3.1.1 Describe in detail the ICD-11 taxonomy of chronic pain
Chronic pain is PERSISTENT or RECURRENT pain for at least 3 months
Chronic pain classification codes are now placed together (rather than in anatomical or phenotypic groups
Chronic primary pain - A classification where pain itself is the disease. Classified into further groups
Chronic secondary pain - As it sounds
ICD-11
ICD 10 pain was not represented systematically
Negatively impacted billing and therefore insurers and policymakers to identify the human and financial impact of chronic pain
Systematic classification of clinical conditions with chronic pain
Divides into subgroups defined by etiology or affected organ system
Allows subgroup where pain is not completely understood
Gathers pain codes into one place
Chronic primary pain should be acknowledged in its own right
May minimise unnecessary further investigations/treatments in primary pain conditions
ICD-11 Described by FPM
1. Chronic pain is admitted as a taxonomic entity
2. Pain is a problem in its own right – in addition to underlying process or disease contributing
3.1.2 - Critically discuss the main descriptors of pain (nociceptive, neuropathic and nociplastic) in the International Association for the Study of Pain (IASP) taxonomy.
Nociceptor: A high threshold sensory receptor of the peripheral somatosensory nervous system capable of tranducing and encoding noxious stimuli
Noxious Stimuli: A stimulus that is damaging, or threatening to damage, normal tissues
Neuropathic pain: Pain caused by a lesion or disease of the somatosensory nervous system (NB: This is a DESCRIPTION not a DIAGNOSIS)
Central neuropathic pain: Pain caused by a lesion or disease of the centra somatosensory nervous system. (Peripheral neuropathic pain is peripheral...)
Nociplastic pain: Pain that arises from altered nociception despite no clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptors or evidence for disease or lesion of the somatosensory system causing the pain
3.1.3 Understand the historical evolution of those IASP descriptors of pain.
Links on website currently are unavailable.
3.1.4 Describe the anatomy of the peripheral and central nociceptive pathways in the somatosensory system
Neurobiology
Primary afferent nerves innervate into
Rexedes lamina 1 (Marginal zone – C-fibres and a few Adelta),
Rexedes lamina 2 (Substantia gelatinosa – C-fibres and Adelta - & lots of interneurons)
Rexedes lamina 5 (Nucleus propius) (3,4,5, 6 has lost of Abeta fibres)
Neurons in lamina 5 also receive non-noxious input. It is also where visceral inputs arrive. This the site for convergence theory for referred pain
Transmission:
Some afferent fibres travel in lasseurs tract called the intersegmental system before connecting with their second order neuron
Anterior spinothalamic tract - carries crude touch
Lateral spinothalamic tract - carries pain and temperature
CNS Reception
These tracts go to the thalamus and synapse with third order neurons
Projections go to:
Primary and secondary somatosensory cortices
Primary somatosensory cortex – postcentral gyrus (parietal lobe)
Limbic system (emotions)
Anterior cingulate gyrus (ethics and decisions)
Insular cortex (Homeostatic emotions like hunger and pain)
Remember – Dorsal columns travel up the SAME side until decussation in the medulla and these carry tactile sensation and limb proprioception – which can be sensitised
Other pathways:
Spinoreticular and spinomesencephalic – medulla and midbrain for nociceptive information affecting arousal, homeostatic and autonomic responses – Affect/mood
Anterior cingulate cortex, insular, prefrontal cortex à PAG and Rostroventromedial medulla
Modulation of the system
Segmental inhibition – Gate theory
Endogenous opioid system
Descending inhibitory system
Descending inhibitory system involves:
Periacqueductal grey (around the acqueduct)
Locus Coeruleus (literally ‘blue spot’ – synthesis of noradrenaline!)
Nucleus raphe magnus (Releases serotonin. Main nucleus for descending inhibition. Gets message from PAG)
3.1.5 Describe mechanisms of transduction, transmission and modulation in nociceptive pathways.
NB: The 'somatosensory' system is part of the sensory nervous system. It is a complex system of sensory neutrons and neural pathways that responds to changes at the surface, or inside the body.
- Nociceptor activation occurs in the periphery
- Adelta fibres (thinly myelinated) and C fibres (unmyelinated)
- Cell body is in the dorsal root ganglion (DRG)
- Noxious stimuli activates receptors from these nociceptors
- The stimuli causes these receptors to open leading to influx of Ca+ and Na+
- This lowers activation threshold and axon fires
(Other things around the damage cause this to lower also - e.g. tissue damage and inflammatory soup)
(Image - for example - one type of trigger opens this one type of channel causing depolarisation)
- Abeta fibres are fastest (A comes first!) - but Adelta are tastest noxious stimuli messengers with acute/sharp pain. C fibres mediate 'second' wave of delayed, diffuse, dull pain.
- Conduction of the action potential occurs via voltage-gated Na+ and Ca+ channels
(For example, thought there are more of these Ca channels in chronic pain - target of gabapentin/pregabalin)
- These Aδ and C fibres initially travel up or down for 1-2 vertebral levels in Lissauer's tract before synapsing with second order neurons in the DRG.
- When these action potentials arrive, depolarisation leads to activation of N-type calcium channels and this causes release of excitatory neurotransmitters such as substance P and glutamate
- Glutamate and Substance P trigger excitatory postsynaptic currents in the second-order neutrons in the dorsal horn
- This causes firing of the second order neuron
(Glutamate and substance P also affect glial cells. Glia are thought to play a role in pain enhancement)
- In the dorsal horn, primary nociceptor afferent nerve fibres synapse into specific laminae
- Mainly primary afferent nerve fibres innervate into Rexed's laminae 2 (substanstia gelatinous) and 5 (nucleus proprius).
- Spinal cord neurons in lamina 1 and 2 are generally responsive to noxious stimuli, whereas neutrons in lamina 3-4 are responsive to non-noxious stimuli (ABeta).
- Neurons in lamina 5 receive non-noxious AND noxious inputs via Aδ/Aβ inputs
- These ones in 5 are referred to as 'Wide dynamic range (WDR)' neurons because they respond to a wide amount of intensities
- 5 is where visceral inputs also come in. This convergence of somatic and visceral may explain referred pain.
- Second order neutrons then cross the spinal cord and ascend in the spinothalamic tract to the thalamus.
- In the thalamus, there is a third-order neuron where a synapse occurs
(Explains why thalamic strokes can lead to pain without involvement of messages from the spinothalamic pathway).
Remember:
- In the face things are a little different. Noxious stimuli are transmitted through nerve cells in the trigeminal ganglion and cranial nuclei 7, 9, and 10.
- These then travel to the medulla, cross the midline, and ascend to the thalamic nerve cells on the contralateral side.
Perception:
- In the thalamic nuclei, third order neurons conduct impulses to the somatosensory cortices.
- The thalamus also receives normal sensory stimuli - so can assimilate the information to give an idea of location and intensity.
- The thalamus also sends messages to the limbic (a group of subcortical structures (such as the hypothalamus, the hippocampus, and the amygdala) of the brain that are concerned especially with emotion and motivation) structures - the anterior cingulate cortex and insula - where emotional and cognitive components are processed
Modulation:
Three main types to remember: segmental inhibition, endogenous opioid system, descending inhibitory nerve system
Segmental inhibition
Melzack and Wall's 'gate theory of pain control' - Activating Abeta fibres stimulates and inhibitory nerve that inhibits synaptic transmission
Endogenous Opioid system
Endogenous opioid receptors are in lamina 2, periacqueductal grey matter, and ventral medulla.
Descending inhibitory system
Periacqueductal grey matter in upper brain stem, locus coeruleus, nucleus raphe Magnus, and nucleus retigularis gigantocellularis in rostroventral medulla, contribute to descending pathway suppression
3.1.6 - Peripheral and central sensitisation
Peripheral
Increased inflammatory/chemical mediators
Change in sodium and calcium channel expression with reduced threshold for action potential
Ephaptic connection and recruitment
Glial cell activation
Central Sensitisation
Spinal glial cells activated
Wind up and activation of wide dynamic range neurons
Increase in ascending facilitation
Decrease in descending inhibition
Cortical reorganisation
Adrenoceptor changes
Features that suggest neuropathic pain
Pain with no ongoing tissue damage
Pain in sensory loss
Paroxysmal or spontaneous pain
Allodynia
Hyperalgesia
Dysaesthesias ('ants crawling on the skin’)
Characteristic of pain: burning, pulsing, stabbing pain
Delay in onset of pain after nerve injury (NB some neuropathic pain has immediate onset)
Hyperpathia: increasing pain with repetitive stimulation; ‘after response’ (continued exacerbation of pain after stimulation); radiation of pain to adjacent areas after stimulation
Tapping of neuromas / positive Tinel’s sign
Poor response to opioids
Associated major neurological deficit (e.g. brachial plexus avulsion)
3.1.7 Discuss current concepts of referred pain and radiation of pain
Definition
'Pain that is received in a region that has a different nerve supply to the original source of pain'
Mechanism of REFERRED pain
Multiple primary sensory afferents converge on a single second-order neuron
Somatosensory cortex cannot differentiate between the multiple sites of input. These may be somatic and visceral
Referred pain is perceived on the SAME SIDE of the midline
Felt axially as a deep visceral pain or peripherally commonly in a dermatomal distribution
May be contiguous or separate from the nociceptive stimulus site
Mechanism of radiating pain
This is related to a specific spinal segment
Somato-somatic
Viscero-somatic
Viscero-visceral
Somato-visceral
3.1.8A Glia's role in the generation of chronic pain and pain signalling
Glia within the nervous system work to up or down regulate pain signalling
Macroglia encapsulate and surround synapses modulating synaptic communication
Macroglia include astrocytes, oligodendrocytes, ependymal cells, radial cells, and schwann cells (that make myelin)
Astrocytes are the most common glia (50%)
Macroglia, such as astrocytes, may themselves hypertrophy and up regulate signalling control systems leading to sensitisation
Microglia are immune surveillance and debris clearing cells originating from microcytes or macrophages
Activation of glia can occur through:
Primary afferent neurons releasing activating factors such as substance P and glutamate
Neuromodulators such as prostaglandins and NO can also directly activate glia cells
Damaged neurons release ATP/heat-shock proteins that can activate glia
Glia enhances pain signalling by:
Creating new connections between glial cells and activating further local glial cells
Release pro-inflammatory cytokines such as TNFa, IL1, IL6. These can increase release of Substance P, CGRP, and glutamate.
Release D-serine activating NMDA receptors
Increasing noradrenaline fibre bundles
Increase permeability of the BBB
Receptors on Glia:
Toll-like receptor 4,
Cannabinoid receptor type 2
NMDA,
Opioid receptors - Mu, Kappa, Delta
OR-1
Glia has an effect on opioids:
Repeated opioid doses may also activate glia leading to pro inflammatory cascade
Increasing opioid receptors on glia, from exposure to opioids, may lead to more NO and PKC release
Toll-like receptor 4 is stimulated by M3G and methadone and local debris from damaged neurons
Inhibition of TLR4 leads to:
In animals shows reduced neuropathic pain
Likely naloxone works on these receptors also – not sure why
Lead to increased opioid analgesic effects
Reduces opioid tolerance
Reduces OIH
Reduces reward/dependence behaviour
Less withdrawal effects
Less resp depression
Opioid induced tolerance, dependence, reward mechanisms
Receptor decoupling and down regulation
Modulation of NMDA receptors
Reduced glutamate transporters
NO release
Anti-analgesia system such as CCK and dynorphin
Glia activation – with up regulartion of receptors on Glia
- Glial modulation
Corticosteroids are thought to play a local role
Minocycline has been shown to reduce microglial activity by reducing NO synthesis
- Microglia play a role in initiating, sustaining, and moderating neuropathic pain
- Microglia include: Fibroblasts, astrocytes, oligodendrocites, mast cells
- Microglial cells are usually quiescent within the body. They are activated by infection immune processes and/or inflammation
- Microgliosis is where the microglia migrate and proliferate in a required area
- Nerve injury à Release of mediators nuregulin-1, MMP and CCL2 à Toll-like receptor activation à Activates microglia à Increased activation through TNFalpha and decreased inhibition of interneurons and activating more microglial cells à Increased pain
- Microglia also releasre inflammatory cytokines IL6, TNFalpha,
- Minocycline inhibits microgliosis
The overall effect of the above changes is:
· effects on receptors and channels result in
è increased opioid tolerance, opioid induced hyperalgesia and withdrawal from effect on Toll like receptors.
è Changes in neural plasticity resulting in central sensitisation.
· regulation of cytokines, chemokines, growth factors and proteases (all recognised as glial mediators) in glia which are pro-inflammatory e.g. TNF, IL6
è increased pain sensitivity
è TNF activated astrocytes in the spinal cord result in persistent mechanical allodynia
è Proteases (matrix metalloprotesase 2) released after spinal injury maintain neuropathic pain
· Modulation of excitatory and inhibitory synaptic transmission
è This happens at the spinal cord level via glial mediators (chemokines, cytokines, growth factors)
è With excitatory synaptic transmission pro-inflammatory cytokines and chemokines work on excitatory post synaptic currents (EPSC) which result in increased spontaneous frequency and amplitude of EPSC. It also results in central sensitisation via extrasynpatic pathways through TNF
è Inhibitory pathways: there is loss of inhibitory synaptic transmission resulting in central sensitisation.
Not all doom and gloom.
Glial cells also produce anti-inflammatory and anti-nociceptive mediates (IL4, IL10) which help with recovery and resolution of pain.
Minocycline is a microglial inhibitor. It has been found to potentiate acute morphine analgesia and prevents onset of enhanced pain.
NMDA antagonists inhibit microglial activation.
Inflammatory Soup
Bradykinin
Acidic environment
Histamine
Serotonin
Eicosanoids
Cytokines
Nitric Oxide
Excitatory Amino Acids
Overall these can increase sensitivity at the site of inflammation resulting in peripheral sensitisation which manifests as hyperalgesia.
Prolonged inflammation can result in transition from acute to chronic pain.
Management:
1. Pharmacotherapy to manage pain.
use of drugs to block inflammation e.g. NSAIDS, Steroids
2. Glial cells and how using opioid can result in OIH, Dependence and withdrawal.
3. The microglial inhibitor minocycline but this has no clinical efficacy.
4. NMDA antagonists also inhibit microglial activation
Peripheral Antihyperalgeisc Mechanism.
· There are mediators that limit pain transmission and they can also be part of the inflammatory soup
1. Opioids
2. Acetylcholine
3. Gamma-aminobutyric acid
4. Somatostatin.
3.1.8B Define the following terms and their neurobiological bases:
Sensory threshold
Pain threshold
Pain tolerance
Allodynia
Hyperalgesia
Hyperpathia
3.1.9 & 10 - Demonstrate ability to infer nociceptive, neuropathic and nociplastic descriptors of pain on the basis of clinical examination
This fabulous table has been borrowed from: Cohen, S. P., Vase, L., & Hooten, W. M. (2021). Chronic pain: an update on burden, best practices, and new advances. The Lancet, 397(10289), 2082-2097.
3.1.11 Screening tools Over the past decade, 5 screening tools have been developed and validated for the identification of neuropathic pain.
Tools rely on verbal reports of pain qualities (i.e. pain descriptors).
Leeds assessment of neuropathic symptoms and signs (LANSS)
Neuropathic pain questionnaire (NPQ)
ID Pain
The ability of these questionnaires to detect neuropathic pain is very good to excellent, with sensitivity ranging from 67% to 85% and specificity from 74% to 90%.
Limitations of Screening tools Screening tools for neuropathic pain validated only in patients with pain in a single location. Difficulty assessing patients with pain in multiple sites and should not be used in patients with widespread pain. The screening tools fail to pick up 10-20% They provide no information as to the cause of the neuropathic pain Not suitable for assessment of treatment response.
3.1.12 Explore why most neurological injury results in loss of function rather than pain.
3.1.13 Describe the pain syndromes that may be associated with:
Spinal cord injury
Traumatic peripheral nerve injury including that incurred during surgery
Brachial plexus injury
Compression neuropathy
Post-amputation injury
Traumatic brain injury
3.1.14 Discuss the pain syndromes that may occur in the following neurological diseases (See the links below to other pages)
Stroke
Trigeminal neuralgia
Parkinson's disese
Multiple sclerosis
Syringomyelia
Peripheral neuropathies
Acute herpes zoster infection and post herpetic neuralgia
Guillian Barre Syndrome
Neurofibromatosis
Erythromelalgia
3.1.15 Critically discuss the limitations of a mechanism-based approach to the pharmacological treatment of pain.
A mechanism-based approach to pain immediately narrows your therapeutic options when choosing pharmacological options for your patient. While having an understanding of the likely mechanism of pain generators (e.g. inflammation around injured tissue cause local primary afferent activation), this often does not completely explain a patients pain due to our fractured understanding of the pathophysiology involved.
For example, while using NSAIDs to treat inflammation in an area of damage, once the visual damage and 'lesion' is gone, if the patient is still experiencing residual pain, a mechanism-based approach would suggest 'no further therapy is required'. However, this ignores other possible processes such as nociplastic centralised changes, that while a clear mechanism has not been defined, there is clear evidence of adjunct pharmacological therapies that can provide patients relief.
A counter perspective to consider is also that not all pharmacological mechanisms are understood either. For example, paracetamol's true mechanisms of action are not clearly defined - however as one of the worlds most used analgesics this has clearly not stopped its use being considered to alleviate the suffering of patients across the world.
Does not take into account other genetic and phenotypic/epigenetic presentations also.