Lecture 19: Opioids II Flashcards
What drugs are used to manage severe acute pain?
Opioids
Why are Opioids not the best to treat chronic pain?
Because of their side effects
Why are opioids such good drugs at blocking pain?
Because opioid receptors are distributed along the entire neural axis that transmits pain to the brain and processes pain into an experience
What neurons are mu, delta and kappa opioid receptors located on?
Primary and secondary afferents in the skin and spinal cord
How does agonist binding to opioid receptors affect pain transmission?
Agonists binding to opioid receptors inhibit pain transmission from skin to brain
What are nociceptors?
Primary afferent neurons that are specifically tuned to the detection of pain
What do opioid receptors localized in the brainstem (rostroventral medulla) do?
Increase diffuse noxious inhibitory control
Which part of the brain is important in controlling the endogenous pain system?
The rostroventral medulla
What is the diffuse noxious inhibitory control?
The endogenous pain system of the body that dampens the experience of pain
When is the diffuse noxious inhibitory control activated?
When pain fibers are activated in the skin. Basically when there are pain signals being transmitted from the skin to the brain
What is the diffuse noxious inhibitory control comprised of?
Descending excitatory and inhibitory neurons in the medulla that inhibit or activate pain synapses in the spinal cord
What can the excitatory and inhibitory neurons in the diffuse noxious inhibitory control system do?
The can amplify or inhibit the transmission of pain from the primary to secondary afferent
What are the On cells in the diffuse noxious inhibitory control system?
The descending neurons that project from the rostral ventral medulla to the spinal cord
What does activation of the On cells in the diffuse noxious inhibitory control system do?
Amplify pain
What are the On cells in the rostral ventral medulla under the control of?
Neurons that express opioid peptide
What receptors do the on cells of the rostral ventral medulla express?
Mu opioid receptors
What does the release of opioid peptides on the rostral ventral medulla on cells do?
Inhibits the activity of On cells and reduces the signals of nociceptive signals reaching the brain
What is Dopamine involved in?
Motivated behavior and reward
where are dopamine neurons located primarily?
In the ventral tegmental area (VTA)
What are Mu opioid receptors in the VTA located on?
Inhibitory GABAergic interneurons
What do Mu opioid receptors on GABAergic neurons do?
They inhibit activation of GABA neurons which stops them from releasing GABA which is an inhibitory neurotransmitter onto dopamine neurons causing dopamine neurons to produce more dopamine (disinhibition)
What are the two ways opioid receptors inhibit pain?
- Decreasing nociception at the level of the nociceptor, in the spinal cord, and in the brain step
- Decreasing the emotional and cognitive aspects of pain (make the pain bother you less)
Which opioid receptor do most opioid agonists use to target pain?
Mu receptors
What are examples of drugs that for pain that are mu agonists?
- Morphine
- Fentanyl
- Codeine
- Oxycodone
What are Delta agonists being developed for?
Chronic migraines
Why was development of delta agonists initially limited?
Because of severe side effects (seizures)
Why has enthusiasm been renewed with delta agonists?
Because the analgesic effects can be isolated through biased agonism that activates the G protein pathway and not the beta arrestin pathway
What is an example of a biased delta opioid agonist?
TRV250
Why haven’t kappa agonists that penetrate the brain been developed for pain?
because of dysphoria/hallucinogenic effects
What don’t peripherally restricted kappa agonists not do?
Cross the BBB
What do kappa agonists do?
Bind to kappa receptors in the skin and inhibit pain transmission while avoiding CNS adverse events
What is an example of a kappa agonists?
CR845
What are the effects of CR845?
- Potent analgesic
- Anti-inflammatory
- Anti-itch properties with little CNS effect
What is Tolerance?
Decrease response to the effects of a drug, requiring even larger doses to achieve the same effect
What does opioid tolerance develop to?
The analgesic, euphorigenic, sedative and respiratory effects of the drugs
What causes Tolerance?
Following agonist binding and G-protein signalling, Beta arrestin is also recruited to shit off signalling and pull the receptor off the membrane leading to less receptors on the membrane
When does Physical dependance develop?
Following chronic opioid use and is revealed following abrupt discontinuation of drug as withdrawal
What are the symptoms of acute withdrawal?
- Rhinorrhea (runny nose)
- Lacrimation (tearing eyes)
- Chills
- Muscle aches
- Diarrhea
- Yawning
- Anxiety
What is addiction?
A brain disease driven by disfunction in reward, motivation, memory circuitry
What is addiction characterized by?
- Inability to abstain consistently
- Impairment of behavioral control
- Drug craving
- Diminished recognition of significant problems with one’s behaviors and interpersonal relationships
- Dysfunctional emotional response
How are physical barriers a treatment for opioid use disorder?
Physical barriers prevent chewing/crushing of oral tablets for intravenous/intranasal drug use
How are chemical barriers a treatment for opioid use disorder?
They can be added to resist extraction of the opioid by common solvents like water/alcohol
How are Agonists/Antagonist combination be barriers a treatment for opioid use disorder?
An antagonist can be added to an agonist to interfere with euphoria associated with abuse. The antagonist is only release when oral tablet is tampered with (crushed, injected)
What is Agonist Replacement therapy?
A comprehensive treatment approach including maintenance on an opioid agonist and cognitive behavioral therapy
What are the advantages to agonist replacement therapy?
- Reduced drug cravings
- Better participation in addiction treatment since withdrawal symptoms aren’t a distractions
- Improved social functioning
- Reduction in infectious disease/death associated with illicit drug use
What drugs are used in agonist replacement therapy and why?
Methadone and Buprenorphine because they have a longer half life
What is Methadone?
A long-acting full agonist at the mu opioid receptor used in agonist replacement therapy
What is the disadvantage to methadone?
It is a full agonist so overdose is still possible
Which receptors do Buprenorphine work on?
It is a partial agonist at the mu opioid receptor and an antagonist at the kappa and delta opioid receptor used for agonist replacement therapy
What is Buprenorphine marketed as?
Suboxone and is mixed with naloxone
Why does Buprenorphine have a safer agonist profile?
Because it is a partial agonist
What is Injectable opioid therapy (iOAT)?
When clients are prescribed specific doses of injectable opioids and are expected to self administer them at the iOAT clinic
What is Naloxone?
A non-selective competitive opioid receptor agonist
