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
Differing affinities and efficacies: Full
and partial agonists
- Strong and moderate agonists usually have a high affinity for MOP and lower affinities for DOP and KOP.
- Full agonists are generally well-tolerated when given in a dose sufficient to relieve severe pain.
- Partial agonists will cause intolerable side effects if given in doses sufficient to relieve severe pain.
- For this reason, lower concentrations of moderate
opioids are sometimes coupled with NSAIDS for pain treatment.
Strength of opioids as agonists
Strong:
- morphine
- fentanyl
- methadone
Mild:
- Hydrocodone (vicodin)
- pethidine
Mixed actions:
- buprenorphine
Morphine
the “gold standard”
- MOA covered previously
- Used for severe pain management
- Tolerance is a key factor in long-term use
- Tolerance occurs differently to
the analgesic, respiratory depression and minimally to constipation side effects
Fentanyl
50-100x potency of morphine
- Greater potency and lipophilicity
enable fentanyl to be used in patches, injection or lozenge for
severe or chronic pain. - As metabolized by CYP3A4, care
needs to be taken re other drugs
using same pathway and no
grapefruit. - Can be used to bring down large
mammals (a.k.a. large elephants) due to faster onset than morphine. - Lacks active metabolites, making
it useful in renal failure.
Methadone
strong long-acting synthetic agonist
- Used to treat opioid/heroin addiction or chronic pain. Does not cause euphoric effects; can reduce criminal behaviour, reduce needle sharing and transmission of HIV and hepatitis B or C.
- Methadone can be lethal in overdose if injected, or when combined with other drugs such as alcohol and minor tranquilisers (benzodiazepines).
- Can be given just once a day to control withdrawal. Addicts to heroin may be placed on a methadone maintenance program.
Hydrocodone (Vicodin)
semi synthetic - moderate
Pethidine
synthetic moderate
- Tends to cause restlessness, euphoria, and has antimuscarinic effects as well; but no miosis.
- Preferred to morphine during
labour as it does not affect
uterine smooth muscle function. - May cause issues with respiratory depression in the neonate, however, as its elimination is relatively slow.
Buprenorphine
partial agonist
- Ceiling effect exists for respiratory
depression making buprenorphine safer as addicts are less likely to overdose. - Interestingly, buprenorphine has been combined with naloxone in a 4:1 ratio (Suboxone), to alleviate worry that the sublingual tablet would be dissolved or injected by addicts seeking to get a high
from higher concentrations. - Naloxone is poorly absorbed sublingually and orally, but well absorbed when injected i.v.
- This means that a user injecting
Suboxone would experience withdrawal symptoms due to naloxone occupying mu receptors!
Naloxone (and Naltrexone)
Antagonists
Compounds prevent or abolish unnecessary respiratory depression caused by morphine or related compounds
Compete for opioid receptor binding sites
It blocks the euphoric effect of heroin when given before heroin, and is short acting.
Naltrexone’s actions resemble those of naloxone, but naltrexone is well absorbed orally and is long acting, making it useful in narcotic treatment
Key points #3
- Opioids have a number of effects beyond pain relief, which can impact
patient comfort and management. - Hypotension and constipation are common, and tolerance may or may not occur to these.
- High doses of opioids can cause respiratory depression and pin-point pupils, and potentially death if tolerance has not occurred.
- Opioids can be generally classified as “strong” or “moderate” depending upon their efficacy. Combination of moderate agonists with NSAIDs are common for mid-range pain.
- Antagonists, such as naloxone, prevent the opioid from binding to receptors and can reverse life-threatening effects.
General pain management plan
Step 1 (mild pain rated 1-3)
- non-opioid (NSAID)
- non-pharmacological +_ adjuvants
Step 2 (moderate pain rated 4-6)
- non-opioid and weak opioid combination
- non-pharmacological +_ adjuvants
Step 3 (severe pain rating 7-10)
- strong opioid +_ adjuvants
- non-pharmacological
