Pharmacology of analgesia Flashcards
Which analgesics act at the site of injury?
NSAIDs decrease nociceptor sensitisation in inflammation primarily by blocking synthesis of prostaglandins
Which analgesic suppress nerve conduction by blocking/inactivating voltage-activated sodium channels?
Local anaesthetics such as lidocaine
Which analgesics suppress synaptic transmission of nociceptive signals in the dorsal horn of the spinal cord?
Opioids and some anti-depressants
Which analgesics work by activating (or potentiating) descending inhibitory controls?
Opioids, select tricyclic antidepressants
Which analgesics target ion channels unregulated in nerve damage?
Antiepileptics of several types such as GABA pentinoids
What are the stages on the WHO analgesic ladder?
- NSAID and/or paracetamol 2. Weak opioid 3. Strong opioid
List the strong opioids?
- Morphine - oxycodone - hydromorphone - heroin - fentanyl
List the weak opioids?
Codeine, tramadol, dextropropoxyphene
List the NSAIDs?
Aspirin, diclofenac, ibuprofen, naproxen, indometacin
Define opiate
Substances extracted from opium or of a similar structure to those in opium
Define opioid
Any agent (including endogenous peptides, known collectively as endorphins/enkaphalins) that act upon opioid receptors
What mediates supra spinal anti-nociception?
Descending pathways from the brainstem
What brain areas are involved in pain perception and emotion and to where do they project?
- cortex - amygdala - thalamus - hypothalamus Project to specific brainstem nuclei
What to neurones of brainstem nuclei give rise to?
Efferent pathways that project to the spinal cord to modify afferent input
In pain regulation excitation of the ___ by ________ stimulation produces profound ________. Endogenous opioids (________), or morphine and related compounds, also cause ______ (by inhibiting inhibitory GABAergic interneurones)
In pain regulation excitation of the PAG by electrical stimulation produces profound analgesia. Endogenous opioids (enkephalins), or morphine and related compounds, also cause excitation (by inhibiting inhibitory GABAergic interneurones)
Activated PAG neurons projecting to ______ _____ ______ excite __________ and __________ neurones projecting to the dorsal horn resulting in ________ of nociceptive transmission
Activated PAG neurons projecting to nucleus raphe magnus excite serotonergic and enkephalinergic neurones projecting to the dorsal horn resulting in suppression of nociceptive transmission
Morphine causes what?
Excitation of nucleus raphe magnus neurones
Locus coeruleus noradrenergic neurones projecting to the dorsal horn are also excited by what?
Electrical stimulation of PAG
NRM causes inhibition through……
Serotonin and enkephalins
LC causes inhibition through….
noradrenaline
Opioid action is mediated by _ _______-______ opioid receptors, all of which signal preferentially to ______
Opioid action is mediated by G protein-coupled opioid receptors, all of which signal preferentially to Gi/o
Signalling of Gi/o by opiods produces
- inhibition of opening of voltage activated Ca2+ channels
- opening of K+ channels
- inhibition of adenylate cyclase
How does inhibition of opening of voltage-activated Ca2+ channels act to provide analgesia?
Suppresses excitatory neurotransmitter release from nociceptor terminals- mediated by the Gi/oβγ subunit
How does opening of K+ channels contribute to opioid analgesia?
Suppreses excitation of projection neurones- mediated by the Gi/oβγ subunit
What mediates inhibition of adenylate cyclase
Gi/oα subunit
What are opioid receptors typically classed as?
- μ responsible for most of the analgesic effects- major adverse effects
- δ contributes to analgesia but activation can be proconvulsant
- κ contributes to analgesia at the spinal and peripheral level and activation associated with sedation, dysphoria and hallucinations
What are the effects of opoids on the respiratory system and what is the mechanism?
Apnoea
Blunting of medullary respiratory centre to CO2 (Hypercapnic response; pain opposes this, but natural sleep is synergistic) involves μ and δ receptors
What are the effects of opioids on the cardiovascular system and what are the mechanisms?
Orthostatic hypertension
- Reduced sympathetic tone and bradycardia (via actions on the medulla)*
- Histamine- evoked vasodilation. Morphine, but not all opioids cause mast cell degranulation which can trigger bronchospasm in asthmatics.*
What are the effects of opioids on the gastrointestinal system and what are the mechanisms?
Nausea, vomiting, constipation, increased intrabiliary pressure.
- Action on CTZ (outside the BBB)*
- Increased smooth muscle tone, decreased motility, via enteric neurones- involves μ and δ receptors*
What are the adverse effects of opioids on the CNS and what is the mechanism?
Confusion, euphoria, dysphoria, hallucinations, dizziness, myoclonus, hyperalgesia (with excessive use)
- Occur to different degrees dependent upon the specific opioid drug and receptor subtypes activated.
Which opioids are agonists and achieve analgesia mainly through prolonged activation of of μ-opioid receptors?
Morphine
Diamorphine (3, 6- diacetylmorphine, heroin)
Codeine (3- methoxymorphine)
Fentanyl
Pethidine
Buprenophine
Tramadol
Methadone
Etrophine (immobilon)
Describe the metabolism of morphine?
Metabolised in the liver by glucoronidation at the 3 and 6 positions yielding M3G that is inactive and M6G that retains analgesic activity and is excreted by the kidney.
In acute severe pain morphine may be given __ (as ________ doses in high-dependency areas), or __, __ and ______ (in general wards),
In chronic pain ____ administration is most appropriate [as ________ (e.g. oramorph, or ________ release (MST continus) formulations]
In acute severe pain morphine may be given __ (as ________ doses in high-dependency areas), or __, __ and ______ (in general wards),
In chronic pain oral administration is most appropriate [as immediate (e.g. oramorph, or sustained release (MST continus) formulations]
Specialist administration by _______ and _________ routes provides profound analgesia
Specialist administration by epidural and intrathecal routes provides profound analgesia
Diamorphine is more _________ than morphine.
Diamorphine is more lipophilic than morphine.
Describe the use and action of diamorphine?
Rapid onset when administered IV
Can be used for severe post-operative pain
Describe codeine?
Naturally occuring weaker opioid for mild/moderate pain
How is codeine metabolised?
Hepatic metabolism by demethylation (in relatively small amounts) to morphine by CYP2D6 and CYP3A4 accounts mainly for analgesia, subject to genetic variation
How is codeine administered?
Orally, NOT IV
What are the benificial side effects of codeine?
Anti-diarrhoeal and antitussive activity that can be useful
What are the derivatives of codeine with higher potency?
Oxycodone
Hydrocodone
Fentanyl is _______ fold more potent than morphine
Fentanyl is 75-100 fold more potent than morphine
How can fentanyl be administered?
Given IV to provide analgesia in maintenance analgesia (remifentanil used similarly has very rapid onset and offset of analgesia)
Suitable for transdermal (and buccal) delivery in chronic pain states, but not in acute pain
When is pethidine used?
Acute pain, particularly labour
Describe the onset and duration of action of pethidine?
Rapid onset of action when given IV, IM or SC but short duratio nof action
Use of pethidine in conjunction with MAO inhibitors causes;
excitement, convulsions, hyperthermia
What is norpethidine?
Neurotoxic metabolite (seizures)
Buprenorphine is a ______ _____ which is useful in _____ pain with patient-controlled _______ systems.
It has a ____ onset, but ____ duration of action.
Can be given by ________, or _________.
Buprenorphine is a partial agonist which is useful in chronic pain with patient-controlled injection systems.
It has a slow onset, but long duration of action.
Can be given by injection, or sublingually.
Tramadol is a weak _-receptor agonist. How does it work?
ramadol is a weak μ-receptor agonist.
It probably exertes se
How is Tramadol administered and who should it be avoided in?
Orally
Patients with epilepsy
Methadone is a weak _-agonist of the _________ class, with additional actions where?
Methadone is a weak μ-agonist of the phenylheptylamine class, with additional actions;
in the CNS including
- potassium channels
- NMDA glutamate receptors
- some 5-HT receptors
Given _________, methadone has a ____ duration of action (plasma half life >__hours)
Given orally, methadone has a long duration of action (plasma half life >24 hours)
What are the uses for methadone?
Can be useful in treating patients with chronic pain in terminal cancer or assisting in withdrawal from ‘strong opioids’ such as heroin.
Which opioids are antagonists?
Naloxone
Naltrexone
Alvimopan, methylnatrexone
Naloxone is a ______ antagonist at _-receptors (to a lesser extent κ- and δ-receptors)
Naloxone is a competitive antagonist at μ-receptors (to a lesser extent κ- and δ-receptors)
What is naloxone used for?
To reverse opioid toxicity (i.e. respiratory and/or neurological depression) associated with ‘strong opioid’ overdosage
How is naloxone administered?
Incrementally IV. IM and SC routes are alternatives.
Why must a patient on naloxone be closely monitored?
Because of its short life, opioid toxicity to longer acting agonists can recur
Could also trigger an acute withdrawal response
What is naltrexone?
Similar to naloxone, but with the advantage of oral availability and a much longer half-life.
What are alvimopan and methylnatrexone used for?
To reduce G.I. effects of surgical and chronic opioid agonist use
What are the non-selective NSAIDs?
aspirin
ibuprofen
naproxen
diclofenac
indometacin
What are the selective NSAIDs? How do they work?
Etoricoxib
Celecoxib
Lumiracoxib
Inhibit COX-2 enzyme
How do NSAIDs work?
Inhibit COX-1 and COX-2 enzymes to prevent the production of prostaglandins
COX-1 is ________ active, COX-2 is induced _______ at sites of ____ by various cytokines
COX-1 is constitutively active, COX-2 is induced locally at sites of pain by various cytokines
The therapeutic effect of NSAIDs derives from what?
Inhibition of COX-2
NSAIDs can act both centrally and peripherally to;
(3)
- suppress the decrease in the activation threshold of the peripheral terminals of nociceptors that is caused by prostaglandins.
- decrease recruitment of leukocytes that produce inflammatory mediators
- if they cross the BBB, suppress the production of pain-producing prostaglandins in the dorsal horn of the spinal cord (that, for example reduce the action of the inhibitory neurotransmitter glycine)
Why is acetaminophen not an NSAID
Acts only centrally and lacks anti-inflammatory effect
Why do NSAIDs lack analgesic efficacy?
Because multiple signalling pathways, several of which do not involve arachidonic acid metabolism, cause nociceptor sensitization.
Why are COX-2 inhibitors not used instead of non-selective NSAIDs?
They are prothrombotic
Long term administration of non-selective NSAIDs may result in what?
Gastrointestinal damage (PGE2 produced by COX-1 protects against the acid/pepsin environment)
In what conditions is neuropathic pain felt?
What are the treatment options for neuropathic pain?
Gabapentin and pregabalin
Amitriptyline, nortryptilline and desipramine (tricyclincs)
Carbamazepine
How do antiepileptics (Gabapentin and pregabalin) work?
Reduce the cell surface expression of a subunit (α2δ) of some voltage gated Ca2+ channels (high-voltage-activated subgroup) which are upregulated in damaged sensory neurones.
What does reducing cell surface expression of α2δ result in?
decrease of neurotransmitters, such as glutamate and substance P from the central terminals of nociceptive neurones
Gabapentin is used for what?
Pregabalin is used for what?
Gabapentin: migraine prophylaxis
Pregabalin: painful diabetic neuropathy
How do tricyclic antidepressants act on neuropathic pain?
Act centrally by decreasing the reuptake of noradrenaline
How does carbamaxepine act on neuropathic pain?
Blocks subtypes of voltage-activated Na+ channel that are upregulated in damaged nerve cells
What is the first-line treatment to control pain intensity and frequency of attacks in trigeminal neuralgia?
Carbamazepine
