exam 5 lecture 3 Flashcards
What are the two classifications of pain
Acute and chronic
Difference between acute, subacte and chroncic pain
Chronic- lasts >3 months
acute<1 month
Subacute- 1-3 months
Explain the dfferent types of pain
Noriceptive- result of inflammatory condition like OA or RA. skin/deep tissue
Neuropathic- Can occur from a central mechanism (as a result of stroke, MS, spinal cord injury) or from peripheral pain (viral infection, diabetic neuropathy)
Visceral- Pain/pressure around internal organ (pancreatitis, IBS)
Mixed- lower back pain, cancer, fibromyalgia
What is the function of pain
Warning system (avoid injury) aid in repair (hypersensitivity)
Describe the different characterizations of pain
Temporal features- Onset, duration, course, pattern
Intensity- Average, least, worst, current pain
Location- Focal, multifocal, generalized, referred, superficial, deep
quality-
inflammatory- throbing, pulsating
neuropathic- stabbing, shooting, burning, tingling
visceral- squeezing
Explain pain circuiting in the periphery
Start with a peripheral stimulus of some sort (damage, inflammation) and then signal is conducted into the spinal cord where the signal is processed.
It is then sent to the brain for processing and is sent back down to spinal cord (descending modulation) to help control the action of the afferent neuron that is bringing information into the spinal cord
What are peripheral receptors and channels involved in pain signalling
1)Temperature sensitive
-transient receptor potential cation channels (TRP)
-TRPV- Heat
-TRPM- Cold
2)Acid sensitive
-Acid sensing ion channel (ASIC)
-activated H+
-conduct Na+
3)chemical irritant sensitive
-histamine
-bradykinin
Are there reflexes that can bypass CNS and go to muscle?
Yes, Reflex upon painful stimuli
Which ions are responsible for sending afferent signal from peripheral to spinal cord
Na and K+ ions
Which Na is responsible for conduction of pain signals
NA 1.8
What can targeting NA 1.8 do as pain killers
It is an important drug target to block pain by non-opioid mechanism
What is the major neurotransmitter plays an important role in pain conduction in spinal cord
Glutamate
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What are the dfferent pain fibers present in the body
AB fibers
Aδ fibers
C fibers
what is the AB fiber important for? Structural features?
conducting non-noxious (not pain related). Producing touch + pressure.
Thick Myelin coating and very fast. No pain.
What are Aδ fibers important for? structura features?
Important for pain and cold.
Myelinated (not as thick as AB fibers), fast but slower than AB.
1st pain, sharp prickly
What are C fibers important for?
Prolonged pain.
Temeprature, touch, pressure, itch
unmyelinated, slow, second pain (dull, achy)
What neurotransmitter plays an important role in heightening pain
Substance P
What does repeated firing do to firing threshold
Repeated stimuli REDUCES firing threshold
What is substance P? What is it used for?
Substance P is a peptide released during injury/insult.
It stimulates 1. Vasodilation
2. Degranulation of mast cells
3. Release of histamine
4. Inflammations and prostaglandins
Increase in expression of pain receptors known as peripheral sensitization
In neuropathic pain sensitization, what does nerve injury lead to
Peripheral nerve degeneration (neuroma)
in peripheral nerve sensitization, what occurs after peripheral nerve degeneration
3 things-
1. spontaneous afferent activity
2. Spinal sensitization
AB afferent fibers
Describe spontaneous afferent activity caused by peripheral nerve sensitization. (EXAM)
afferent neuron carrying information begins tofire due to expression of NA channel subtypes, contributing to increased cellular excitability and generation of ectopic action potential.
Leads to spontaneous dysthesia, ahooting, burning pain
Describe spinal sensitization caused by peripheral nerve sensitization
due to neuropeptides being released (CGRP, substance P and glutamate) in spinal cord, leads to AMPA and NMDA expression and sensitivity.
What does AMPA and NMDA expression and sensitivity of spinal sensitization lead to
leads to spontaneous dysthesia (shooting, burning pain) and allodynia (light touch hurt)
What does AB afferent fibers lead to in nerve injurt/nerve sensitization
leads to allodynia (light touch hurt) as a result of increased AMPA and NMDA expression and sensitivity
What is the pain circulatory system in the brain
Peripheral injury sends info to the spinal cord
Spinal cord sends info to brain for processing
There are high expressions of opioid receptors in brainstem along descending pathway (inhibit transmission into brain)
Mu Opioid receptor plays an important role in modulation of pain signals in CNS
What does activation of Mu opioid in brain do?
alter mood
Produce sedation
Reduce emotional rxn
What does Mu opioid receptor in brainstem do?
increases activity of descending fibers
What does Mu opioid receptor in brain do?
-alter mood
-produce seation
-reduce emotional rxn
What does Mu opioid receptor in spinal cord do?
Inhibit vesicle release
hyperpolarize post synaptic membrane
What does Mu opioid receptor in periphery do?
-reduce activation of primary afferent neurons
-modulate immune activity
What are the two types of alkaloids contained in opioids
-Phenanthrenes
-Benzylisoquinalones
What are the types of phenanthrenes? Types of benzylisoquinolones?
Phenanthrenes- Morphines
codeine
Thebaine
Benzylisoquinolone- Noscapine
Papaverine
What are the opioids that occur naturally called?
Opiates
Explain the SAR pf phenanthrenes
3 position substitution ester or esther products decrease potency (codeine)
6 position increases activity (hydromorphone or hydrocodone)
14 position OH has increased potency (oxycodone)
What are the names of some peptides active endogenously
Pro-opiomelanocortin (POMC)
Preproenkephalin
preprodynorphin
Nociceptin/orphanin
What is pro-opiomelanocortin (POMC) cleaved to? What does it then act on?
Cleaved to B endorphin and acts on Mu opioid receptor
What is preproenkephain cleaved to? What does it then act on?
Preproenkephalin is cleaved to
1)leu-enkephalin- which ats on delta opioid receptor
2)Met-enkephalin- which acts on Mu and delta receptors
What is preprodynorphan cleaved to? What does it act on?
cleaved to Dynorphan which acts on Kappa opioid receptors
What are the main opioid receptors
Mu Opioid receptors
Kappa Opioid receptors
Delta opioid receptors
They are all GPCR Gi coupled
What are the endogenous compounds that act on the Opioid receptors
Mu-endorphin
Kappa- dynorphin
Delta- enkephalin
nociceptin- nociceptin
How do opioids work at a molecular level to reduce firing of pain signals
Action of opioids open K channels to hyperpolarize membrane and close calcium channel. This makes it harder for neurons to fire.
opioid receptor of sigma molecule
does not exisyt
Presynaptic and post synaptic action of opioid receptors
Presynaptic- inhibits Ca channel, decrease in neurotransmitter release
Postsynaptic- activate GIRK channel. efflux of K+, leading to hyperpolarization
Where do B-endorphins come from?
B endorphins are the endogenous opioids that work on Mu opioid receptors.
Come from pro-opiomelanocortin
What is the therapeutic use of Mu opioid receptor
Analgesia
Sedation
Antitussive
What type of analgesis is My opioid receptors involved in?
Not as effective for chronic pain, useful for acute pain. Can be used for cancer pain, palliative pain and PCA.
Opioid induced side effects are mostly
ON TARGET effects
What does it mean that Mu opioid side effects are mostly on target
This means that they are a result of action of mu opioid receptor activation
What are the side effects associated with opioids
Respiratory depression (action in brainstem and medulla)
Constipation and GI tract
Pruritis (Itch)- not allergic response
Addiction- nucleus accumbens
Urine retention
N/V
Miosis- caused by oculomotor nerve
can we use some opioids as antidiarrhea meds
Yes, Some opiods do not cross BBB
Kappa opioid natural ligand? Effect on body? therapeutic use?
preprodynorphin, dynorphin is natural ligand.
Activation is dysphoric (negative effect)
Potential use for treatment of addiction, reduce dopamine release.
Opposite effect of Mu opioid receptor
Delta opioid receptor natural ligand? adverse effects in body?
Enkephalin is natural ligand
Role in hypoxia, ischemia, stroke.
Hypernation also includes release of enkephalin opioid.
Use of Delta Opioid receptors
reduce anxiety and depression
Treat alcoholism
Relieve hyperalgesia, chronic pain
NO FDA approved delta opioid (seizure is side effect)
What are opioid sites of action ion the brain. Uses of these areas
Nucleus accumbens and ventral tegmental area (VTA)
both important for reward. Linked to addiction.
All substances of abuse have connection in this circuit.
How do opioids affect VTA and nuc acc and GABA
Opioid peptides and neurons have connections to Nuc Acc and into GABAergic interneuron (main inhibitory neuron in brain)
GABA is inhibited by opioid receptors increasing dopamine and reward
Can depressants cause opioid release
Yes
How addiction happens in opioids
Opioid binds to Mu receptor
GI signalling inhibits GABA release
Less GABA to activate GABA a
Less inhibition of dopamine neuron activity
increase dopamine release
leads to addiction
Administration routes of opioids
IV
IM
oral
Topical
epidermal
PK of the different routes of administration of opioids
Oral dose- slow rise. We want it to go past analgesia threshold, but below CNS side effect
SC/IM- fast rise/fast fall
IV- Rapid rise in concentration, much greated risk of side effects
PK of morphine? Fentanyl?
Morphine has slow rise
Fentanyl has rapid peak
Explain the metabolism and bioavailability of morphine
Readily absorbed, significant 1st pass metabolism
Bioavailability 25%
Enzymes for morphine absorption
Hepatic- 2D6 and 3A4
Excretion of morphine
glomerular filtration (kidney)
What are some opioids that are prodrugs
Heroin, Codeine, tramadol
Which opioids do not produce active metabolites
Fentanyl and methadone
How does lipophilicity influence onset/duration of opioids? Give examples
Morphine- low lipophilicity, slower passage, prolonged duration of action
Fentanyl- high lipophilicity, rapid onset, short durationC
Codeine is metabolized to
Morphine and hydrocodone
Heroin is metabolized to
Morphine
What is the enzyme that transforms codeine to morphine
2D6
Which enzyme is responsible for making the Nor- metabolites (norhydrocodone, noroxymorphone)
CYP3A4
Mnemonic to remember 3A4 and nor
Four=Nor=less active
Which enzymes play an important role in drug-drug interaction in opioids
2D6 and 3A4
What are the types of metabolizers of oipioids
PM-poor metabolizer
IM- intermediate metabolizer
EM- extensive metabolizer
UM- ultra rapid metabolizer
Which phenotype causes more side effects
ultra rapid metabolizer
Which phenotype has no therapeutic effect from codeine
PM
How potent is fentanyl? What is it used for?
100x more than morphine
50x more than heroine
used for palliative care and breakthrough pain
What are some opioid agonists that are used in hospital procedures
fentanyl (sufentanil, remifentanil)- Anesthesia/sedation.
break down is by plasma esterase due to esther linkage
hydromorphone, oxymorphone- no opioid active metabolite
morphine
hydrocodone/oxycodone
What are some non-phenanthrene opioids
Tramadol
Maperidine
Methadone
What kind of drug is tramadol? What is it used for?
Tramadol is a drug with SNRI like properties that is used as a painkiller
What is Meperidine used for? Toxic metabolite name? What does this toxic metabolite lead to?
Used to treat rigors.
Has a toxic metabolite called normeperidine.
Metaboliet is devoid of analgesic activity and has neurotoxic effects.
Not recommended without good justification.
What is an opioid that is an NMDA antagonist
Methadone
WHat is methadone used for? Side effects?
Methadone- primarily used for opioid dependence. Causes prolonged QTc.
Why would we want to block NMDA receptors?
NMDA is important for the conduction of pain signals. Blocking this leads to blocking pain signals.
What are some opioids used as antitussives
Codeine
Dextromethorphan- limited opioid activity
What are some anti-diarrheal opioids? How do they act?
Diphenoxylase
Loperamide
Eluxadone
Slow GI tract and lower diarrheal
What are some opioids that act in MOR (Mu) and KOR (kappa) that are used for moderate pain
- Pentazocine and butorphanol
- Nalbuphine
3, Buprenorphine
How do Pentazocine and butorphanol act? Side effects?
K agonist and partial agonist/antagonist at Mu
side effects- Less dysphoria
Hallucinations
increased HR and BP
How does Nalbuphine work?
Full agonist at K, antagonist at Mu
How does buprenorphine work? What is it used for?
Partial Mu agonist, weak K agonist and gamma antagonist.
Primarliy used in opioid replacement therapy
Preventative and acute management of constipation
Senna
PEG
Sodium docusate
Biggest risk of death in opioid withdrawn patients
Respiratory depression
What is opioid induced hyperalgesia?
Occurs when there is a prolonged exposure to opiates and a secondary pain pathway begins to form.
What is opioid induced hyper algesia linked to neurotransmitter wise
Glutamate
will giving more opioid give an analgesic effect in opioid induced hyperalgesia
Giving more opioid will not give analgesic effects because of the glutamate pathway
Symptoms with limited/no tolerance
Constipation
Itching
Miosis
Treatments for opioid dependence
- methadone- full agonist
- Buprenorphine- partial agonist
- Naltrexone/Narcan- antagonist
How does Methadone treat opioid dependence
Provides relief from withdrawal.
Slow acting (reduced risk of high) 2-4 hrs
Slow PK- accumulates with repeated doses
NMDA antagonist
How does Buprenorphine treat opioid dependence
Blocks full agonist effect of heroin as an antagonist
provides some activation as agonist to prevent withdrawal
subutex- Some abuse potential
How does Naltrexone treat opioid dependence?
Antagonist taken once month IM inj
Decent oral bioavailability.
Are Naloxone and Naltrexone interchangeable?
Naloxone- antidote for OD, limited oral bioavailability, rapid onset, short t1/2
Naltrexone- Decent oral bioavailability, medium half life
Not interchangeable
How often to give naloxone to a patient that has overdosed and is going through respiratory depression
Repeat every 2-5 minutes if not conscious (short half life and rapid onset)
Effect of opioid abuse on neonates?
Causes serious withdrawal lasting 4-6 months and may even cause seizures
How to treat neonatal abstinence syndrome non pcol
Swaddling, hypercaloric formula, frequent feedings, observation (sleep, weight gain/loss, temperature), Rehydration
How to treat neonatal abstinence syndorme Pcol
Morphine sulphate
Buprenorphine sublingua
Methadone
Morphine and buprenorphine linked with shorter hospital stay
than methadone
summary for opioid receptors
μ (Mu) Opioid
- Analgesia, euphoria and mood
effects, respiratory depression,
miosis, neuroendocrine
regulation, decreased GI motility,
autonomic regulation, tolerance
and withdrawal
Endorphins > Enkephalins >
Dynorphins
κ (Kappa) Opioid
Analgesia, diuresis, sedation,
dysphoria and psychotomimetic,
less miosis, less respiratory
depression, little dependence
Dynorphins»_space; Endorphins and
Enkephalins
δ (Delta) Opioid
Analgesia, mood, reduced anxiety,
ischemic protection, little
dependence
Enkephalins > Endorphins and
Dynorphins
Orphanin Opioid-Receptor-Like
Subtype 1 (ORL1), Nociceptin
cntroversy actions
opposes classic μ effects,
mediate pain
Nociceptin /Orphanin FQ
40
