Pain revision.docx

**Pain revision** [Ascending nociceptive pathway] - A-beta fibre -- discriminative touch - A-alpha fibre -- proprioception - A- delta fibre -- temperature and fast pain - C fibre -- slow pain Not nociceptive - send non-painful stimuli - A-alpha (Group I) muscle spindle and Golgi ten...

**Pain revision** [Ascending nociceptive pathway] - A-beta fibre -- discriminative touch - A-alpha fibre -- proprioception - A- delta fibre -- temperature and fast pain - C fibre -- slow pain Not nociceptive - send non-painful stimuli - A-alpha (Group I) muscle spindle and Golgi tendon organ - A-beta (Group II) Touch, pressure  - Both have thick myelin - Quicker messaging to maintain muscle tone Nociceptive - A delta (Group III) temperature, painful pressure, crude touch, painful thermal  - C (Group IV) pain, painful thermal Nociceptive (Ad & C) Afferents - Each afferent type can also be identified by the receptors that they EXPRESS (are produced by them and can be found inside them): - Aδ-fibres:  - Express TRPM8, TRPV1 = thermo-receptors  - Express Nav1.8, TRPA1 = nociceptors - C-fibres express:  - TRPA1, TRPV1, Nav1.7, 1.8  - Substance P, NGF, NO - I.e. when you hit your elbow, activating Aδ-fibres: you tend to straightaway rub the area gently which will activate the touch fibres (A beta) which transmit the signal faster. - Getting to the brain quicker, they cut off the Aδ-fibre signal on the way (general principal) - Then after a little bit you start feeling the throbbing pain which is the slower fibres getting their message across eventually (19min prework video) - When the system gets confused/efficient (e.g. with chronic pain) the AB afferents start to express these receptors so the system starts to signal pain even from touch receptors. NOT GOOD e.g. allodynia  1. ***Reception/transduction*** - Nerve endings are stimulated by chemical, mechanical or thermal insult - Noxious insults activate several classes of nociceptors; activation occurs via ion-channel depolarization - Change in the balance of Na and K in the cell - If sufficient will activate a cellular response = signal - Relay protein and secondary messages activating the nerve to begin transmission of the signal along the nerve - Is a sufficient stimulus arrives at the nerve ending membrane, an action potential may be transmitted  2. ***Transmission*** - Action potential - Signals transmitted along afferent sensory peripheral nerves to the dorsal horn of the spinal cord - Theses impulses are either amplified or suppressed in a process called ***modulation*** - In the dorsal horn - Laminae 1-2 = C-fibres slow achy pain - Laminae 3-4 = AB-fibres non-painful touch - Lamina 5 = Ad-fibres fast, immediate, sharp pain 3. ***Projection*** - Signals projected through numerous pathways to the brain centres for processing into pain - The peripheral neuron synapse with either - Interneuron - Chance the message will stop due to inhibitory interneuron - Long projection neuron (2^nd^ order neuron) - Message gets to the brain 4. ***Perception*** - Pain is perceiving initially at the level of the thalamus and subsequently localises in the sensory cortex **[Peripheral sensitisation]** - At the beginning of the peripheral nerve - When damage occurs in the periphery -- inflammatory cells (T-cells, neutrophils, macrophages, mast cells...) either engulf and clean up or they spill proinflammatory molecules - Some proinflammatory molecules are: - [Activators]: Their job is to generate action potentials  - ***Hydrogen ions *** - Potassium ions  - Adenosine Triphosphate  - ***Bradykinin *** - ***Serotonin*** - [Sensitisers]*:* Their job is to reduce membrane potential, which increases the number of action potentials generated - ***Prostaglandins*** (PGE2) - Leukotrienes  - Serotonin  - ***Histamine *** - Nitric oxide  - Interleukins  - TNFα  - ***Substance P *** - Calcitonin gene related peptide (CGRP) - [Activators] directly bind to receptors on the nociceptors and open Ca and Na channels and allow the positive ions into the neuron to reach threshold and activate action potential - [Sensitisers]: sensitise neuron to make it easier to reach threshold - When the nociceptor is stimulated to send an action potential, it releases [neurogenic inflammatory chemicals]. - [Neurogenic inflammatory chemicals:] - Substance P - CGPR - Cytokines - Chemokines - Stimulate the inflammatory process to cause cyclic effect of activation of nociceptors until the cause is taken away - If it continues after the cause is taken away it's called PERIPHERL SENSITISATION **[Central sensitisation]** - Changes related to synapses in the CNS (mainly dorsal horn of the spinal cord) - [Definition]: Increased responsiveness of nociceptive transmission neurons in the central nervous system to their normal or sub-threshold afferent input - Key mechanisms: modifications to synapse function and structure in the dorsal horn of the spinal cord - Leads to  - amplification of nociceptive signals  - non-nociceptive signals accessing nociceptive pathways Modulation Pain gate theory - touch (A-beta) fibre with also activate an inhibitory interneuron which will inhibit the pain (C-fibre), blocking/reducing it from being transmitted to the brain and being 'felt" - with sensitisation there is poorer inhibition and therefore increased pain being 'felt' 1. *Define* a. *Pain (IASP definition)* an unpleasant sensory or emotional experience associated with, or resembling that associated with, actual or potential tissue damage - Pain is always a personal experience that is influenced to varying degrees by biological, psychological and social factors - Pain and nociception are different phenomena. Pain cannot be inferred solely from activity in sensory neurons - Throughout their life experiences, individuals learn the concept of pain - A persons report on an experience of pain should be respected - Although pain usually serves an adaptive role, it may have adverse effects on function and social and psychological wellbeing - Verbal description id only one of several behaviours to express pain; inability to communicate does not negate the possibility that a human or a nonhuman animal experiences pain b. *Nociception* The neural process of encoding noxious stimuli c. *Nociceptive pain* Pain that arises from actual or threatened damage to non-neural tissue and is sue to the activation of nociceptors Pain occurring with a normally functioning somatosensory nervous system d. *Neuropathic pain* Pain caused by a lesion or disease of the somatosensory nervous system \*Clinical description not a diagnosis e. *Nociplastic pain* pain that arises form altered nociception despite no clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptive or the evidence for disease or lesion of the somatosensory system causing the pain 2. *Briefly describe /explain* f. *Difference between nociception and pain.* Nociception is the physiological process of decoding noxious stimuli sensed and pain is the response after processing in the CNS g. *Peripheral sensitisation* - Changes related to nerve fibres in the periphery where the nerve starts. - When inflammation is triggered, immune cells release proinflammatory cytokines that upregulate inflammation and increase the action potentials being sent by nociceptors. The proinflammatory molecules activate and/or sensitise. - [Activators]: include hydrogen ions, bradykinin and serotonin generate action potentials by binding to receptors on nociceptors, opening ion channels to let in calcium and sodium. This changes the membrane potential and an action potential is sent. - [Sensitisers]: such as prostaglandins, histamine and substance P, make it easier for the membrane potential to be reached generating an action potential by raising the resting potential in the nerves. - The activated nociceptors release [neurogenic inflammatory chemicals] including substance P, CGRP, cytokines and chemokines that stimulate the inflammatory process and cause the cycle to continue. - If it continues after the cause is taken away it's called PERIPHERL SENSITISATION h. *Central sensitisation* - Changes related to the synapses in the CNS, mainly in the dorsal horn of the spinal cord where the peripheral nerve synapses with an interneuron or a projection neuron. - Increased responsiveness of nociceptive transmission neurons in the CNS to their normal or sub threshold afferent input - Modification to synapse structure and function in the dorsal horn leading to - Amplification of nociceptive signals - This is achieved by - Increased expression of the neurotransmitters i.e. glutamate, substance P, CGRP - Glial cells amplify the signal by also releasing them - Increased expression of ion channels/receptors e.g. NMDA receptors - As the process continues, gene transcription means changes becoming more long lasting and embedded - Loss of inhibition: inhibitory interneurons and inhibitory neurotransmitters e.g. GABA - Non-nociceptive signals accessing nociceptive pathways - This is achieved by - Wide dynamic range neurons in the dorsal horn receiving both nociceptive and non-nociceptive input - With the loss of inhibition form loads of input from A-delta and C-fibres, the WDRN become more active and sensitive and begin to project non-nociceptive information - Because they are sensitised, A-alpha and A-beta signals can be projected though them i. *Descending modulation of nociception* This is the top-down control of pain where the Periaqueductal grey (PAG) and the Rostral ventral medulla (RVM) release neurotransmitters that inhibit or facilitate nociceptive signals, reducing or increasing pain respectively. When people are anxious, stressed or expecting pain, brain areas such as the amygdala are highly active, they signal the PAG and RVM to release pro-nociceptive chemicals, enhancing the pain experience. Modulation from the brain released by the PAG and RVM include neurotransmitters such as opioids, serotonin, noradrenaline, GABA, and endocannabinoids and can act on the pain gate in the spine as well. j. *Descending inhibition of nociception* When someone is more clam or in a life altering situation when pain us unhelpful, anti-nociceptive neurotransmitters are released instead and pain is scaled down. k. *Altered nociceptive processing* l. *Gate control theory of pain (Pain gate theory)* m. *Ectopic pacemakers in neuropathic pain* 3. *Outline nociceptive apparatus include afferent fibre types, types of neurons, spinal tracts, the areas of the CNS and brain.* [Transduction]: nerve endings are stimulated by mechanical, chemical or thermal insults in the periphery Afferent nerve fibres include: A-alpha fibres are stimulated by proprioception (i.e. muscle spindles and Golgi tendon organs) These have very thick myelin and therefore very quick messaging A-beta fibres are stimulated by discriminative touch/pressure (non-noxious mechanical) These have slightly thinner myeline therefore slightly slower messaging but still very fast A-delta fibres are stimulated by temperature and crude touch (noxious mechanical and thermal stimuli)\ these are thinner myelin again and therefore slower C-fibres are stimulated by nociceptive input, thermal and chemical stimuli [Transmission]: when threshold potential is reached by positive ions entering the neuron, the action potential is - Theses impulses are either amplified or suppressed in a process called ***modulation*** - In the dorsal horn - Laminae 1-2 = C-fibres slow achy pain - Laminae 3-4 = AB-fibres non-painful touch - Lamina 5 = Ad-fibres fast, immediate, sharp pain [Projection]: the peripheral neuron synapses with a projection neuron that travels up to the brain. [Perception]: Pain is perceiving initially at the level of the thalamus from the spinothalamic tract and subsequently localises in the sensory cortex in the respective area of the homunculus The spinocerebellar terminates in the cerebellar, the dorsal column medial lemniscus terminates in the somatosensory cortex. The nociceptive pathways: - The spinothalamic tract terminates in the thalamus were majority of the nociceptive signals perceived as pain occur. The thalamus then relays the information to the other parts of the bran that need to know about it. - The spino-reticular tract terminates in the reticular formation where the message may be noticed ignored or modulated - Amygdala; emotions - Insula; perceive pain and awareness about the body - Pre-frontal cortex: decision making - Primary somatosensory cortex: sensation - Motor cortex: muscle movement - Hippocampus: memory learning and emotion 4. *List common types of neuropathy and neuropathic conditions (peripheral and central) and their possible causes that can result in neuropathic pain* Neuropathic pain v neuropathy.... - You can have neuro-pathy without pain  - ***but*** you can't have neuropathic pain without neuro-pathy (neuro-pathology). Peripheral  - Trigeminal neuralgia  - Post-herpetic neuralgia (shingles) - Peripheral nerve injury (ie carpal tunnel) - Polyneuropathy (multiple nerve dermatomes) - Painful radiculopathy Central  - Spinal cord injury  - Brain injury  - Post stroke  - Multiple sclerosis  5. *List mechanisms (components) that contribute to neuropathic pain* Enhanced central sensitisation  - Hyper-excitability due to peripheral ectopic and strange input  - Also reduction in inhibition in spinal cord -- reduced response to inhibitory neurotransmitters (opioids)  - Decreased descending inhibition and local inhibition - Inhibitory interneurons die  - Microglia cells (immune systems) are important in increasing and facilitating nociceptive messaging in the spinal cord - Microglia release cytokines which stimulare CNS pain projection neurons. - Microglia also block the actions of inhibitory interneurons - May induce cell death - apoptosis 6. *List clinical features of neuropathic pain (both peripheral and central neuropathic pain conditions)* Key (distorted) pain features:  - Spontaneous, ectopic, erratic pain, difficult to calm, heat makes it worse  - Electric, shooting, burning pains  - Dysesthesia (tingling, pins and needles, crawling sensations)  - Paraesthesia (numbness, loss of sensation) [Diabetic neuropathy Symptoms:] - Usually numbness and tingling - Pain, weakness and unsteadiness - Always starts distally usually at the toes - Stocking-glove appearance in hands [MS] - May have a combination of nociceptive and neuropathic pain - Dysaesthetic extremity pain (burning, tingling aching predominantly in the lower extremities) - Paroxysmal pain (shock-like sensation travelling back towards lower limbs or trigeminal neuralgia sudden brief stabbing in one or more branches of the trigeminal nerve) - Migraine -- long lasting headaches possibly due to brain lesions - Spasticity pain -- excessive muscular work and mechanical muscle pain - Painful tonic spasms -- spasmodic muscle contractions, ischemic muscle pain [Cervical myelopathy - cervical spondylosis] - Gate disturbances - Balance issues - Stiff lower limbs - Uncoordinated movements - dysesthesia/paresthesia - Non-dermatomal pain - Non-myotomal upper and lower limb weakness - Electric shock into spine 7. *Outline the neuropathic pain grading system* **[Neuropathic pain grading system]** 1. Medical history with a clinical presentation that suggests a relevant neurological lesion 1. 1. 1. 1. 2. Whether the pain distribution is neuroanatomically plausible 1. 3. Whether the pain is associated with sensory signs in the same neuroanatomically plausible distribution 1. 1. 4. Objective diagnostic test 1. \*\*Treatments recommended for neuropathic pain from probable onwards 8. *Discuss typical 'neuroanatomical' pain distribution and/or pain distributions related to peripheral, central or disease related neuropathic pain* If it is at the level of the spinal cord the distribution will likely be myotome If at the level of the spinal nerve the distributions will be dermatomal 9. *List neuropathic pain screening questionnaires* 10. *To explain how pain spreads briefly outline what is:* n. Radiculopathy o. Radicular pain p. Somatic referred pain [Radiculopathy] - Pain from the injured nerve root (irritated or squished)  - In a dermatomal pattern  - Pain may include dysesthesias/paraesthesia, shooting pain, spontaneous pain, electric shocks  - May have conduction changes e.g. sensation changes, possible motor  - Palpation around nerve root evokes symptoms as opposed to opposite side - Hyperalgesia/allodynia [Neuropathy] - Pain from the compressed nerve as it passes underneath a very tight piriformis muscle  - Localised to the buttock area  - Pain may include dysesthesias, shooting pain, spontaneous pain, electric shocks  - Any spread is non-dermatomal (somatic referred pain)  - May have conduction changes, most likely sensory  - Palpation around piriformis evokes symptoms [Somatic referred pain] - Pain coming from distorted sensory messaging in the spinal cord  - due to central sensitization  - NOT in a dermatomal pattern  - NO changes in conduction -- no sensory or motor changes  - Pain is diffuse and can't be localised 11. Explain what clinical sensory testing is and interpret clinical sensory testing findings 12. Outline criteria for classification of nociplastic pain +-----------------+-----------------+-----------------+-----------------+ | | **Nociceptive | **Neuropathic | **Nociplastic | | | Pain** | Pain** | Pain** | +=================+=================+=================+=================+ | **History ** | Often history | History of a | No history of a | | | of body tissue | lesion or | lesion, damage | | | injury, | disease of the | or disease of | | | inflammation or | nervous system | the nervous | | | increased | or | system Pain not | | | loading | post-traumatic/ | strongly | | | | post-surgical | correlated with | | | | damage to the | history of body | | | | nervous system | tissues injury, | | | | | localised | | | | | inflammation or | | | | | increased | | | | | loading | +-----------------+-----------------+-----------------+-----------------+ | **Stage ** | *Typically* | Any | Typically \>3 | | | more recent \< | | months since | | | 3 months | | onset | +-----------------+-----------------+-----------------+-----------------+ | **Behaviour** | Pain tends to | Indications | No indications | | | diminish | from diagnostic | from diagnostic | | | according to | examinations to | examinations of | | | natural healing | reveal an | neuropathy or | | | phases, changes | anomaly in the | specific | | | to mechanical | nervous system | nociceptive | | | loading | | driver | +-----------------+-----------------+-----------------+-----------------+ | **Relationship | Related to | Related to | No medical | | to pathology ** | damage or | medical, local | cause for the | | | potential | or systemic | pain is | | | damage e.g., an | cause e.g., | established | | | ankle sprain or | stroke, herpes, | | | | burning a hand | nerve | | | | | compression | | +-----------------+-----------------+-----------------+-----------------+ | **Region of | Local pain  | Pain and | Pain is | | pain and | | sensory | neuroanatomical | | associated | Most often | dysfunction are | ly | | clinical | with  | neuroanatomical | illogical and | | findings** | | logical | segmentally | | | → diagnostic | | unrelated to a | | | signs of | | primary source | | | oedema, | | of nociception. | | | haematomas, | | Several regions | | | skin | | of hyperalgesia | | | colouration  | | at sites | | | | | outside and | | | → and/or | | remote to the | | | positive | | symptomatic | | | responses to | | area. | | | mechanical | | | | | stress tests | | | | | (tests that | | | | | stress body | | | | | tissue)  | | | | | | | | | | i.e., pain | | | | | related to a | | | | | primary source | | | | | of nociception | | | +-----------------+-----------------+-----------------+-----------------+ | **Pain | Pain is | Pain is | Pain most | | descriptors ** | described as | frequently | frequently | | | sharp, aching, | described as | described as | | | or throbbing | burning, | vague or dull | | | | shooting or | | | | | pricking | | +-----------------+-----------------+-----------------+-----------------+ 13. Outline mechanisms underpinning peripheral sensitisation 14. Outline mechanisms underpinning central sensitisation 15. Outline contributors to altered nociceptive processing 16. Describe clinical features of peripheral & central sensitisation and impaired descending modulation of nociception (how do patients present?) 17. Be able to use metaphors to describe different aspects of pain and pain sensitisation