Mechanisms of Analgesia Flashcards
Describe the efferent, supraspinal ant nociception regulation of pain
Supraspinal anti-nociception is mediated by descending pathways from the brainstem:
- Brain regions involved in pain perception and emotion (cortex, amygdala, thalamus and hypothalamus) project to specific brainstem nuclei
- Neurons of brainstem nuclei give rise to efferent pathways that project to the spinal cord to modify afferent input
Describe important brainstem regions involved in efferent, modulation of pain (supraspinal anti-nocicpetion)
PAG (midbrain) Locus coeruleus (pons) - NA to dorsal horn Nucleus Raphe Magnus (medulla) - 5-HT and enkephalinergic to dorsal horn
Describe the role of PAG in anti-nociception
Excitation via electrical stim of PG produced a profound analgesia
Endogenous opioids (enkephalins) or morphine and related compounds also cause excitation of the PAG (via inhibiting inhibitory GABA-ergic interneurons i.e. disinhibition)
Excitation of PAG results in excitation of NRM and LC which act to decrease nociception transmission in the DH of SC (descend via dorsolateral funiculus DLF)
What are the 3 mechanisms by which NA and 5-HT/enkephalin impacts in the DLF act as anti-nociceptive agents
Direct presynaptic inhibition
Direct post synaptic inhibition
Indirect inhibition
Describe the mechanisms of direct presynaptic inhibition in the anti-nociceptive effects of NA and 5HT/enkephalin in more detail
Inhibition of nT release from nociceptors (A-delta, c fibre) onto projection neuron
This works via GPCR (5HT metaboreceptors) to suppress the opening of voltage gated calcium channels and therefore calcium influx required for nT exocytosis and vesicle docking at the presynaptic membrane
Describe the mechanisms of direct post synaptic inhibition n the anti-nociceptive effects of NA and 5HT/enkephalin in more detail
Works via GPCRs opening K+ channels in the projection neuron causing hyperpolarization and reduced excitability
The effect of descending inhibition can be mimicked by exogenous opioids such as opioids. These work on GPRC to open voltage activated K+ channels. Threshold for action potential increased
Describe the mechanism of indirect inhibition n the anti-nociceptive effects of NA and 5HT/enkephalin in more detail
Works via activation of inhibitory interneurons (enkephalinergic and GABAergic) that suppress transmission by both pre and post synaptic mechanisms
Gating theory; myelinated Ab-beta non-nociceptor units act on inhibitory interneurons to increase activity
Increase of enkephalin (endogenous opioids)
Describe the action of opioids on the DLF
Inhibit K+ channels directly; hyperpolarizing the projection neuron
Mimic the activity of enkephalins on the inhibitory interneuron
Overall; suppression of excitability of projection neuron
How do analgesics reduced nociception?
Local action to decrease nociceptor sensitization in inflammation (NSAIDs)
Block nerve conduction (local anaesthetics)
Suppress the transmission of nociceptive signals in the DH of the SC (opioids and amitriptyline)
Activation (potentiation) of descending inhibitory controls (opioids)
Targeting ion channels upreg in nerve damage (carbamazepine)
What type of receptor is an opioid receptor?
Metabotropic via Gi/o
- Inhibition of opening of voltage activated calcium channel of the central terminal of nociceptive neurons. Suppressed excitatory transmission release mediated by the Gi/o beta gamma subunit
- Opening of K+ channels at the post synaptic membrane. Suppresses excitation of projection neurons. Mediated by Gi/o beta gamma subunit
- Inhibition of adenylyl cyclase; mediated by the Gi/o alpha subunit. Decreased in abundance of cAMP in the cells.
What are the different forms of opioid receptors?
Mu; analgesic effects and major adverse SE
Delta; analgesia and proconvulsant
Kappa; analgesia at the spinal and peripheral level, activation assoc with sedation, dysphoria and hallucinations
Describe the respiratory side effects of opioids
Apnoea
Occurs via blunting of the medullary resp centre to carbon dioxide (hypercapnic response; pain opposes this)
Involves mu and delta
Describe the cardiovascular side effects of opioids
Orthostatic hypotension
Reduced symp tone, and bradycardia (via actions on the medulla)
Histamine evoked vasodilation - morphine can cause mast cell degranulation which can trigger bronchospasm in asthmatics
Describe the GI side effects of opioids
N+V
Constipation
Increased intrabiliary pressure
Action on CTZ (out with BBB)
Incr smooth muscle tone, decreased motility via enteric neurons
Involves mu and delta
Describe the CNS SE of opioids
Confusion, euphoria, hallucinations, dizziness, myoclonus, hyperalgesia
Occurs to different degrees dependent on the specific opioid drug and receptor subtypes activated
Describe morphine
Widely used for severe pain
Hydroxyl group at 3 and 6 Carbon
Metabolised in the liver by glucuronidation at the 3 and 6 positions yielding M3G that is inactive and M6G that retains analgesic activity and is excreted by the kidney (water soluble)
Can be given IV, IM, s/c or PO
Chronic oral administration; oramorph or MST (12-14 hrs)
Describe diamorphine (3,6-diacetyle morphine, heroin)
Acetyl groups (lipophilic) at 3 and 6. MORE lipophilic than morphine. Enters CNS much better than morphine due to diffusibility of BBB
Severe post-op pain
Describe coedine
3-methoxy substituent at 3 carbon group with a methyl group
Naturally occurring weak opioid
Pro-drug; requires metabolism to become active. This occurs via hepatic metabolism
Codeine molecule is demethylated to morphine via CYP2D6 and CYP3A4 (subject to polymorphisms)
Additional anti-diarrhoeal and antitussive activity
Semi-synthetic derivatives with a higher potency include oxycodone and hydrocodone
Describe fentanyl
75-100x more potent that morphine
Part of phenylpiperidine class of opioid agonist
Given IV to provide analgesia in maintenance anaesthesia (remifentanil - rapid onset and offset) to reduce GA required
Transdermal and buccal delivery in chronic pain states
Describe pethidine
Used in acute pain, esp labour
Rapid onset and offset of action when given IV, IM or s/c
Should not be used in conjunction with MAO inhibitors (causes excitement, convulsions and hyperthermia)
Norpethidine is a neurotoxic metabolite (seizures)
Describe buprenorphine
Partial agonist
Useful in chronic pain with patient controlled injection systems
Slow onset but long duration of action
IV or sublingually
Describe tramadol
Weak mu opioid receptor agonist
Exerts significant analgesic action by potentiation of descending supraspinal serotonergic (NRM) and adrenergic (LC) systems
Given PO
AVOID in patients with epilepsy
Describe methadone
Weak mu agonist of phenyheptylamine class with additional actions at other sites in CNS such as K+ channels, NMDA glu receptors and 5-HT receptors
Given PO, with a long duration of action (1/2 >24hrs)
Useful in tx of chronic pain, and terminal cancer
Assists in withdrawal from “strong opioids” such as heroin
Describe the relationship between half life and addictive potential
Agents with abuse potential that have a short half life are more addictive than those with a long half life
Describe naloxone
Competitive antagonist at mu receptors (lesser extent to kappa and delta)
Used to reverse opioid toxicity (i.e. resp and/or neurological depression)
Give incrementally with IV, however can be given IM and s/c
SHORT 1/2. Clinically, you must monitor the effect of naloxone very carefully, titrating the individual dose, and frequently to that required reverse opioid toxicity
The opioid will have a longer half life than naloxone.
Describe naltrexone
Similar to naloxone, but orally available and with a much longer half life
Describe alvimopan and methylnaltrexone
Do NOT enter CNS
Reduce GI effects of surgical and chronic opioid agonist use
Describe NSAIDs
Widely used to reduce mild/mod inflammatory pain
Analgesic, antipyretic and anti-inflammatory actions
Inhibit the synthesis and accumulation of prostaglandins byCOX1 and Cox 2
Describe the pathway from phospholipids to prostaglandins
Phospholipids = arachidonic acid via phospholipase A2
Arachidonic acid to endoperoxides via COX 1 + 2
Endoperoxides to prostaglandins (PGE2, PGD2)
What are the effects of prostaglandins?
Hyperalgesia
Allodynia
Pain
Where do NSAIDs (aspiring, ibuprofen, naproxen, diclofenac, indomethacin) act to prevent prostaglandin production?
COX-1 and COX-2
Therefore, prevents the formation of endoperoxides via arachidonic acid
Where do COX-2 selective inhibitors (etoricoxib, celecoxib, parecoxib) act?
COX-2 to prevent creation of endoperoxides from arachidonic acid
Describe the difference between COX1 and COX2
COX1 is constitutively active
COX2 is induced locally at sites of inflammation by various cytokines
Therapeutic benefit is largely derived from inhibition of COx2
Do NSAIDs act peripherally and centrally?
Yes
Suppresses the decrease in the activation threshold of the peripheral terminals of nociceptors that is caused by PGEs
Decrease recruitment of leucocytes that produce inflammatory mediators
If cross BBB, suppress the production of pain-producing prostaglandins in the DH of the spinal cord (for example, reduce the action of the inhibitory nT glycine)
Where does paracetamol act?
No anti-inflammatory activity
Acts only centrally
Precise mechanism is still debated but may involve several of its metabolites
Why is long term use of NSAIDs not reccomended?
GI damage; PGE2 produced by COx1 protects against the acid/pepsin environment
Nephrotoxicity can occur due to inhibition of COX2 constitutively expressed in the kidney. Inhibition can compromise renal haemodynamics
Describe conditions whereby neuropathic pain predominates
Traumatic nerve, spinal cord, or brain damage (e.g. stroke) Trigeminal neuralgia Diabetic neuropathy HIV/AIDs neuropathy Post-herpetic neuralgia MS Phantom limb pain
Does neuropathic pain respond to typical analgesics?
No; no response to NSAIDS and relative insensitivity of opioids
There is evidence that there is downregulation of mu opioid receptors, or reduced signalling via such receptors occurs following nerve injury
Which drugs are used to treat neuropathic pain?
Gabapentin and pregabalin
TCAs
Describe the gabapentinoids
Reduced cell surface expression of alpha-2 delta-1 subunit of voltage calcium channels (high voltage activated sub-group) which are upregulated in damaged sensory neurons. Alpha-2 delta-1 isoform is associated specifically with excitatory neurons
Decrease in abnormally enhanced release of nT, such as glutamate and sub P, from the central terminals of nociceptive neurons
Gabapentin; migraine prophylaxis
Pregabalin; painful diabetic neuropathy
Describe TCAs for neuropathic pain
Act centrally by decreasing the reuptake of NA (and 5-HT)
Duloxetine and venlafaxine additionally decrease the reuptake of 5-HT
SSRIs do NOT provide analgesia`; suggesting the important role for NA
Describe carbamazepine in neuropathic pain
Blocks subtypes of voltage activated sodium channels which are upreg in damaged nerve cells
1st line to control pain intensity and frequency of attacks in trigeminal neuralgia
