Opioids Flashcards
How many Canadians report pain (both acute and chronic)?
More than 40% of Canadians report poorly managed pain
What is the definition of pain?
An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage
What are the four G-protein coupled opioid receptors found in the human body?
- Mu
- Kappa
- Delta
- Nociceptin
How do opioid receptors modify perception of pain?
These receptors are Gi or Go coupled proteins.
When an agonist binds to these proteins, cAMP decreases and Inwardly rectifying K+ channels are inhibited
“Calms down pain signals”
Where are the opiod receptors located?
Peripheral, spinal, and brain receptors
What are some examples of endogenous opiods?
- Enkephalin
- Dynorphin
- Substance P
- Endorphin
What are some characteristics of endogenous opioids?
They are short peptide molecules
Need to undergo some post-translational modifications and metabolic activity to become active
Released from synaptic vesicles
What is the biggest source country of pharmaceutical grade exogenous opioids?
Tasmania, an Australian state
Which opioids undergo both Phase I and II metabolism?
- Codeine (Morphine–>Morphine-6-glucoronide)
- Hydrocodone (Hydromorphone–>Hydromorphone-6-glucoronide or Norhydrocodone)
- Oxycodone (Oxymorphone–>Inactive metabolites or Noroxycodone)
What opioids undergo Phase II metabolism only?
Morphine (Morphine-6-glucoronide)
What opioids undergo Phase I metabolism only?
- Fentanyl (Norfentanyl)
- Methadone (inactive metabolites
- Tramadol (O-desmethyltramadol)
In general, how does Acetaminophen impart an analgesic effect?
It is a CNS-selective cyclooxygenase inhibitor
Anandamide reuptake inhibitor (boost endocannabinoid levels)
In general, how do NSAIDs impart an analgesic effect?
- They are COX inhibitors (and subsequently inhibit prostaglandins, which are mediators of pain, inflammation, and fever
In general, how do cannabinoids impart an analgesic effect?
Activate CB1 (a G-protein coupled receptor involved in neurotransmission)
Once CB1 is activated by a cannibinoid, it inhibits release of neurotransmitter
What distinguishes endogenous opioids from exogenous opioid drugs?
Endogenous opioids are peptides
What is the common mechanism of action for pain relief with opioid and cannabinoids?
Both inhibit neurotransmitter release from the pre-synaptic neuron
What is the definition of poor metabolizers?
At least 2 loss of function alleles
What is the difference between normal and extensive metabolizers?
They are the same
What is the definition of ultra metabolizers?
At least 3 copies of functional alleles
What are the CYP gene polymorphisms?
- SNP
- Indels
- Whole-gene
- Duplication
- CNVs
For prodrugs or active metabolites, what is the impact of polymorphisms that increase metabolism?
Increase drug efficacy and ADRs = reduced safety
For active drugs, what is the impact of polymorphisms that reduce metabolism?
High drug concentrations and reduced safety
For active drugs, what is the impact of polymorphisms that enhance drug metabolism?
Reduced efficacy and can be misconstrued as drug-seeking behaviour
If an individual is a CYP2D6 poor metabolizer, how is their response to codeine different from a normal metabolizer?
Less analgesia than NM
If an individual is a CYP2E1 ultra metabolizer, what is their response to codeine?
Higher risk of hepatoxicity
What drugs do we have guidelines for dose adjustment according to CYP polymorphisms?
- Codeine and CYP2D6
- Tramadol and CYP2D6
What is the interaction between cannabinoids and opioids?
The PD effects likely synergistic
They act on nociceptive neurons and can saturate the same CYP enzymes
What are the common CYP enzymes involved in opioid metabolism?
3A5
3A4
2D6
What are the common CYP enzymes involved in cannabinoid metabolism?
3A4
2D6
2C9
What are the common CYP enzymes involved in NSAID metabolism?
3A4
2D6
2C9
What is the impact of uncontrolled pain on overall health?
- Can delay healing
- Decrease appetite
- Introduce and augment stress
- Disturb sleep
- Lead to anxiety and depression
What is the goal of pharmacogenomics in opioid therapy?
- Optimize pain relief
- Prevent adverse effects
Information about pharmacogenomics and clinical factors (age, weight, clearance, DIs) can help acheive personalized pain management
