6d. Pharmacology of Pain Flashcards
Pain
- Definition
An unpleasant and emotional experience associated with or resembling that associated with actual or potential tissue damage or described in terms of such danger
Nociception
- Definiition
The neural process of encoding noxious stimuli
Chronic Pain
- % of Population
Affects 43% of humans at some point in their lifetime
Chronic Pain
- Definition
Pain that occurs in >1 location in the body for >3 months
Chronic Pain
- Most Common Cause
Arthritis and osteoarthritis
% of Patients who Feel that Their Medication Provides Adequate Pain Relief
36%
2 Types of Nociceptive Fibre
- Thinly myelinated A-delta fibres
- Unmyelinated C fibres
Ion Channels
- 4 Heat Activated
- TRPV1
- TRPV3
- Anoctamin-1
- TRPA1
Ion Channels
- 2 Cold Activated
- TRPM8
- TRPA1
Ion Channels
- 3 Proton Activated
ASICs
- TRPV1
- TASKS
Ion Channels
- Mechanically Activated
- Piezo1/2
- TRPV4?
- ASICs?
Heat Pain Threshold
> 42 degrees C
Nociceptor Sensitisation
- Definition
When a stimlulus is great enough to cause tissue damage the response to subsequent stimuli increases
Nociceptor Sensitisation
- Hyperalgesia
A stimulus that causes pain now causes more pain
Nociceptor Sensitisation
- Allodonia
A stimulus that usually causes no pain (innocuous stimuli) now causes pain
- Taking a shower when sunburnt
Nociceptor Sensitisation
- Sensitising Agents Definition
Agents that active and sensitise nociceptors
Nociceptor Sensitisation
- Internal Sensitising Agents
Released upon cell stress or tissue damage
Can:
- Sensitise nociceptors
- Directly activate nociceptors
- Both
Internal Sensitising Agents
- 3 Excitatory Agents
Directly activate nociceptors
- ATP from damaged cells
- Bradykinin formed by kallikrein cleavage of kininogen
- Acid released by anaerobic metabolism during anoxia or metabolic overload
Internal Sensitising Agents
- 2 Sensitising Agents
- Prostaglandins
- Nerve growth factor
Nociceptor Sensitising Agents
- 3 Excitatory and Sensitising Agents
- ATP
- Bradykinin
- H+
Non-Sensitising Agents Released by Nociceptor Terminals
Release:
- CGRP
- Substance P
Trigger vasodilation and increase the permeability of blood vessels
Directly and indirectly trigger mast cell degranulation through substance P
Substance P
Creates a flare at the site of injury called neurogenic inflammation, by:
- Inducing mast cell degranulation releasing histamine
- Vasodilation
- Increasing vascular permeability
Neurogenic Inflammation
Activated nociceptor terminals release GCRP and substance P, which trigger vasodilation, increase in vascular permeability and mast cell degranulation (substance P).
Causes the development of a flare surrounding the site of injury.
Prostaglandins
- Synthesis
- Arachidonic acid is metabolised to prostaglandins by COX
- AA is cyclised and oxygenated forming PGG2
- PGG2 is reduced to form PGH2 - PGE synthase converts PGH2 into PGE2
Arachidonic acid and COS-2 are up-regulated in inflammation, increasing PGE2 synthesis
Prostaglandins
- Action
PGE2
- Enhances bradykinin excitation of nociceptors, sensitising them
Prostaglandins
- Receptors
EP1-4
EP4 is up-regulated in inflammation, so is important for inflammatory pain.
- Gs coupled so activated AC, increasing cAMP, activating PKA which phosphorylates voltage gated Na+ channel Nav1.8, reducing its activation threshold. Therefore smaller depolarisation is able to evoke action potential firing.
Nociceptive Afferents
- Cell Body Locations
- Dorsal root ganglion (body)
- Trigeminal nucleus (head)
Nociceptive Afferents
- Termination Locations
Dorsal horn
- Lamina I (marginal soleria)
- Myelinated A-delta fibres
- Unmyelinated C fibres - Lamina II (substantia)
- Myelinated A-delta fibres
- Unmyelinated C fibres - Lamina V
- Large diameter Aβ fibres (mechanoreceptors)
- Myelinated A-delta fibres
- Unmyelinated C fibres
Nociceptive Afferents
- Higher Pathways
- Synapse in dorsal horn
- Fibres decussate
- Run up anterolateral system
Either:
- Synapse in the PAG or reticular formation within the trigeminal nucleus , synapse in the thalamus and then to the ACC and insula
- Bypass PAG or reticular formation, synapse in the thalamus and run to the primary somatosensory cortex
Cortical Representation of Pain
- Primary Somatosensory Cortex
Discriminate pain or nociception:
- Comparing 2 different painful stimuli to determine which is greatest
- Determining when pain stimulus is increasing
Cortical Representation of Pain
- ACC
Part of the limbic system responsible for the emotional/motivational element of pain.
Increases firing in response to witnessing someone elses pain, perhaps underlying empathy
Cortical Representation of Pain
- Insula Cortex
Homeostatic pain, contributing to the autonomic component of the overall pain response
Intensity Theory of Pain
Transmission neurones have a wide dynamic range so can increase spike discharge frequency over a wide range of intensities
Dynamic Range
- Wide
Transmission neurones have a wide dynamic range so can increase spike discharge over a wide range of intensities
Dynamic Range
- Narrow
Can only signal changes in intensity over a narrow range of amplitudes
Several different types of narrow dynamic range neurones are required, each responding to a different stimulus intensity.
Projections
- Lamina I
- Lamina V
Neurones travel prefernetially to the insula and ACC
Neurones travel preferentially to the primary somatosensory cortex (S-I)
Pain Modulation
- 3 Descending Systems
- PAG of midbrain
- Raphe nuclei
- Other nuclei of the rostral medulla
Pain Modulation
- Function
Allows integration of pain perception with many other body systems, including:
- Skin reflexes
- Autonomic regulation
- Emotion
- Attention
Pain Modulation
- PAG Inputs
Inputs from:
- Ascending anterolateral systems (nociceptors)
- Higher cortical centres (cortex, thalamus, hypothalamus)
Electrical stimulation of the PAG produces sufficient analgesia to perform abdominal surgery, while non-painful sensations are left intact
Pain Modulation
- PAG Stimulation
Electrical stimulation of the PAG produces sufficient analgesia to perform abdominal surgery, while non-painful sensations are left intact
Pain Modulation
- Naloxone
Injection of naloxone, which is an opiate antagonist, into the PAG blocks
- Morphine-induced analgesia
- Electrically-induced analgesia
Suggests that the electrical system evokes the internal analgesic system giving an opioid response.
Pain Modulation
- Dorsolateral Funiculus Transection
Blocks:
- Electrically evoked analgesia
- Morphine induced analgesia
Pain Modulation
- Raphe Nucleus
Raphe nuclei neurones project to the substantia genaltinosa in the dorsal horn.
Produce 5-HT which activates opioid containing interneurones, triggering the release of opioids which depress transmission from nociceptors.
- At least part of depression is via presynaptic inhibition
- Opioids influence Aβ nociceptive transmission so are involved in gate control
Pain Modulation
- PAG Termination
Raphe nuclei in the medulla
Pain Modulation
- Specific Raphe Nucleus
Raphe magnus (NRM)
Placebo Effect
- Definition
Administration of a substance known to be non-analgesic produces an analgesic response when the subject is told it is analgesic.
Placebo Effect
- Examples
- Asthma
- Cough
- Diabetes
- Ulcers
- Multiple sclerosis
- Parkinsonism
Placebo Effect
- Experiment
IV injection of capsaicin into all 4 limbs
Placebo cream applied to one limb only gave placebo analgesia only in that limb, not in the whole body as expected.
Spatially specific placebo response was abolished with IV infusion of naloxone (opioid antagonist), suggesting that it is mediated by an endogenous opioid system.
Placebo Effect
- Somatotopicity
Somatotopicity is found in the PAG, which is maintained through the endogenous opioid system, allowing the endogenous opioid systems to give analgesia.
In rats, stimulation of different areas of the PAG gives analgesia in different cutaneous regions
Referred Pain
Pain from internal organs is often felt as pain from a more superficial region due to viscero-somatic convergence onto the same neurone in the dorsal horn of the spinal cord
Neuropathic Pain
- Defintiion
peripheral nerve damage that results in pain that outlasts the initial injury, often indefinitely, with on-going hyperalgesia and allodynia.
Caused by changes in nociceptive processing at spinal and higher centres, which are likely involved in disease progression
Neuropathic Pain
- Examples
- Phantom limb pain
- Infectious disease (HIV, leprosy, heptatitis)
- Diabetic neuropathy
- Trigeminal neuralgia
- Postherpetic neuralgia
Congenital Pain Insensitivity
- Causes
Mutation in either:
- Nerve growth factor NGF gene
- Nerve growth factor receptor (TrkA)
Cause nociceptive fibres to fail to innervate their target during development and subsequently die.
Congenital Pain Insensitivity
- Causes of Death
- Traumatic injury
- Respiratory infection as nociceptors in the lungs are required to trigger coughing
NSAIDs
- Mechanism of Action
Inhibit COX enzymes, preventing prostaglandin production which decreases nociceptor sensitisation and therefore pain.
NSAIDs enter the hydrophobic channel in COX and form hydrogen bonds with Arg120, preventing the entrance of fatty acids, such as arachidonic acid, into the catalytic domain
Reversible inhibition
NSAIDs
- COX-2 Activation
Up-regulated in inflammation and activated by cytokines such as TNF-α
NSAIDs
- COX-2 and COX-1 Inhibition
COX-1 inhibition:
- Results in unwanted side effects
COX-2 inhibition:
- Anti-inflammatory
- Analgesic
NSAIDs
- Selective COX-2 Inhibition
Bulky side group of COX-2 allows NSAIDs with large sulfur containing side groups to selectively inhibit it
NSAIDs
- Aspirin
Weakly COX-1 selective.
Aspirin is an a-typical NSAID as it irreversibly acetylates COX. COX can be resynthesised in cells but thromboxane production by platelets is halted for their lifetime (10 days).
Longer duration of action due to irreversibly inhibition
NSAIDs
- Analgesic Action
- In the CNS headache may result from vasodilation, so NSAIDS inhibit prostaglandin-mediated vasodilation
- In the periphery, preventing nociceptor sensitisation and subsequent inflammation
NSAIDs
- 4 Drugs
- Aspirin
- Ibuprofen/Phenylbutazone
- Paracetamol
- Etoricoxib/Robenacoxib
NSAIDs
- Ibuprofen/Phenylbutazone
Ibuprofen = humans Phenylbutazone = animals
Weakly COX-1 selective
Used to treat:
- Rheumatoid arthritis
- Gout
- Soft tissue disorders
NSAIDs
- Paracetamol
- Analgesic
- Antipyretic
- Poor anti-inflammatory drug
NSAIDs
- Etoricoxib/Robenacoxib
Etoricoxib = humans Robenaxocib = animals
COX-2 selective
Used to treat chronic inflammatory pain conditions such as:
- Osteoarthritis
- Rheumatoid arthritis
Only advised in patients for whom conventional NSAIDs pose a significant GI risk after cardiovascular risk assessment
NSAID
- Side Effects
Due to COX-1 inhibition
- GI bleeding and ulceration
- PGs inhibit gastric acid secretion and increase mucin production
- Patients are given a drug to counteract gastric acid secretion - Renal insufficiency
- PGE2 and PGI2 are involved in maintaining renal blood flow - Stroke/myocardial infarction
- COX-2 is constitutively expressed in endothelial and vascular smooth muscle so a decrease in PGI2 production causes platelet aggregation - Bronchospasm
- COX inhibition is implicated in bronchospasm bu an unclear mechanism
Opioids
- Opioid Definition
Substance producing morphine-like effects that are reversed by antagonists such as naloxone
Opioids
- Opiate Definition
Substance found in the opium poppy
Opioids
- Mechanism of Action
Free OH and nitrogen atom on the benzene ring are important for opioid activity
Opioids
- Receptor Types
4 Types
- µ
- Kappa
- Delta
- ORL1
Opioids
- Receptor Cascade
All Gi/o coupled
- α subunit
- Inhibits adenylyl cyclase - βy subunit
- Activates inwardly rectifying K+ channels (GIRKs) to hyperpolarise the cell
- Inhibit opening of Cavs, mainly N-type, which decreases Ca2+ entry and neurotransmitter release
Opioids
- Peripheral Analgesia
Adenylyl cyclase inhibition counteracts sensitising effects of prostaglandins
Opioids
- Spinal Level Analgesia
Opioids act:
- Presynaptically to decrease neurotransmitter release
- Postsynaptically to reduce dorsal horn neurone excitability
Opioids
- Supraspinal Level Analgesia
Activation of the endogenous inhibitory systems, which is largely mediated by µ receptors
Also induce euphoria
Opioids
- Uses
- Acute pain
- Chronic pain
Not used for neuropathic pain as doses required give excessive side effects
Opioids
- Examples
- Morphine
- Diamorphine
- Codeine
- Buprenorphine
- Etorphine
Opioids
- Morphine
Widely used for aute and chronic pain
Opioids
- Diamorphine
Heroin
Pro-drug that is metabolised to morphine
Acts more rapidly than morphine when injected IV because of its higher solubility and ability to cross the blood brain barrier
Opioids
- Codeine
Pro-drug
Given in combination with NSAIDs for mild pain
More reliably absorbed when administered orally
Less analgesic effect and fewer side effects than morphine
Opioids
- Buprenorphine
Partial opioid receptor agonist with high affinity and low efficacy allows it to antagonise other opioids.
Moderate analgesia with less respiratory depression than full agonists
Uses:
- Post-surgery pain
- Patch treating chronic pain in humans
Opioids
- Etorphine
1,000x more potent than morphine, so is given with a vial of naloxone to counteract effects from a pinprick injury, which causes respiratory depression.
large animal use
Combination Analgesics
- Principle
Opioids and NSAIDs are commonly combined because they induce analgesia via different mechanisms giving additive analgesia.
Less of each can be given, which reduces side effects
Combination Analgesics
- Co-Codamol
Combination of paracetamol and codeine
Naloxone
Opioid receptor antagonist that reverses respiratory depression following:
- Overdose
- Newborns following use of opioids during labour
Opioids
- Side Effects
- Respiratory depression
- Nausea and vomiting
- Constipation
Opioids
- Respiratory Depression
µ receptors
- Inhibition of respiratory rhythm
- Inhibition of central chemoreceptors
Opioids
- Nausea and Vomiting
Delta receptors
µ receptors
Opioids
- Constipation
µ receptors
Kappa receptors
Delta receptors
Opioids
- Chronic Use
- Tolerance
- Physical dependence
Future Analgesics
- 4 Examples
- Antidepressants
- Gabapentin/Pregabalin
- Voltage gated Na+ inhibitors
- Ziconotide
Future Analgesics
- Antidepressants
Serotonin selective reuptake inhibitors are largely inefficacious to block pain
- Fluoxetine
Serotonin-noradrenlaine reuptake inhibitors (SNRIs) and tricyclic antidepressants, provide pain relief for neuropathic pain
- Duloxetine (SNRI)
- Amitriptyline (TCA)
Shows importance of the descending inhibitory modulation of pain system from locus coeruleus involving noradrenaline
Future Analgesics
- Gabapentin/Pregabalin
GABA analogue to treat epilepsy but has no efficacy at GABA receptors but is efficacious against neuropathic pain but not acute pain
Decreases cell surface expression of voltage gated Ca2+ α2delta1 subunit, which usually increases voltage gated Ca2+ current density and is up-regulated in some forms of neuropathic pain.
Decreasing voltage gated current density decreases spinal cord neurotransmitter release .
Pregabalin is a gabapentin successor has favourable pharmacokinetics.
Future Analgesics
- Voltage Gated Na+ Channel Inhibitors
Lidocaine is a local anaesthetic that blocks vg Na+ channels and provides analgesia when applied topically as a patch.
Prevents spontaneous neurone discharge associated with neuropathic pain
Used in trigeminal neuralgia patients to provide pain relief when eating
Carbamezepine blocks vg Na+ channels and is used as an ani-epileptic and to treat neuropathic pain such as trigmeinal neuralgia
Future Analgesics
- Ziconotide
Synthetic analogue of N-type vg Ca2+ blocker W-conotoxin (MVIIA)
Administered intrathecally.
Expensive, invasive and potentially dangerous route of administration, so is only recommended in cases where other treatments have failed.
Analgesics
- Pain Ladder
WHO published
Developed for cancer pain
- Non-opioid treatment such as NSADIS with or without an adjuvant
- Weak opioid treatment such as codeine, with or without a non-opioid adjuvant
- Strong opioid, such as morphine, with or without a non-opioid and with or without an adjuvant
Adjuvants are additional painkillers such as gabapentin
Future Analgesics
- Further Targets
- Subtype specific vg Na+ blockers as vg NA+ 1.7-9 have key roles in nociception and pain
- Anti-NGF antibodies such as tanezumab which is currently in phase 3 clinical trials
Future Analgesics
- Unsuccessful Cases
- NK1 receptor antagonists are efficacious in animal models but non-efficacious in humans
- TRPV1 antagonists may be useful but cause hyperthermia
