced transmitter release from nerve terminals
• When this occurs on afferent nerve terminals-pain relief

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45
Q

Describe the mechanism of gabapentin and why it works well for neuropathic pain

A

 Gabapentin-mechanism:
• In neuropathic state:
o VGCC α2δ-subunit expression enhanced on many afferent types
o More VGCCs, so more release from afferents and more pain transmission
• Gabapentin administration-
o Binds to the VGCC α2δ-subunit
o Decreases VGCC membrane expression in central terminals of afferents and they are less active
o Less neurotransmitter release when afferents are activated
o Reduces pain transmission

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46
Q

What is the advantage of targeting VGCCs for alleviation of neuropathic chronic pain

A

o Wide distribution of VGCCs in afferents so it affects allodynia (unlike opioids)

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47
Q

What is a limitation of gabapentin use for treatment of chronic neuropathic pain

A

o Takes time for effect as alters trafficking of VGCCs, not an acute inhibition of channel opening (such as by VGCC blockers, or opioids)
 Can take days or weeks to feel full blown effect of drug

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48
Q

What are the types of voltage gated calcium channel blockers that can be used to treat chronic neuropathic pain? How are they administered and why?

A

 Great for chronic pain, but has to be delivered spinally due to major systemic side-effects
 Mediate neurotransmitter release
 Multiple types- L, N, P/Q, T-type VGCCs

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49
Q

Where do N-type VGCC blockers act in neuropathic pain relief? How is it delivered due to this?

A

 N-type VGCC in :
• Afferents, including central presynaptic terminals of afferents entering the spinal cord
• Wide distribution in afferents- so many sensory modalities
o Better pain relief, especially in chronic pain (e.g.allodynia)
• Wide distribution elsewhere- side effects
• Intrathecal (spinal delivery), as of systematic side-effects if given systematically

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50
Q

What are N-type VGCC blockers made from? Give an example

A

 N-type blockers- toxins from cone snails e.g. ziconotide (prialt)

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51
Q

How do VGCCs relieve neuropathic chronic pain? What allows them to do so? Why are they such good neuropathic pain relievers?

A

 Mechanism-
• VGCCs on all afferent terminal inputs into the spinal cord
• They have a crucial role in synaptic transmission
• In neuropathic state-
o VGCC expression is increased, so more release from afferents-> so there is greater pain transmission
• VGCC blockers:
o Bind to VGCCs
o Reduces calcium influx into afferent terminals
o Less transmitter release
o Less transmission- all modalities from nociceptors and non-nociceptors (allodynia)
• Due to wide distribution of VGCCs in afferents (both nociceptors and non-nociceptors), allodynia is targeted (better than opioids)

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52
Q

What older antidepressants were used to relieve neuropathic chronic pain

A

 Older= tricyclic antidepressants (TCAs) e.g. amitriptyline, nortiptyline

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53
Q

What newer antidepressants are used to relieve neuropathic chronic pain

A

 Newer= dual serotonin/noradrenaline reuptake inhibitors (SNRIs) e.g. duloxetine (Cymbalta), amy.nortriptyline and desipramine, venlafaxine (Effexor), milnacipran (savella) developed for fibromyalgia
• SNRIs have proven efficacy. Also some evidence for NRIs but SSRIs not so effective (that is blockade of noradrenaline is essential)

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54
Q

Describe the strengths and limitations of using antidepressants for neuropathic chronic pain?

A

 Effective in several types of neuropathic pain
 Commonly used but there are side effects
 Presence of depression not required for their analgesic effect (that is, SNRI > SSRI). But may be particularly useful in patients with inadequately treated depression

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55
Q

Describe the mechanisms behind antidepressant allevation of chronic neuropathic pain

A

 Mechanism-
• Blockade of NA and 5HT transporters- elevation of endogenous NA and 5HT
o More subtle effect than globally acting agonists, fewer side-effects
• Have some mixed actions at a number of receptors- 5HT2,H1/2, mAChR, etc.
• Some TCAs, such as amitriptyline, are also channel blockers (VGCS blockade)-possible analgesic mechanism

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56
Q

What is the role of 5HT antidepressants in modulating factors involved in chronic pain?

A

• 5HT-activates central descending systems (and also spinal action)- involved in mood modulation of pain systems

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57
Q

What is the role of NA antidepressants in modulating factors involved in chronic pain?

A

• NA- released from lateral descending pathways in spinal cord which inhibit ascending pain transmission
o In spinal cord, NA acts on α2 receptors, Gi/o-coupled receptor (inhibitory)
o α2-receptors on primary afferent terminals- reduce glutamate release from nociceptive afferents and possibly other afferents
o α2-receptors on dorsal horn neurons directly inhibit pain pathways

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58
Q

How do opioids treat acute pain?

A

 Opioids- acute pain
• Mu-opioid receptors (uORs) on:
o Nociceptor terminals
o Ascending pain tract neurons
• Process-
o Morphine activates opioid receptors on nociceptor terminals
 Reduces calcium influx (critical for transmitter release)
 Reduces transmission onto ascending pain tract neurons and less pain signalling in the brain
o Morphine activates receptors on ascending pain tract neurons
 Directly inhibits neurons
 Reduces activation of ascending pain tract neurons
• Less ascending pain transmission= analgesia
• Opioids act at other sites- other parts of ascending, plus descending analgesic pathways

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59
Q

How do opioids alleviate chronic neuropathic pain and how does this work? What are its limitations and why?

A

 Opioids and chronic neuropathic pain-
• If nerve is damaged, can get downregulation of opioid receptor
o Some reduction in opioid receptors
• Opioid receptors not on non-noxious afferents
o No effect on pain transmission from non-noxious afferents
• But opioid receptors on ascending pain tract neurons
o So some reduction in activation of ascending pain tract neurons
• As chronic neuropathic pain results in a bit less ascending pain transmission, opioids can only offer some analgesia- but less than for acute pain

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60
Q

Why are opioids not great for long term use in chronic pain?

A

 Opioids and chronicity
• The problem is that chronic pain is a chronic condition, so drug treatment has to be chronic- this has led to the opioid crisis
o Addiction, overdosing, tolerance

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61
Q

What receptors does capsaicin act on? Give examples of receptors in that receptor class and what they do

A

• Acts on transient receptor potential ion channels- LGICs-
o TRPV1: senses painful heat (above 40 degrees)
 Gets activated first in hotplate assay
o TRPV2- senses very painful heat (above 52 degrees)
o TRPM8- senses cool (below 28 degrees)
o TRPA1-senses some noxious chemicals and maybe intense cold

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62
Q

Where is TRPV1 located and what is its role?

A

• TRPV1
o Located on a major group of nociceptive afferents- in their terminals within the skin
o TRPV1- normal role is to sense painful heat (protective)

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63
Q

How is capsaicin administered for relief of neuropathic chronic pain?

A

• If apply capsaicin to skin, it results in intense thermal pain
o Nerves are damaged by capsaicin, but can be repaired quickly
• Capsaicin can be used for localised neuropathic pain- diabetic, shingles, amputation, etc
• Apply to skin- cream, patch
o Either high or low dose capsaicin is given- if a high dose is given, people usually have to be sedated as it hurts quite a lot

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64
Q

How does capsaicin relieve neuropathic chronic pain?

A

• Paradoxically it reduces neuropathic pain, particularly spontaneous pain
• Long-lasting mechanism- animal work suggests that is due to
o Dysfunction of nociceptors
o Depletion of nociceptors- loss of dermal afferent fibres
o Requires TRPV1 agonism. This is known because:
 TRPV1 antagonists not as good
 TRPV1 antagonists reverse neve loss caused by capsaicin

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65
Q

Is only a singular chronic pain treatment used most of the time?

A

o People often receive combination treatment

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66
Q

What other approaches besides pharmacology can be used to manage chronic pain?

A

• Multifaceted approach: in addition to pharmacology
o Psychological interventions- helping people manage mood/cognitive/sleep disorders
o Physiotherapy- movement
o Electrical stimulation- e.g. spinal cord (dorsal column)
 Mimic pharmacological approaches

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67
Q

What are the animal models used to study neuropathic and inflammatory chronic pain? Describe

A

• Animal models
o Some basic models in rodents (rats, mice) mimic the injury associated with that form of chronic pain
o Neuropathic pain can be stimulated with:
 Peripheral nerve injury e.g. sciatic nerve partial damage
 Spinal cord injury
• Mechanical force on spinal cord, chemical injury
 Disease e.g. diabetes (streptozotocin), cancer (bone cancer etc.)
 Chemotherapy drugs, e.g. paclitaxel
o Inflammatory pain
 Intraplantar inflammation, e.g. Complete Freund’s Adjuvant, carrageenan
• Inject these under the hind paw of the animal-> induces inflammation that lasts for differing amounts of time

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68
Q

What simple measures are used to measure amount of mechanical allodynia in mice? Give an example

A

 Mechanical allodynia-sensitivity to mechanical stimuli that aren’t normally painful
• E.g. von Frey filaments (push onto paw)- measure the threshold force for pain-like response NB: range of hairs from 0.1-30 grams force
o Graded response

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69
Q

What techniques are used to measure amount of cold allodynia in mice? Give an example

A

 Cold allodynia- sensitivity to cool stimuli that aren’t normally painful
• E.g. acetone drop (around 20 microlitres)- measure number of pain-like responses (acetone evaporates and cools paw).

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70
Q

What techniques are used to measure amount of mechanical hyperalgesia in mice? Give an example

A

 Mechanical hyperalgesia-things that were painful that are now even more painful
• E.g. Randall-Sellito device (applies pressure to paw)-measure threshold force for paw withdrawal
o Normal rat will pull away at 200g
o Injured rat will pull away at 50g or less

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71
Q

What are simple measures of chronic pain reflexes?

A

 Mechanical allodynia
 Cold allodynia
 Mechanical hyperalgesia

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72
Q

Are assays of acute pain the same as assays of chronic pain?

A

o Assays of acute pain are mostly different: e.g. for chronic pain the stimulus to assess allodynia is not painful in normal animals

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73
Q

What can be inferred from a dose-response graph for a drug?

A

o To assess potency and efficacy of drug, should construct dose-response curve of the drug
o Can determine therapeutic window of known side effects by constructing dose- response

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74
Q

What is the aim of analgesic drugs and why?

A

o Ascending and descending pathways
 Ascending nociceptive pathway
 Descending analgesic pathway
• Aim of analgesic drugs-
o Decrease ascending pain transmission (spinal cord and higher levels)
o Activate descending systems which then release transmitters in spinal cord that inhibit ascending pain transmission

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75
Q

What does injury of peripheral afferents cause and what are the consequences of this? (how does it cause neuropathic pain)

A

• Changes in neuropathic pain
o Injury of peripheral afferents causes:
 Changes resembling those active during development= neurotrophins released (a role for the immune system)
 Changes in the surviving peripheral afferents- all of them = nociceptors and non-noxious
o Consequences:
 Reduced threshold to activate and increased sensitivity of afferents
• Reduced thresholds and increased pain responses= hyperalgesia
 Some surviving nerve fire spontaneously (nociceptors and non-noxious)= spontaneous pain
 Nerve sprouting and non-noxious afferents activate pain circuits= allodynia
 There are also changes in the brain
o Both noxious and normally non-noxious afferents access pain pathways
 Pain pathways are more sensitive

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76
Q

In what order are drugs for chronic pain used? What are the first, second and third line of defense?

A

• First line drug treatments are NPS
o Gabapentin, pregabalin, amitriptyline and duloxetine
• But others are used, or recommended, as 2nd/3rd line in various countries
o Ziconotide
o Opioids and tramadol
o Local- capsaicin and lignocaine (systemic)
o Cannabinoids
o Plus others

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77
Q

What percentage of people do migraines affect? Describe the gender division

A

• Affects 10-15% of population

o 18% in females and around 6% in males

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78
Q

At what age do migraines usually begin/peak?

A

o Onset is usually in adolescence

o Peak prevalence between ages 35-45

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79
Q

What are the two main types of migraines and what % of migraines are they responsible for?

A

o Classical migraine (with aura) is about 20%
o Common migraine (without aura) is about 80%
o Other forms including hemiplegic migraine

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80
Q

What are the phases of migraines?

A 
o	Interictal phase
	Between attacks 
o	Prodrome and aura (in 20% of sufferers)
o	Headache
o	Termination
o	Postdrome
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81
Q

What are the symptoms of a migraine?

A

• Symptoms of migraine
o Aura may precede headache
 Zig-zag lines, blurred vision or blind spots (scotoma)
 Sometimes aphasia (impaired production/comprehension of speech), chills, tremor, vertigo and parasthesia (weakness/numbness of limbs)
 Progresses slowly across an area of the visual field

 Unilateral, localised, throbbing
• May spread to contralateral side
 Nausea (and vomiting), photophobia (light sensitivity), phonophobia (sound sensitivity) and prostration (have to lie down)

82
Q

How long do migraines persist for?

A

o Headache persists 4-72 hours

83
Q

What is the pathogenesis of migraines?

A

• Pathogenesis
o Headache originates from extracerebral structures- meninges and large arteries
 Innervated by nociceptive sensory nerves of trigeminal pathway
o Migraine now considered a neurovascular disorder
 Highlights important interaction between nerves and blood vessels

84
Q

What are the causes of migraines?

A

• Causes-
o What triggers migraines is not well understood- dependent on individual
o May be:
 Abnormal neuronal discharge triggered by biochemical event
 Many environmental triggers
 May be heritable (but polygenic)
 Rare familial cases involve genetic mutations in calcium channel or sodium/potassium/ATPase
 Maybe a form of hyperalgesia, allodynia or sensitisation
• May get lowered threshold to previously innocuous stimuli

85
Q

What are the anatomical components in the neurogenic inflammation theory of migraine?

A

• Neurogenic inflammation theory of migraine
o Trigemino-cerebrovascular system
 Trigeminal nerves/ganglia
 Major vessels for regulating cerebral blood flow
 Smaller vessels in meninges
o Trigeminal ganglion cells innervate:
 Large cranial vessels
 Smaller meningeal vessels
 Meninges
 Trigeminal nucleus caudalis and spinal cord trigeminocervical complex
• Trigeminocervical complex- includes Spinal nerve I, spinal nerve II, trigeminal nucleus caudalis

86
Q

Describe the peripheral sensitization process of the neurogenic inflammation theory of the migraine

A

o Process in the periphery- (peripheral sensitization)
 Something triggers constriction of intracranial blood vessels
 Constriction causes antidromic release of CGRP from ophthalmic division of trigeminal nerves, as well as substance P, nitric oxide and NKA release
• These vasodilate intracranial and meningeal blood vessels
o Results in plasma protein leakage
• Cause mast cell degranulation
o Results in secretion of serotonin, bradykinin, histamine and prostaglandins
• Leads to sterile inflammation, which causes neurogenic inflammation and peripheral sensitisation
o Sterile inflammatory process causes sensitisation. lowering the threshold to pain responses
 Circular process- positive feedback

87
Q

Describe the CNS sensitization process of the neurogenic inflammation theory of the migraine

A

o Process in the CNS- (central sensitization)
 Trigeminal nerve fibres provide a pathway for nociceptive information originating in the meninges to be transmitted to CNS
• Trigeminal nerves release further CGRP
 The trigeminal nerves synapse on the trigeminal nucleus caudalis (in the brainstem) via the spinal tract
 The trigeminal nucleus caudalis synapses on the ventroposterior medial thalamus via the trigeminothalamic tract
• Important region of the brain involved in experience of pain, nausea, vomiting associated with migraine
 The ventroposterior medial thalamus synapses on the somatosensory, insula and cingulate cortices
• Register pain at a conscious level

88
Q

What types of fibres are trigeminal nerves?

A

C fibres

89
Q

What are C fibres and what can they be triggered by?

A

 C fibres-small unmyelinated fibres that conduct polymodal sensory information from the periphery to the CNS
o Can be triggered by thermal, mechanical or chemical stimuli that the body considers noxious

90
Q

What is the process of non-sterile inflammation (how does inflammation occur after tissue injury)?

A

o When there is non-sterile inflammation (tissue injury)
 Release of inflammatory mediators: bradykinin, 5HT and prostaglandins
 This triggers C fibres (act on C fibres)
 This triggers release of substance P and CGRP (calcitonin G related peptide)
 This leads to mast cell degradation and subsequent release of histamines
 This makes C fibres sensitized
• Synapse on dorsal horn of spinal cord and activate ascending pain pathway

91
Q

How are CGRPs correlated with migraines?

A

• CGRP is released in parallel with pain of migraine
• As CGRP concentration increases, migraine pain increases
o Concentration correlates with intensity of headache experienced

92
Q

What is 5-HT?

A

• Monoamine-indoleamine

93
Q

How many 5-HT1 receptors are there?

A

• 7 receptor types (5-HT1-7)

94
Q

What are the two types of receptors important for migraines?

A

• Receptors important for migraines-
o 5-HT1 receptors
o 5-HT2 receptors

95
Q

Describe 5-HT1 receptors in terms of activation product, coupled protein and isoforms

A

o 5-HT1 receptors
 Inhibitory
 Gi protein coupled
 Isoforms: 5-HT1A,1B,1D,1E,1F

96
Q

Describe 5-HT2 receptors in terms of activation product, coupled protein and isoforms

A

o 5-HT2 receptors
 Excitatory
 Gs protein coupled
 Isoforms: 5-HT2A, 2B, 2C

97
Q

How was the role of 5-HT during migraines elucidated?

A

 90% of serotonin comes from the gut
o Platelet concentration of 5-HT falls-plasma concentration in 5-HT isn’t as important in influencing arterial tone but may influence other aspects of migraine
 9% of serotonin from platelets
 1% of serotonin from brain
o Migraine sufferers show perturbation of 5-HT metabolism and transmission

98
Q

Where are 5-HT1b and 5-HT2 receptors found and what are they responsible for in migraines respectively?

A

o 5-HT1B and 5-HT2 receptors found on intracranial blood vessels
 5-HT1B -> vasoconstriction
 5-HT2 -> indirect vasodilation via release of nitric oxide when activated
• 5-HT2 receptors on meningeal blood vessels

99
Q

What types of receptors are trigeminal ganglion and nucleus cell bodies/terminals rich with? Describe

A

o Trigeminal ganglion and nucleus cell bodies and terminals rich in 5-HT1B/1D/1F receptors
 5HT1 receptors are inhibitory
 5-HT1B/1D on trigeminal ganglion cell body
 5-HT1D on trigeminal ganglion presynaptic terminal
 5-HT1B/1D/1F on trigeminal nucleus caudalis cell body

100
Q

What drugs were used to treat migraines in the pre-19th century and what was the problem with those drugs?

A 
•	Pre-19th century (all these cures are painful)
o	Potassium cyanide
o	Strychnine
o	Atropine
o	Digitalis
o	Hashish
o	Hemlock
101
Q

What drugs were used to treat migraines in the post-19th century and what was the problem with those drugs?

A 
•	Post-19th century
o	Ergot derivative (ergotine)
	Fungus derivative (found on wheat)
	Precursor to LSD 
	Hallucinogen
102
Q

What drugs are used to treat acute migraine attacks?

A

 Non-steroidal anti-inflammatory drugs (NSAIDs)
 Ergotamines
 Triptans

103
Q

What are the limitations of NSAIDs for migraine management?

A

 Non-steroidal anti-inflammatory drugs (NSAIDs)
• More effective when given early during an attack
• Not good for severe migraine

104
Q

Describe the biochemical pathway of inflammation (production of inflammatory agents)

A

• Process of inflammation:
o Membrane phospholipids produces arachidonic acid via phospholipase A2 activity
o Arachidonic acid produces:
 5-HPETE via 5-lipoxygenase
• Produces leukotrienes
 Cyclo-endoperoxidases via cyclo-oxygenase activity
• Produces thromboxane, prostacyclin and prostaglandins

105
Q

How do NSAIDs provide migraine pain relief?

A

• NSAIDs inhibit cyclo-oxygenase (inhibit production of inflammatory agents thromboxanes, prostacyclin and prostaglandins
o By inhibiting prostaglandin synthesis, decreases inflammation (reduces neurogenic inflammation)

106
Q

What are the targets of ergotamines and why are they effective in migraine management?

A

• E.g. ergotamine, dihydroergotamine
• 5-HT1D partial agonists
• Also act at other monoamine receptors (5-HT1, 5-HT2, D1,D2, α1 and α2 receptors)
• Cause vasoconstriction (including coronary vessels)
o Contraindicated in cardiovascular disease
• Block trigeminal nerve transmission

107
Q

What are the advantages and limitations of using ergotamines for migraine management?

A

• Adverse effects include nausea and vomiting
o Because of their location and role of the area postrema in the brainstem
• Can be given into a headache (not necessarily before, but can be given during)
• Whilst they are effective, not great for everyone
o Can amplify side effects and cannot be taken if pregnant (fetal damagers)

108
Q

Which drugs are ideally used for acute migraine management?

A

 Triptans

• First line of treatment

109
Q

What are the targets of triptans and why are they so effective in acute migraine management?

A

• Many types available with different half lives (depending on their functional group)
• 5-HT1B/1D/1F agonists
• Inhibit trigeminal nerve transmission peripherally (ganglia) and centrally (trigeminal nucleus caudalis)
o Inhibit release of neuropeptides from trigeminal ganglia (CRGP, SP and NO release)
o Inhibit trigeminal ganglia activation
o Inhibit trigeminal transmission
o Inhibit trigeminal nucleus caudalis activation
• Inhibit release of vasoactive peptides from meningeal blood vessels
o Reduce neurogenic inflammation
• Stimulate 5-HT1B receptors-> vasoconstriction: helps restore normal vascular tone
• Reduce both peripheral and central sensitization

110
Q

What are the advantages and disadvantages of using triptans for acute migraine management?

A

• As these drugs only act on 5-HT, will relieve nausea and vomiting as well (little side effects)
• Limitations-
o Contraindicated in ccardiovascular disease due to vasoconstrictor properties (can’t take them if you have cardiovascular disease)
 5-HT1B receptors on coronary arteries
o 70-80% of patients respond to triptans within 2 hour administration: can take 30-60 minutes to work
 There is a treatment-resistant group
o 20%-40% of people taking them get a headache occurrence 24 hours after the initial relief (rebound)

111
Q

When is prophylactic treatment needed for migraines?

A

2 attacks of migraine per month

112
Q

What are the abilities of prophylactic drugs for migraines?

A

o These drugs can reduce migraine intensity and can reduce migraine frequency (by 50%)

113
Q

What drugs can be used for prophylactic management of migraines?

A 
	Beta-adrenoceptor antagonists
	Antidepressants
	5-HT2 receptor antagonists
	Anticonvulsants
	Calcium channel antagonists
	CGRP receptor monoclonal antibodies
114
Q

How do beta-adrenoceptor antagonists work to manage prophylactic migraines? What are their limitations?

A 
	Beta-adrenoceptor antagonists
•	E.g. propranolol, metoprolol
•	Mechanism of action unknown
•	Contraindicated in asthma
o	Cannot be taken with asthma 
•	Side effects include fatigue and bronchoconstriction
115
Q

How do antidepressants work to manage prophylactic migraines?

A

• Tricyclic antidepressants
• 5-HT and NA transport inhibitors -> leads to increased 5-HT and NA concentration-> increased inhibition of spinothalamic neurons due to increased activity of rostroventromedial medulla
o Blocking 5-HT reuptake- further activates descending pain pathway which inhibits ascending pain pathway
• Rostroventromedial medulla- contains 5-HT cell bodies that originate in the nucleus of Raphe magnus
o Part of the descending pain pathway
• When rostroventromedial medulla activated, it projects to dorsal horn of spinal cord- further inhibits incoming noxious stimuli
• By blocking 5-HT uptake, can increase activity of the descending pain pathway and block activation of ascending pain pathway

116
Q

How do 5-HT2 receptor antagonists work to manage prophylactic migraines? What are their limitations?

A
  • E.g. pizotifen, cyproheptadine, methysergide
  • Prevents 5-HT2 receptor-induced vasodilation (secondary to NO) and consequent inflammation
  • Adverse effects include weight gain, antimuscarinic effects (not completely selected for 5-HT2)
117
Q

How do anticonvulsants work to manage prophylactic migraines? What are their limitations? Under which theory of migraines does this work under?

A

 Anticonvulsants
• E.g. sodium valproate, gabapentin, topiramate
• Range of mechanisms
• Reduce cortical excitability by altering ion channel activity
o Reducing cortical excitability= reduce incidence of migraine attacks
o Decrease trigeminal neurotransmission
o Decrease cortical spreading depression (a phenomenon observed in migraine with aura)
• Teratogens (can’t take the if you are pregnant)

118
Q

How do calcium channel antagonists work to manage prophylactic migraines? Under which theory of migraines does this work under?

A

 Calcium channel antagonists
• E.g. nifedipine, verapamil
• Decreasing calcium entry reduces cellular excitability
• In alignment with the theory that migraines are caused by cortical excitability

119
Q

How do CGRP receptor monoclonal antibodies work to manage prophylactic migraines?

A

 CGRP receptor monoclonal antibodies
• Erenumab
• Potently and specifically competes with CGRP-> inhibits function of CGRP receptor
• Acts on CGRP receptor
• Proven to be effective for patients with frequent attacks of migraine

120
Q

What needs remain for improved drugs for acute migraines? Give examples

A

• Need remains for improved drugs for acute migraine
o Greater selectivity
o Fewer side effects
o Better response rate
• Need for drugs acting selectively at receptor isoforms
o Drugs acting selectively at 5-HT1D/1F receptors on trigeminal ganglion cells
 Removes 5-HT1B-induced constriction of coronary and cerebral arteries
 Lasmiditan- 5-HT1F antagonist under investigation
o CGRP antagonists- liver toxicity
o Drugs inhibiting neuropeptide release

121
Q

What is addiction?

A

• Addiction- a state where drug use continues in spite of serious potential or actual harm to the user or others
o Compulsive drug seeking

122
Q

What two factors are the drivers of long-term drug addiction?

A

o Counter-adaptations and tolerance is driver to long-term addiction
 When chronic use is stopped these counter-adaptations result in withdrawal and drug craving
 Need to consider counter-adaptations in treatment strategy

123
Q

Describe the drugs and percentage of drug use in Australia in the last 12 months

A 
o	In the last 12 months
	Alcohol- 84% (39% weekly, 7.2% daily)
	Nicotine- 17% (1.5% weekly, 15.9% daily)
	Cannabis- 11%
	Methamphetamine/cocaine-5%
	Pharmaceuticals- 4%
•	Opioids, benzodiazepines
	Ecstasy- 4%
	Inhalants- 0.6%
	Heroin-0.5% (1/2 in treatment)
124
Q

What issues are there in studying illicit drug use?

A

o Issue in drug use studies that people may underreport illicit drug use

125
Q

What age group has the highest drug use in Australia?

A

20-29 year olds

126
Q

Why do people take drugs?

A 
•	People take drugs:
o	To feel good
	New sensations (MDMA/ecstasy)
	New experiences (LSD)
	Pleasure (euphoric drugs- opioids)
	Community (sharing) (alcohol/nicotine)
o	To feel better (a lot of alcohol in this category)
	Escape problems (worry, despair, boredom) 
	Lessen anxiety
	Reduce fear
	Reduce depression
	To feel something
127
Q

What is the problem with people continuing to take drugs?

A

• People continue to take drugs to continue to feel good or better but:
o Need more drug to achieve same effect (drug tolerance)
o Start feeling bad when the drug wears off (Drug withdrawal)
o Start wanting the drug all the time (drug craving)
o Drug use starts to interfere with daily life

128
Q

What is the cost of alcohol?

A

o Alcohol- 18.3 billion dollars

129
Q

What is the cost of nicotine?

A

o Nicotine- 31.5 billion dollars (1/8 of disease burden in Australia)

130
Q

What is the cost of illicit drug use?

A

o Illicit drug use- 8.2 billion dollars

131
Q

How can % of people addicted by calculating using drug use data?

A

• Work out % of addicted people using drug use data by looking at how many people are actually using the drug

132
Q

What natural rewards are the reward centres triggered by?

A

• Activated by natural rewards- food, sex and water

133
Q

What areas produce reward when electrically stimulated and why?

A

• Electrical stimulation of VTA (ventral tegmental area) and nucleus accumbens is rewarding
o VTA have dopaminergic cell bodies and send their axons to the nucleus accumbens and prefrontal cortex to release dopamine in these areas: associated with reward and reinforcement

134
Q

What system do major drugs of abuse stimulate? How? What does this produce?

A
  • All major drugs of abuse stimulate dopamine activity in this neural system
  • Microinjection of heroin, cocaine and nicotine in these areas is rewarding although molecular mechanisms of action differ
  • Anticipation of drug use promotes dopamine release in this system in animals and humans
  • Reward centres are there to respond to environmental stimuli that are pro-survival so that we are encouraged to do these activities again
  • Drugs of abuse disrupt natural reward signal so that high dopamine concentration extracellularly-> means more activation of dopamine receptors and higher reward
135
Q

What are the brain circuits associated with addiction and what aspect are they responsible for?

A

• Brain circuits associated with addiction
o Reward prediction and pleasure-initial drug use
 Nucleus accumbens and ventral pallidum
o Cognitive control- decisions about drug use
 Prefrontal cortex
 Anterior cingulate cortex
o Motivation drive and salience attribution-drive and importance: assign the reward value to an object
 Orbitofrontal cortex
o Learning and memory- associate drug use with particular environment or use
 Amygdala
 Hippocampus

136
Q

Is addiction more commonly associated with anatomical or cellular changes?

A

• There are morphological changes due to addiction, but more on a cellular level than a gross anatomical level

137
Q

What are the risk factors of addiction/factors that make people susceptible to addiction?

A 
o	Complex disease- mix of biological and environmental factors determine susceptibility
•	Risk factors of addiction
o	Biology/genes
	Genetics
•	Neurotransmitter proteins 
•	40%-60% of your vulnerability
•	People can have more impulsive traits than others
	Gender
•	Being male is an increased risk factor-> due to later developmental timeline of prefrontal cortex 
	Mental disorders
o	Environment
	Chaotic home and abuse
	Parent’s use and attributes
	Peer influences
	Community attitudes
	Poor school achievement 
o	Drug
	Use of administration 
	Effect of drug itself
	Early use
	Availability
	Cost
138
Q

What are approaches for long-term harm minimization to treat heroin/opioid addiction?

A 
•	Medically assisted detox
•	Replacement therapy-
o	Mu(μ)-agonist
o	Mu(μ)-antagonist
o	Mu(μ)-partial agonist
•	Anti-craving 
•	Cognitive behavioural therapy-some evidence 
•	Vaccines-
139
Q

Can cultural/society influences influence treatment method of opioid addiction?

A

• Cultural/society attitudes influences treatment

140
Q

How does medically associated detox work in treating heroin/opioid addiction and what are its advantages/disadvantages?

A

• Medically assisted detox
o Provide support/drugs to reduce symptoms of withdrawal signs
o Clonidine (alpha2 agonist), benzodiazepines
o High relapse rate
 But doesn’t do anything about craving
o Not a great option for long-term harm minimisation

141
Q

How does mu agonist therapy work in treating heroin/opioid addiction and what are its advantages/disadvantages?

A

 μ agonist with long half-life t1/2=22 hours (good for dosing)
• People will come in every day and need to ensure they have taken the dose
 Users don’t like it as much as heroin
• Due to pharmacokinetics
 Stops withdrawal and craving without intoxication at correct dose
 Overdose possible- multiple doses of naloxone (antagonist) needed
 Works best with counselling and social support
 Used for over 30 years- results in low illicit drug use, injecting prostitution, high retention
• Very good harm minimisation outcomes
 Used by 70% of opioid treatment patients in Australia
 In some countries heroin available too
• Harm-minimisation heroin

142
Q

How does mu antagonist therapy work in treating heroin/opioid addiction and what are its advantages/disadvantages?

A

o Mu(μ)-antagonist-Naltrexone
 Orally active antagonist
 Occupies receptor and prevents agonist binding-> doesn’t produce rewarding effects
 Need to detox before use
 Poor compliance because although it occupies the receptor, it doesn’t do anything about the craving
 Poor outcomes for long-term reduction of opioid use

143
Q

How does mu partial agonist therapy work in treating heroin/opioid addiction and what are its advantages/disadvantages?

A

o Mu(μ)-partial agonist-Buprenorphine
 Occupies receptor and prevents full agonists like heroin producing effect
 Partial agonism should reduce craving
 Less overdose risk than methadone
 Prevents withdrawal in all but the most addicted
• Some people will want to go straight back to heroin
 Not all patients stable on buprenorphine (may change to methadone)
• Trickier to stick to
 More freely available than methadone-doesn’t have the same abuse potential as methadone
• Don’t need to go to clinic as much
 Can be combined with naloxone to prevent injection
• To make sure people are taking it orally-> if injected and go straight to the brain, buprenorphine will not have an effect
 Used by 30% of opioid treatment patients in Australia

144
Q

What are the disadvantages of using vaccines to treat opioid addictions?

A

• Vaccines-still in development but may have some problems as antagonists
o Need a vaccine for every type of opioid
o Don’t do anything about opioid craving

145
Q

What are the best approaches/most successful treatments to reduce illicit opioid use and why?

A

• Best approaches/successful treatments to reduce illicit opioid use (harm minimization) target craving:
o Agonist and partial agonist method as they address the cravings
 Some occupation of receptors means craving circuit is not going into overdrive

146
Q

What are the two main characteristics of a highly addictive opioid?

A

• Characteristics of a highly addictive opioid
o Quick entry into the brain
o Efficacious agonist

147
Q

Why is heroin such a highly addictive opioid and what changes does it have to undergo to be so?

A

 Heroin and its metabolite 6-monoacetylmorphine are more lipophilic than morphine= faster into brain= greater rush
 Heroin has low affinity for opioid receptors-> needs to be made into morphine by chopping off acetyl group (which replaced OH of morphine) before it can act at receptor
 Pharmacokinetic property of heroin that makes it a very desirable elicit opioid

148
Q

What is opium derived from and how long has it been used?

A

o Opium is derived from the juice of the opium poppy, Papaver Somnifferum
o Opium extract has been used for thousands of years

149
Q

When was morphine first isolated from opium?

A

o 1806 morphine was first isolated from opium

150
Q

By whom and when was heroin first synthesised?

A

o Heroin was first synthesised in 1874 by CR Alder Wright

151
Q

What was the original use of heroin?

A

o 1898-1910 heroin was sold by Bayer as a non-addictive substitute for morphine and as a cough suppressant

152
Q

What is the colour of street heroin?

A

o Street heroin is white, brown powder or black tar

153
Q

What was the initial use of oxycodine and which crisis is it responsible for now? Why? What is the oxycodine situation in Australia?

A

• Prescription opioids-oxycodine
o Heroin use stable at 0.5% and was dominant opioid abused
o 1995 slow release oxycodone and morphine came on the market- crushed for injection
o Higher use resulted in higher diversion and misuse- massive increase in last 15 years
o 2.5% of Australians report recent use of pain-killers for non-medical purposes

154
Q

How can heroin be self-administered?

A

o Can be snorted, injected or smoked- all routes can result in addiction

155
Q

What is the result of heroin administration?

A 
o	Injection results in a surge of euphoria but also:
	Dry mouth
	Warm flush of skin
	Heaviness of limbs
	Clouded mental function
	Nausea/vomiting
156
Q

How is heroin administered for optimal enjoyment?

A

o Non-injection may miss the rush but get other effects

o Euphoria is better when drug is smoked or injected than taken orally

157
Q

Where are opioid receptors expressed in the brain and how is this related to addiction?

A

• Opioid receptors are expressed throughout the brain
o Expressed in regions of the ventral tegmental area, nucleus accumbens and amygdala
o Expressed in regions important for initial effects of drugs and other subsequent effects

158
Q

What is the effect of heroin stimulation of the brain (where, how and consequences)

A

• Heroin stimulation of the reward pathway
o Receptors for opioids are located on the GABA interneurons (mu receptors) and not on the dopaminergic neurons
o Therefore, morphine bind on mu receptors of GABA cells and dampens down their activity-> they release less GABA-> there is less inhibition-> neighbouring dopamine neurons are more excited->release more dopamine in the nucleus accumbens and prefrontal cortex
o The speedy response increases the associative power: easier to address euphoric feeling to heroin cue
 Very important in addiction
o But there are also a lot of opioid receptors in the medulla
 Areas in the medulla control respiratory depression, blood pressure, arousal, nausea/vomiting and constipation

159
Q

What are problems with regular heroin use (especially from the street)?

A

• Problems with regular heroin use:
o Street drug means dose unknown- 60% users overdose
o IV users have high rate infection- 60% HepC
o Injection of contaminated/toxic street drugs result in:
 Collapsed veins
 Heart and heart valve infections
 Abscesses
 Liver and kidney disease
 Clogged blood vessel damage target organ
 Due to both the fact that it’s a street drug (contamination) and heroin
o Poor outcomes for use during pregnancy
o Social exclusion as spend time chasing drug/money
o Contact with criminals

160
Q

What is the impact of chronic heroin use?

A

• Chronic heroin use results in neuroplasticity
o Tolerance
o Counter-adaptations

161
Q

Why can tolerance occur as a consequence of chronic heroin use?

A

 Decreased response to same dose

 Can be due to changed receptor response

162
Q

What counter-adaptations can occur as a consequence of chronic heroin use and what are the consequences of these

A

o Counter-adaptations
 Attempt to compensate for ongoing/frequent opioid inhibition
• If acutely take morphine, will activate opioid receptors and inhibit adenylyl cyclase
• Apply morphine over 24 hours-> adaptations in terminals/cells to restore cAMP levels up to baseline (can involve restoration of adenylyl cyclase activity)
o But when stop taking drug, opioid inhibition of adenylyl cyclase is stopped but the adaptative increase of adenylyl cyclase is still occurring
 cAMP overshoot seems to be extremely important in opioid withdrawal and cravings
• cAMP is stimulatory-> can drive neurotransmitter release during opioid withdrawal which drive withdrawal behaviours
o Increased cAMP levels due to loss of opioid inhibition but continuation of adaptation mechanism means that an increased amount of GABA is released-> dopamine release is inhibited-> results in dysphoria
 Result in craving and physical withdrawal if opioid use stops
• Due to aberrant excitability of cells due to previous drug use

163
Q

What are the symptoms of heroin withdrawal and how long do they last?

A

• Withdrawal is intensively aversive and unpleasant
o Restlessness
o Muscle and bone pain
o Diarrhea
o Vomiting
o Cold flashes with goose bumps (cold turkey)
o Kicking movements (kicking the habit)
• Short-term (relative to craving) and only lasts for a few days but impediment to completely stopping

164
Q

What are the cellular mechanisms of opioid withdrawal?

A

• Cellular mechanisms of opioid withdrawal
o Higher activity of adenylyl cyclase-> promotes activity of GABA transporter which depolarises the neurons and makes them release a lot more GABA
 Subvert the neural circuits that they are regulating
 Inhibit more strongly cells in the hypothalamus and medulla-
• Hypothalamus- change in temperature responses
• Medulla- dysregulation of pain responses

165
Q

What are the end points of addiction studies?

A

• Need to define end points for study- could be
o Abstinence
o Reduced use
o Harm minimization

166
Q

Why are addicted populations very difficult to study?

A

• Testing any drug for effectiveness produces a variety of responses
• Addicted populations are very difficult to study
• Results highly variable between studies
o Due to population or heterogeneity of addictions

167
Q

How is tobacco used?

A

• Tobacco- can be used in cigarettes, pipes, snuff, chewing tobacco
o Cigarettes has the fastest rise time

168
Q

Why are cigarettes the most common form of tobacco use? What other things besides tobacco is there in cigarettes?

A

• Cigarettes- most common
o Efficient and highly engineered
o Rapidly deliver nicotine (first peak <10 seconds after smoke inhalation)
o High associative learning
 Fast change in occupation of receptors and activation of reward centres is extremely good for associative learning
• Smoke contains more than 4000 chemicals including nicotine, carbon monoxide, formaldehyde, cyanide and ammonia

169
Q

Describe tobacco usage in Australia vs now and the groups which have an increased risk of using tobacco

A

• Tobacco usage-
o In 1964, almost half of Australians over the age of 15 smoked
o In 2000s, now only 16% of Australians smoke
 Higher use in 40-49 year olds, males, low SES, Aboriginal/Torres Strait Islander, remote communities, mental health issues, people in prisons, people who inject drugs
 Australian use is low compared to many other countries

170
Q

What are the cellular and physiological effects of tobacco/nicotine? Are these all due to nicotine/tobacco?

A

o Nicotine increases release of adrenalin from the adrenal glands
 Increased blood pressure
 Increased heart rate
 Increased respiration
 Increased blood glucose
o Increases dopamine release in reward centres
o Increases alertness, reduces anxiety and tension
o May be other active compounds- e.g. acetaldehyde which produces other active effects

171
Q

What kind of drug is nicotine?

A

o Nicotine agonist at nicotinic receptors- multiple sub-types

172
Q

Describe how nicotine stimulates the reward pathway

A

o Nicotine stimulation of the reward pathway-
 Nicotinic receptors on the dopaminergic terminals in VTA, when nicotine binds to the receptors, it will depolarise the terminals and stimulate neurotransmitter/dopamine release from these terminals into the nucleus accumbens and prefrontal cortex
 But nicotinic receptors- also on excitatory and inhibitory inputs to dopamine neurons

173
Q

What are the problems with smoking/nicotine use?

A

o Legal freely available drug-can be financial stress (pack a day > $7000 a year)
o Problems due to smoke and nicotine
 Smoke contains >4000 chemicals including- nicotine, carbon monoxide, formaldehyde, cyanide, ammonia. Many of these are carcinogenic
o 1/3 all cancer deaths in Australia due to smoking
 Lung cancer
 Chronic obstructive pulmonary disease
 Ischaemic heart disease
 Stroke
 Oesophagus cancer
 Other
o 1/6 pregnant women smoke- increases complications, premature birth, stillbirth, SIDS (sudden infant death syndrome)

174
Q

How is alcohol produced and why is it used so much?

A
  • Alcohol is produced by the fermentation of yeast, sugars and starches
  • Ethyl alcohol, or ethanol, is an intoxicating ingredient found in beer, wine and liquor
  • Used by most cultures in the world
  • Use is entwined in social/cultural activities which promotes its use
175
Q

How is alcohol absorbed?

A

• It rapidly absorbed from the stomach and small intestine into the bloodstream

176
Q

Describe alcohol use in Australia

A

• Use of alcohol in Australia-
o Overall use- not abuse/dependence (84% yearly, 7.2% daily)
o Australian usage is in middle of world use rates

177
Q

What are the effects of alcohol as alcohol consumption increases?

A 
•	Alcohol experience
o	Initial effect-
	Drinker feels more relaxed or excited 
o	Intake increases
	Drowsiness
	Loss of balance
	Poor coordination 
	Slower reaction times (critical when driving or operating machinery)
	Slurred speech
	Slowed thought processes
	Nausea and vomiting
o	More alcohol consumed-
	Unconsciousness
	Inhibition of normal breathing-this may be fatal, particularly as the person may vomit and can suffocate if the vomit is inhaled
178
Q

What are the cellular actions of alcohol?

A

• Alcohol actions are complicated-no specific target
o Enhance GABAergic and glycinergic synaptic transmission-results in increased inhibition
o Inhibition of Ca channels
o Activation of K channels
o Inhibition of glutamate receptor function
o Inhibition of adenosine transport
o Can make neuronal membranes unstable and wobbly- will not function properly
o Genetic differences in these proteins contribute to addiction potential

179
Q

How does alcohol stimulate the reward pathway?

A

• Alcohol stimulation of reward pathway
o Many possible sites- likely disinhibition plays a role
 Inhibits GABA release so more dopamine release
o Alcohol promotes release of endogenous opioids and endocannabinoids-> involved in alcohol reward
o Starts with increases in dopamine in nucleus accumbens then will start engaging other learning and top-down inhibition

180
Q

What risk factors make people susceptible to alcohol addiction

A

• People change from alcohol use to misuse to addiction due to:
o Psychiatric disorders- especially anxiety and depression (possibly due to different protein expression or self-medication)
o Severe stressful event
o Genetic contribution
 Highest evidence for genetic contribution

181
Q

What are the problems with alcohol dependence?

A

• Problems with alcohol dependence
o Not an illicit drug
o Engage in high-risk behaviours- drink driving
o Inability to engage in normal behaviours
o Neurological degeneration- including cortex and cerebellum
 Morphology of the brain is dramatically changed- ventricles become much larger
o Liver disease- which may result in cirrhosis, failure
o Gastritis-damage to GIT mucosa
o Respiratory depression- risk of pneumonia, lung abscesses
o Immune suppression
o Increased cancer risk-mouth, larynx, oesophagus
o Endocrine changes
o Pregnancy-impairs fetal development
o Males-often feminized and impotent

182
Q

What counter-adaptations does the brain make in response to alcohol and what are the consequences of these?

A

• Counter-adaptations to alcohols
o Adaptations in the reward centres result in craving
o Adaptation in other brain regions result in withdrawal
 Develops after 8-10 hours
 Tremor, nausea, sweating, fever
 Hallucinations
 Then seizures, possibly death (up to 5%)
 Then confusion, agitation, aggression
o Serious withdrawal treated with benzodiazepines (allosteric enhancers of GABA receptors)

183
Q

How does chronic alcohol use change the reward pathway?

A

• Chronic alcohol changes the reward pathway

o Dopaminergic neurons have more AMPA receptors at synapses- more sensitive to glutamate

184
Q

What percentage of smokers attempt to quit, why, and is this easy? Why?

A
  • Most tobacco users know it is harmful and want to stop
  • Each year 20% of smokers attempt to quit but most require multiple attempts (5-6) for long term success
  • Like opioid addiction neuro-adaptations occur that result in physical withdrawal and craving if smoking stopped
185
Q

What are the withdrawal effects of nicotine addiction?

A

• Withdrawal- irritability, attention difficulties, sleep disturbances, increased appetite
o Cells have started to develop counter-adaptations: when stop smoking, people will experience withdrawal effects

186
Q

How long does nicotine craving last?

A

• Craving persists beyond withdrawal and is often intense for first months

187
Q

What are the approaches for long-term abstinence employed for nicotine addiction?

A 
•	Approaches for long term abstinence
o	Agonist therapy/nicotine replacement
o	Partial agonist-Varenicline (alpha4beta2), cytisine
o	Anti-craving
o	Antagonist- mecamylamine 
o	Vaccines- antibodies produced that bind nicotine and prevent it getting into the brain
o	Cognitive behavioural therapy
o	Others such as anti-depressants
188
Q

How does agonist therapy work for long-term abstinence from nicotine addiction, and what are its advantages/disadvantages?

A

o Agonist therapy/nicotine replacement
 Patch, gum nasal spray, inhaler-> eliminates smoke exposure (harm minimization (like methadone))
 Agonist at receptor therefore reduces craving
 Uncouples temporal cues of smoking from delivery of nicotine-encourages long term abstinence
 Gum can satisfy oral craving and decrease weight gain
 When added with behaviour therapy it increases abstinence
 With gum, 22% abstinent at a year (compared to 15% placebo)
 E-cigarettes-
• Significant concerns about the purity of e-cigarettes: nicotinic substance may have carcinogenic contaminants in it
• Does not uncouple temporal cues of smoking-bad for long term abstinence

189
Q

How does partial agonist therapy work for long-term abstinence from nicotine addiction, and what are its advantages/disadvantages?

A

o Partial agonist-Varenicline (alpha4beta2), cytisine
 Reduces craving/reduce smoking satisfaction (similar to buprenorphine)
• Partially binds to nicotinic receptor
 Newer evidence suggests slightly better than NRT- highest success of treatments 25% at one year
• A bit more successful than the nicotine gum
 Main side effects are nausea, sleep issues but generally well tolerated
 Past suicide concern, but that concern has now largely dissipated

190
Q

How does antagonist therapy work for long-term abstinence from nicotine addiction, and what are its advantages/disadvantages?

A

o Antagonist- mecamylamine
 Blocks nicotine reward but no effect on craving
 Side effects- significant drowsiness, dizziness and constipation
 Some evidence may help reduce smoking when combined with nicotine replacement therapy

191
Q

How does vaccine therapy work for long-term abstinence from nicotine addiction, and what are its advantages/disadvantages?

A

o Vaccines- antibodies produced that bind nicotine and prevent it getting into the brain
 No effect on craving
 No better than placebo
 May have role in at risk groups-may be used as a preemptive measure

192
Q

What and how does anti-depressant therapy work for long-term abstinence from nicotine addiction, and what are its advantages/disadvantages? Give an example off 2 drugs

A

 Bupropion
• Widely used antidepressant
• Unclear mechanism (DAT, NET,NR,antag)
o Need to find right setpoint
• Modest reduction craving (may be due to inhibiting dopamine uptake)
• Similar efficacy to nicotine replacement therapy of 22% stopped smoking at 1 year (less than varenicline)
• Limitations- lowers seizure threshold and causes sedation
 Nortryptyline is a tricyclic antidepressant
• NERT and SERT inhibitor
• 2nd line due to significant side effects
 SSRI and MAOI are completely ineffective
 Should be combined with cognitive behavioural therapies and strategies

193
Q

What are the best strategies for long-term abstinence of nicotine?

A

• Best strategies for long term abstinence-
o Nicotine replacement therapy (agonist)
o Partial agonist: Best option
o Bupropion
o Cognitive behavioural therapy in combination with agonist/partial agonist/bupropion

194
Q

What are potential treatments for alcohol addiction?

A
  • Medically assisted detox- very important
  • Block alcohol reward/craving
  • Make alcohol unpleasant to take
  • Unknown mechanisms- acamprosate, topiramate
  • Behavioural therapy
195
Q

Why are agonists, partial agonists, antagonists and vaccines not an option for treating alcohol addiction?

A

not an option due to non-specificity of alcoholic targets

196
Q

How does blocking alcohol reward/craving work as a potential treatment for alcohol addiction and what are its advantages/disadvantages?

A

• Block alcohol reward/craving
o Reward in part due to endogenous opioids
o Naltrexone is opioid receptor antagonist- reduces craving for alcohol
o Either oral daily or extended release injection monthly
o Reduced relapse (placebo 43%, naltrex 28%) and reduces heavy drinking. Modest effects
o Potentially hepatotoxic at high doses (Injections better)- can be a limitation

197
Q

How does making alcohol unpleasant to take work as a potential treatment for alcohol addiction and what are its advantages/disadvantages?

A

o Disulfiram- very unpleasant-flush, palpitations, nausea
 Due to high level of acetaldehyde
o Inhibits aldehyde dehydrogenase-> keep broken down products of acetaldehyde in the liver
 If take alcohol, higher proportion gets stuck in acetaldehyde phase-> makes alcohol unpleasant
o Daily dose but poor compliance
o Monitored dosing best
o Used for high risk occasions-> take when going to places with lots of alcohol
o Can’t blind studies
o No effects on craving

198
Q

How does acamprosate work as a potential treatment for alcohol addiction?

A

o Acamprosate
 May act via inhibition of NMDA receptor (possibly alters plasticity)
 May also act to change GABA or glutamate synaptic transmission
 Similar efficacy to naltrexone

199
Q

How does topiramate work as a potential treatment for alcohol addiction and what are its advantages/disadvantages?

A

o Topiramate
 Antiepileptic
 May alter phosphorylation of sodium, calcium, GABA and glutamate receptor/channels
 Unclear mechanism in addiction- may increase GABA and reduce glutamate synaptic transmission
 Significant reduction in drinking but variable results
 Some evidence that people with polymorphisms in kainate receptors have better treatment outcomes

200
Q

What are the best approaches for long-term abstinence from alcohol addiction?

A

• Best approaches for long-term abstinence are:
o Medically assisted detox
o Block alcohol reward/craving
o Acamprosate

201
Q

Describe the treatment options for addiction in general, how they work, their advantages/limitations

A

• Targets craving (generally most successful)
o Agonist- reduces craving through signalling by binding to similar receptor as drug, efficacious, harm minimization
o Reduce craving mechanism- changes craving plasticity or mechanism, some efficacy
o Partial agonist- reduces craving, blocks abuse, efficacious
• Block response
o Antagonist- blocks abuse, low efficacy, poor compliance
o Vaccine- in development, may have same problems as antagonists, may have some role in at risk groups
• Make drug unpleasant-poor compliance, limited use

PCOL3922 (5 decks)

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