Week 10 Opioids Flashcards
Nociception and Pain
Nociception: the physiological ability to sense pain, as encoded by nociceptor stimulation.
Pain: nociception + subjective (emotional) experience, can be widely varied.
Acute Pain and Inflammation:
signaling
To the spinal chord:
Nociceptive input is transmitted to the spinal cord, and to the brain via the spinothalamic pathway for processing.
The ascending transmission is modulated by descending inhibitory pathways from the brain to the
dorsal horn of the spinal cord. These pathways are rich with opioid receptors that we can make
use of medicinally.
To descending pain control: regions
rich with opioid receptors
Cortical brain regions project
downwards to the
*periaqueductal grey (PAG) region
of the midbrain
*rostral ventromedial medulla
(RVM) and then onwards to
*the dorsolateral funiculus in the
spinal cord.
This pathway is key to the body’s
endogenous pain management
system, which utilises 5-HT
(serotonin) and enkephalins, the
latter of which blocks spinothalamic transmission of pain.
Key points about opioids
- The human body is organized to transmit pain from injury or illness via nociceptors. Inputs travel via the spinothalamic tract to the brain through regions that are rich in opioid receptors.
- Opioid receptors play a key role in the body’s own pain management system, which results in activation of opioid receptors and the reduction of pain signalling.
- Pain is a physiological and psychological experience of a patient, and patients will have different levels of pain. Opioids are used for the higher levels of pain that require management.
Opioid Receptors
The opioid receptors are a family of GPCRs (Gi), activation of which:
* decreases AC function and decreases neurotransmitter release
* ion channel effects may result in hyperpolarization and reduced neurotransmitter release.
The net outcome is inhibitory synaptic function of neurons with opioid receptors, usually reducing release of glutamate as neurotransmitter.
Which opioid receptors are present?
MOP = mu opioid receptor
DOP = delta opioid receptor
KOP = kappa opioid receptor
NOP = nociceptin/orphanin
FQ peptide receptor
Endogenous agonists:
endorphins,= enkephalins, dynorphins, etc.
~75% of opioid receptors are
MOP and are presynaptically
located in CNS
at the synaptic level we can impact
nociception transmission
Opioid activity reduces the afferent signaling pathway activity and promotes activity of the descending
inhibitory pathways, leading to overall reduction of nociception and pain.
Key points #2
- Opioids are a family of compounds which include natural (codeine and
morphine) and manmade compounds which interact with opioid receptors in the spinothalamic pathway and the descending pain management tracts. - Opioid receptors are GPCRs which are located on pre- or post-synaptic sides of synapses.
- Activation of opioid receptors leads to either an inactivation of adenylyl
cyclase enzyme function (reduces intracellular calcium) or increase potassium ion flow out of the neurons, making if more hyperpolarized. Both of these effects will inhibit pain transmission and provide pain relief.
Opioid Drug Class
Full agonists: heroin, morphine, oxycodone, meperidine, fentanyl
Partial mu-receptor agonist: buprenorphine
Mu-receptor antagonist: naloxone
- Note that BBB penetration is not a
real issue.
Opioid respiratory depression
- Opioids bind to and inhibit respiratory centers within the medulla and pons responsible for the rate of respiration (pneumotaxic (amount of air taken in) and apneustic (long and deep breaths)
centers) as well as the control of the
muscles of inspiration and expiration
that govern tidal volume. - Respiratory tidal volume decreases,
breathing rate decreases to 3-4 breaths per minute with overdose - These respiratory effects are quickly
reversed with administration of
antagonist, e.g naloxone, with µ receptors as key agents in this side
effect.
Opioid Miosis effect
- Miosis is an important diagnostic
indicator of opioid overdose, and
this response does not decrease
with repeated use. - Pupil constriction is due to direct
stimulation of the Edinger-Westphal
nucleus of cranial nerve III, which
activates the parasympathetic
innervation of the iris sphincter
muscle. - By inhibiting the inhibitory input
onto the EW nucleus, opioids allow
the nucleus to do what it does best,
and that is constrict the iris by
increasing the parasympathetic
tone (ACh).
Opioids and Constipation
Constipation due to increase in tone and decrease in motility:
* Delay of passage of food (gastric contents) which may lead
to increased retention of water.
* Tolerance does not develop to constipation
Opioids:
Increase circular motion contraction
= cramps
Reduced coordinated peristasis
= slow bowel transit
Reduced secretion of fluids and electrolytes
= dry hard stool
Opioids, Nausea and Vomiting
– Chemoreceptor trigger zone (CTZ)
may detect opioid in the blood, and
signals the medullary vomiting
center;
– opioids may directly stimulate the
vestibular apparatus, as patients note a spinning sensation with their nausea
The chemoreceptor trigger zone (CTZ) has neuronal connections to the vomiting centre (VC), and patients using opioids long term may need to consider antagonist medications.
Nausea and vomiting are reported in ~45% of patients, but tolerance develops with repeated use – action via chemoreceptor trigger zone.
ADME for Codeine and Morphine
Codeine: undergoes less first-pass
metabolism than morphine, so has
greater bioavailability.
Morphine is well-absorbed in the gut
and undergoes extensive first-pass
metabolism in the liver.
Hepatic disease may impact on
metabolism so dosing may be adjusted accordingly.
Codeine is converted to morphine by
CYP2D6, which has significant genetic
variation. Mothers who are rapid
metabolizers of codeine may expose
their foetus or nursing infant to a
morphine overdose.
7/100 people are ultra-fast
metabolisers
Opioid metabolism
CYP2D6 and CPY3A4 are major contributors of metabolism, as is
glucuronidation
