Pharmacology of Pain: Opioids Flashcards
what are the 4 stages in treating chronic pain?
- on diagnosis, OTC pain meds
- NSAIDs, psychological therapy, nerve blocks
- then opioids, neurolysis, thermal procedures
- neurostimulation, implantable surgical intervention, neuroablation
how do opioids work?
- they decrease the signal conduction from the spinal cord to the brain
- prevent the signal from reaching the spinal cord i.e. CNS
what class of opioids are morphine and codeine?
naturally occurring compounds
what is the opioid system made up of?
opioid receptors and endogenous ligands
where does morphine act in the nervous system?
- on nociceptors
- on the spinal cord
- on the supraspinal sites i.e. area above the spinal cord
- on the limbic system - the part of the brain dealing with emotions and memories.
what makes up the limbic system?
- HYPOTHALAMUS - for producing hormones to control water levels (ADH), sleeping cycles, body temp
- THALAMUS - for thinking and movement and our senses
- CINGULATE GYRUS - for transmitting signals between inner and outer parts of the limbic system
- AMYGDALA - for storing memories
- HIPPOCAMPUS - for creating new memories about past experiences
- BASAL GANGLIA - works as a gating area to decide whether or not to carry out a movement.
where are opioid receptors commonly found?
- CNS - cortex, thalamus, spinal cord, periaqueductal gray
- peripheral neurons
- inflamed tissue
- immune cells
- respiratory and GI tract
what are the pharmacological effects of opioids?
- sedation and anxiolysis
- depression of respiration
- cough suppression
- pupillary constriction
- nausea and vomiting
- GI symptoms i.e. constipations
- can affect immune function
- can cause allergic reactions i.e. bronchoconstrictions
what is the mechanism of opioid action?
- activated peripheral nociceptive fibres releases substance P and other pain neurotransmitters from nerve terminals in the dorsal horn.
- this is regulated by endogenous endorphins or by exogenous opioid agonists which act presynaptically to inhibit substance P release - causing analgesia.
- this reduces and inhibits neurotransmission of pain signal
- this works by affecting ion transmembrane conductance mainly potassium and calcium channels.
what intracellular changes occur following the binding of the opioid agonist to the G-protein coupled opioid receptor?
- the opioid agonist binds to the receptor which causes the dissociation of the alpha unit from the beta-gamma unit
- this inhibits cAMP formation from ATP + adenylate cyclase
- also inhibits Ca2+ influx and K+ efflux.
- resulting in cell hyper polarisation i.e. cell not in resting state.
what type of pain are opioids good for?
acute and postoperative pain and cancer pain
what type of pain are opioids less effective in?
chronic non-cancer pain and neuropathic pain
when do opioids become addictive?
when repeatedly used due to their rewarding effects
common side effects of opioids are…?
- drowsiness
- dizziness
- nausea
- constipation
- itching
- breathing slows down
what happens when someone becomes tolerant to an opioid?
-they become tolerant to its analgesic effect leading to increased doses
what is the ‘within’ process of opioid tolerance?
administered drug causes an opposing reaction within the same system - this desensitises opioid receptors.
what is the ‘between’ process of opioid tolerance?
administered drug recruits neuronal circuits to oppose the primary effect of opioids by activating pronociceptors, after opioid administration, which then counteracts opioid analgesia i.e. by engaging NMDA receptors
how does the NMDA receptor work?
- activated when glutamate and Glycine bind to it
- this allows Ca2+ ions into the postsynaptic neurone
- glutamate works as the neurotransmitter from the presynaptic neurone to activate the postsynaptic one.
- Ca2+ influx causes depolarisation in the cell hence pain signal transmission.
- works to increase morphine tolerance to reduce its analgesic effects
what is the effect on Mg2+ and NMDA following the influx of Ca2+ after MOR activation from morphine?
Mg2+ is removed from blocking the NMDA receptor contributing to morphine tolerance
how do NMDA receptor antagonists work?
prevent or reverse morphine tolerance by decreasing the activation of the pronociceptive processes triggered by opioids.
what is opioid induced hyperalgesia?
An enhanced pain response to a noxious stimulus.
what are the opposite effects experienced when one becomes too dependent of opioids?
- restlessness
- sleep disturbance
- hypesthesia
- neuralgia
- irritability
what causes opioid induced hyperalgesia (OIH)?
when opioid administration is abruptly terminated or reversed by giving an opioid antagonist e.g. naloxone
what are the 5 proposed mechanisms of how opioid induced hyperalgesia (OIH) occurs?
- The central glutamatergic system (NMDA, CRGP, sub P),
- Spinal dynorphins (with CCK),
- Descending facilitation (from RVM, on and off cells),
- Genetic mechanisms (genetic polimorphism; 500 genes!),
- Decreased re-uptake of neurotransmitters from the primary afferents.
