RCSI Physiology & Management of Pain (MED Y2, CNS) PDF

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn Physiology & management of pain Class MED Y2 Module CNS Facilitator Niamh Connolly [email protected] Facilitator Dermot Cox [email protected] Date 5th November 2024 LEARNING OUTCOMES I De...

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn Physiology & management of pain Class MED Y2 Module CNS Facilitator Niamh Connolly [email protected] Facilitator Dermot Cox [email protected] Date 5th November 2024 LEARNING OUTCOMES I Define and describe pain as a physiological and pathophysiological process Describe the mechanisms of activation of nociceptors Describe ascending pain pathways including specific, non-specific pathways, and areas of higher cortical processing Describe pain modulation at the level of spinal cord and along descending pathways Describe the different types of pain such as referred, primary, secondary, nociceptive, neuropathic and nociplastic LEARNING OUTCOMES II Outline the use of opioids and NSAIDs in nociceptive pain Describe the role of a multi-disciplinary approach to managing nociplastic and chronic pain Describe the mechanism of action and adverse effects of – drugs that target neuropathic pain – drugs that control migraine – local anaesthetics – general anaesthetics Describe the social consequences of misuse and over use of pain medication PAIN - DEFINITION “An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage” – Pain refers to noxious stimuli https://www.iasp-pain.org Pain is a normal response to injury – Primarily a protective mechanism, and can promote repair – Can become pathological, chronic Pain is typically invoked by tissue damage – (not always – e.g. neuropathic pain) TYPES OF PAIN Nociceptive pain – Pain caused by the activation of nociceptors e.g., trauma Neuropathic pain – Pain caused by damage (injury/disease) to the nervous system Peripheral e.g., diabetic neuropathy, post-surgery neuropathic pain Central e.g., spinal cord injury, demyelinating diseases (MS) – Negative symptoms: sensory loss, numbness – Positive symptoms: spontaneous pain, increased pain sensation Deafferentation pain: occurs following peripheral nerve lesions such as phantom limb pain Nociplastic pain (psychogenic pain) – Persistent pain arising from altered nociception, despite no clear evidence of activation of peripheral nociceptors e.g., Fibromyalgia, migraine Mixed pain – Both nociceptive and neuropathic e.g., cancer pain  TYPES OF PAIN The Lancet 2021 https://www.sciencedirect.com/science/article/pii/S014067 3621003937 ACUTE VS CHRONIC PAIN Acute pain (seconds) – Experienced with real or potential tissue damage – Appropriate protective mechanism Sub-acute (hours-days) – Associated with tissue damage and infiltration of immune cells – Can promote repair Chronic pain – pathological (months-years) – Lasts longer than damage (e.g. neuropathic) – Neither protects nor supports repair – requires treatment – Chronic primary pain: no clear underlying cause/condition that adequately accounts for the pain – Chronic secondary pain: linked to an underlying condition THERE ARE MULTIPLE RESPONSES TO PAINFUL STIMULI Spinal withdrawal reflex Conscious perception of pain ANS changes (e.g., increased alertness associated with pain) Emotional responses – Fear, depression, anxiety, hopelessness Pain behaviour – Grimacing, limping, avoiding activities PERCEPTION OF PAIN (location, intensity, modality) Pain perception has both informational and motivational components (withdrawal, escape, avoidance, fear) Pain perception can be altered – Hyperalgesia: increased sensitivity to painful stimuli (lower pain threshold or exaggerated pain response) – Allodynia: pain in response to non-noxious (non-nociceptive) stimulus e.g., pain in dressing Subjective experience of pain may also be influenced by: – Past experience – Attention, Interpretation – Other contextual factors CLINICAL CHARACTERISATION OF PAIN Sensations – Paresthesia: pins and needles – Dysesthesia: burning sensation CLINICAL CHARACTERISATION OF PAIN - VISUAL ANALOGUE SCALE  PAIN SENSORY RECEPTORS = NOCICEPTORS Nociceptors: Free peripheral nerve endings of Aδ and C fibres that are excited by noxious or painful stimuli Stimuli that excite nociceptors can be mechanical, thermal, or chemical – Mechanical: intense pressure or stretch – Thermal: extremes of hot or cold – Chemical: Stimuli that cause (or have the potential to cause) tissue damage induce the release of substances that either activate nociceptors directly, or sensitise nociceptors (making them more responsive to subsequent stimuli). e.g., – Damaged cells release bradykinins (BK), prostaglandins (PG), ATP, H+ – During inflammation, immune cells release cytokines, chemokines ‘noci’ is derived from the Latin for ‘hurt’ NOCICEPTION = TRANSDUCTION OF PAINFUL STIMULI 1. Detection of noxious stimuli by nociceptors 2. Transduction of electrical signal to the CNS Generator Action Stimulus Nociceptor potential potential NOCICEPTION = TRANSDUCTION OF PAINFUL STIMULI Stimulus Sensory receptor CRM1 Cold extremes TRPA1/TRPM8 of cold or heat VR1 Heat TRPV1-4 Receptor activation (directly or indirectly) leads to opening of non- Protons (H+) ASIC specific cation channels, producing generator potential (depolarisation) Bradykinin B1/B2 Mechanical DRASIC/mDEG PAIN FIBRES (I) ? Aδ fibres Axon Type Aα Aβ Aδ C – Thinly myelinated fibres Diameter (μm) 13-20 6-12 1-5 0.2-1.5 – Speed of conduction ~5-35 m/s – Trigger immediate withdrawal (reflex) – Relay information via the thalamus to the cortex Produce sharp, localised, immediate pain Allow localisation of pain PAIN FIBRES (II) X C fibres X – Slow(er), unmyelinated fibres – Speed of conduction 0.5-2.0 m/s – Produce dull, diffuse pain (secondary pain) – Relay information via the thalamus to cortex Also relay information to the limbic system and hypothalamus Trigger memory of stimulus and emotional response  PAIN PATHWAYS 3rd order neuron Conventional pathway is 3 neuron system Primary pain afferent to spinal cord Contralateral spinothalamic tract to thalamus Thalamus to sensory cortex Ascends in contralateral spinothalamic tract Sensory neurons from one side of the body 2nd order neuron project to the sensory cortex on the 1st order neuron (upper limb) contralateral side Decussation in anterior commissure 1storder neuron (lower limb) Pain from the face travels in cranial nerves (different pathway) NOCICEPTIVE FIBRES IN SPINAL CORD Primary afferent neurons (Aδ and C fibres) – Axons transmit from nociceptor to spinal cord, via dorsal root – On entering spinal cord, they ascend/descend in the tract of Lissauer – Synapse with 2nd order neurons in superficial layers (laminae) of dorsal horn Aδ fibres – synapse in layers I and V (some synapse in layer II) C fibres – synapse in layer II (substantia gelatinosa) 2nd order neurons – Axons cross (decussate) spinal cord within one or two layers – Ascend in contralateral spinothalamic tract – Synapse with 3rd order neurons in the thalamus 3rd order neurons – Axons project from thalamus to somatosensory cortex Grey matter laminae of the spinal cord Polarys – CC BY-SA 4.0  ASCENDING PAIN PATHWAYS (SPECIFIC & NON-SPECIFIC) Reticular formation – increases alertness non-specific Hypothalamus, limbic system – Elicits emotional, behavioural responses specific ASCENDING PATHWAYS (SPECIFIC & NON-SPECIFIC) Specific pathways relay information about a single type of stimulus from one type of receptor to specific primary receiving areas of the cerebral cortex – involved in localisation and perception of pain Non-specific pathways relay information from more than one type of sensory unit to the brainstem reticular formation and regions of the thalamus that are not part of the specific pathways – Involved in behavioural responses – increased alertness, emotional response etc.  VISCERAL PAIN – REFERRED PAIN Visceral pain is poorly localised and felt in areas that may be far away from the site of stimulus ? – e.g., Pain from heart attack is felt in left shoulder, arm or back, rather than in the chest Peripheral afferent neurons from viscera and the peripheral afferent neurons from the skin converge on the same spinothalamic neurons at the same spinal segment – The brain interprets the visceral pain as coming from the area of skin (i.e. the corresponding dermatome) that shares the pathway with the visceral afferents – We say that the pain is ‘referred’ to somatic structures (structures may be quite far from the internal organ) VISCERAL PAIN – REFERRED PAIN  Inhibitory Neuron in Substantia Gelatinosa PAIN - NEUROTRANSMISSION GABA Opioids eCBs NMDA Action Glutamate AMPA Potential Primary afferent/ Sub P sensory neuron NK1 Second Order Neuron in Sub P: Substance P Dorsal Horn of NK1: Neurokinin 1 receptor Spinal Cord eCBs: endocannabinoids MODULATION OF PAIN PERCEPTION Pain perception can be magnified by past experiences or suppressed in emergencies = modulation 1. Gate control theory of modulation in dorsal horn of spinal cord (Melzack and Wall, 1965) 2. Descending pathways influence dorsal horn modulation 3. Endogenous opioids PAIN MODULATION: GATE CONTROL THEORY Somatic non-painful signals can inhibit transmission of pain signals in the spinal cord (analgesia) Touch, pressure, vibration PAIN MODULATION: GATE CONTROL THEORY - TEXT Somatic non-painful signals can inhibit transmission of pain signals in the spinal cord (analgesia) – Interneurons in the dorsal horn substantia gelatinosa inhibit the transmission of pain at the synapse between 1st and 2nd order neurons – Large diameter Aα and Aβ fibres (carrying touch, pressure, vibration, temperature) stimulate these interneurons GABA and endogenous opioids are the released neurotransmitters – Stimulated interneurons act as ‘gates’ that modulate pain impulse in response to non- nociceptive input PAIN MODULATION: DESCENDING / ANALGESIC PATHWAYS Descending analgesic (pain- relieving) modulating pathways Rostroventral Opioid receptor medulla Endogenous opioid Glutamate Endogenous opioids released from descending analgesic pathways bind with opioid receptors on the afferent pain fibre. This inhibits the release of glutamate and Substance P, blocking transmission of pain impulses along the ascending pain pathways PAIN MODULATION: DESCENDING CONTROL Pain can also be modulated by descending pathways Origin of descending modulating pathways: – Peri-ventricular & peri-aqueductal grey matter in midbrain – Rostroventral medulla, including raphe nuclei and locus coeruleus Descending fibres project to dorsal horn cells reducing nociceptor transmission – Neurotransmitters include serotonin & noradrenaline – Endogenous opioids and endocannabinoids also involved ENDOGENOUS OPIOIDS Neuropeptides associated with analgesic modulation of pain – Co-released with classical inhibitory neurotransmitters e.g., GABA Act on (bind) opioid receptors – Opioid receptors are expressed at pre- and post-synaptic sites in the dorsal horn, spinal cord, brain stem, thalamus and cortex – Three main types of opioid receptor: Opioid receptor Location Endogenous ligands μ (‘mu’) Ubiquitous β-Endorphins, dynorphins δ (‘delta’) Spinal cord β-Endorphins, enkephalins κ (‘kappa’) Peripheral nervous system β-Endorphins, dynorphins – Binding at pre-synaptic sites: inhibits release of substance P (and glutamate) – Binding at post-synaptic sites: reduces depolarisation of post-synaptic neuron ENDOCANNABINOIDS Anandamide and 2-arachidonylglycerol (2-AG) – Produced from arachidonic acid derivatives Mediate their analgesic effect via activation of cannabinoid receptors (CB1 and CB2) on the pre-synaptic neuron – Reduce neurotransmitter release – Attenuate nociceptive responses Receptors expressed in the brain, spinal cord, dorsal root ganglion neurons (CB1) and immune cells (CB2) PAIN MODULATION Descending control Gate control theory  Figure 1 The Lancet 2021 3972082-2097DOI: (10.1016/S0140-6736(21)00393-7) PAIN TREATMENT Nociceptive pathways and sites of analgesic drug action Case: Spinal injury Mark, a 45-year-old man is in a car crash and injures his spine. He is in severe pain and any attempt to walk is impossible due to the pain. What type of pain does Mark have? How should the pain be managed? INFLAMMATORY PAIN Inflammatory mediators such as PGs, 5HT and bradykinin sensitise pain fibres Rather than cause pain they sensitise pain fibres making them more likely to respond to other pain signals  NON-STEROIDAL ANTI-INFLAMMATORY NSAID’s are used to treat inflammation Act to inhibit cyclooxygenase and prostaglandin production They are anti-inflammatory, analgesic and anti-pyretic – aspirin (irreversible) – ibuprofen – indomethacin – meclofenamate – diclofenac ANTI-INFLAMMATORY DRUGS Inflammation is a major cause of pain Due to specific inflammatory mediators sensitising pain fibres Primarily prostaglandins and calcitonin gene-related peptide COXIBS COX II inhibitors: celecoxib, rofecoxib developed to protect against Gastric Ulceration – Have similar efficacies to that of the non-selective inhibitors, but the GIT side effects are decreased by ~50%. PARACETAMOL Technically not an NSAID as it is only used for fever and pain and not inflammation MOA is unclear with multiple theories – COX II selective inhibition – Its major metabolite NAPQI activates TRPA1 in the spinal cord producing anti-nociceptive response  Opioid analgesics Opiate – Compounds related to substances found in the opium poppy, e.g. morphine Opioid – Natural or synthetic compounds that cause opiate-like effects ENDOGENOUS OPIOIDS ENKEPHALINASE INHIBITOR Enkephalinase is an enzyme that breaks down enkephalins Thiorphan – Active metabolite of racecadotril – Used as anti-diarrheal – Inhibits enkephalinase Research on developing enkephalinase inhibitors for pain control  Opioid receptors 5 types of opioid receptor – m (MOR) – k (KOR) – d (DOR) – nociceptin/orphanin FQ (N/OFQ) (NOR) – Opioid growth factor receptor G-proteins – Gai-linked Promote opening of K+ channels – Reduces neuronal excitability Inhibit opening of voltage-gated Ca2+ channels – Reduces neurotransmitter release Sites of action of opioid analgesics. The gray pathway shows the sites of action on the pain transmission pathway from periphery to central nervous system. The red pathway shows the actions on pain-modulating neurons in the midbrain and medulla. GABA = γ- aminobutyric acid; MOR = μ opioid receptor. Anesthes. 2011;115(6):1363-1381 Date of download: 4/7/2017 Copyright © 2017 American Society of Anesthesiologists. All rights reserved.  Morphine m, k and d receptor agonist Marked elevation in pain threshold without loss of consciousness (m and k receptors) Euphoria (m receptors): pleasant, ‘floating’ sensation with freedom from anxiety [dysphoria in some subjects (k receptors)] Other sensory modalities not affected  Morphine: pharmacokinetics Given orally, s.c., i.m., i.v. Variable 1st-pass metabolism Modest t1/2 = 3 - 4 hrs Sustained release oral preparations to increase duration of action Patient-controlled i.v. analgesia  Morphine: side effects Sedation, mental clouding/drowsiness Respiratory depression: inhibits brain stem regulatory centre Nausea, vomiting – Use an anti-emetic – dopamine receptor antagonist Constipation: increased GIT muscle tone, decreased propulsive movements, reduced sensory stimuli for defecation reflex – Use a laxative Miosis: important in diagnosis of overdose Tolerance and dependence  Other opioid agonists Pethidine [meperidine in USA] Fentanyl – Efficacy ≤ morphine; – 100+x more potent than morphine – Cancer pain – m > k agonist Oxycodone – Shorter acting; often used in labour Targin (oxycodone + naloxone) – Prevents constipation (naloxone is – Less liable to cause constipation poorly absorbed) Codeine – Prevents injecting the drug – Low efficacy m > k agonist; Tramadol – Also inhibits serotonin and – 10% converted to morphine noradrenaline reuptake – Alleviation of mild-moderate pain – Usually prescribed with – Antitussive [cough suppressant] paracetamol  Carboxyesterase CYP2D6 CYP3A4 Carboxyesterase UGT2B7 UGT2B7 Novel Opioids Nitazines are synthetic opioids with a benzimidazole structure (MOR agonists) – Etonitazene (1000x more potent than morphine) – Isotonitazene – Metonitazene Also known as opioid New Psychoactive Substances Not clinically used due to risk of respiratory depression – 200x more toxic than morphine Evidence of presence in street drugs Structures of significant opioids  Opioid antagonists - Naloxone m > k receptor antagonist Almost inert Reversal of opioid actions, inc. S/Es and acute opioid overdose Short T1/2 [1-2 hours] relative to morphine, hence repeat administration Available as IV, IM and intranasal formulations NALTREXONE Naltrexone is a m antagonist (similar Used at very low dose in to naloxone) inflammatory diseases Long half-life – 1/10th dose used for addiction Available as oral and long lasting Pilot studies show some benefit injectable formulations – Fibromyalgia Approved for treatment of opioid – Crohn’s disease use disorder (OUD) and alcohol Mechanism of action not clear use disorder (AUD) – Anti-TLR-4 activity? Causes hepatotoxicity – Cross-talk between chemokine and opioid receptors Methylnaltrexone is a peripherally – Increase in endogenous opioid acting antagonist that is approved peptides for opioid-induced constipation Nalmefene Similar structure to naltrexone Longer half-life than naloxone and naltrexone m antagonist and k partial agonist Oral, nasal and IV formulations No hepatotoxicity Approved for overdose treatment and AUD Xylazine a2-adrenergic receptor agonist Acts centrally on CNS Developed as an anti-hypertensive but has CNS depressant activity Used as a veterinary sedative – Street name Tranq Used as an additive in opioids such as fentanyl – Zombie drug Prolongs and enhances the effects of opioids Treating overdose is challenging as it is not reversed by naloxone – Give naloxone and support breathing – May not restore consciousness l OPIOID EPIDEMIC Predicted number for year ending May 2023: 112,436 MME: morphine milligram equivalent  BUT…. “No patient [in terminal pain] should ever wish for death because of their physician’s reluctance to use adequate amounts of effective opioids” REMEMBER… 90% of all addictions begin in adolescence Less than 13% of patients treated for overdose were also being treated with chronic pain 75% of people using opiates were not prescribed them by their doctor Main risk factors for opiate addiction are – Poverty – Mental illness – Childhood trauma US ranks 34 out 35 top OECD countries for child poverty (Romania was 35). Probably the main driver of opiate epidemic in US. PURDUE PHARMA Founded in 1892 in NY – Taken over by Sackler brothers (doctors) Focus on pain management Developed Contin sustained release formulation – MS Contin delivers morphine (1984) – OxyContin use this to deliver oxycodone (1996) - blockbuster Promised a 2x day dosing – Not really - Patients required more than prescribed 78% heroin addicts started with OxyContin Sued for bad business practices – $8 billion – Criminal prosecutions of senior management – Company converted into a public interest company Case: Spinal injury continued MRI scans show an intact spinal chord but damage to the lumbar vertebrae. He undergoes spinal surgery to remove bone fragments that are pressing on nerves. Two weeks later Mark is discharged from hospital. In a follow-up visit with the surgeon, Mark complains of bad pain down his legs – often a buzzing sensation or pins-and-needles. What type of pain is Mark experiencing? How should it be managed? NEUROPATHIC PAIN Difficult to treat Conventional medication has no effect Anti-epileptic and anti-depressant medication is most effective – Pregabalin – Gabapentin – Topiramate – Lamatrogine – Amitriptyline Gabapentanoids Pregabalin and gapapentin (gabapentanoids) bind to a2d high voltage Cav accessory protein Not clear if this affects Ca influx Analogues of GABA but do not act on GABA receptors Nerve Block Nerve Block Injection of local anaesthetic (LA) into nerve plexus Can be ultrasound guided Can also include and NSAID or a steroid LAs inhibit Nav – Intracellular portion of a-subunit – Higher affinity for open and inactivated states Adverse effects are seizures and at higher doses heart failure Case: Low Back Pain Thirty-nine year-old Ciara presents to her GP with acute lower back pain. She is prescribed diclofenac to manage the pain and is advised to attend a physiotherapist for an exercise program. Six months later she returns to the GP complaining that she still has the back pain and the medication does not help. MRI shows no abnormalities. What type of pain does she have? How should it be managed? OPAL Study Patients with low back/neck pain recruited Standard of care + oxycodone or placebo End point was Pain at 6-weeks – Opioid group pain score 2.78 – Placebo group pain score 2.25 Borderline significance Opioids of no clinical benefit in low back/neck pain Jones, et al. (2023). Opioid analgesia for acute low back pain and neck pain (the OPAL trial): a randomised placebo-controlled trial. Lancet. doi: 10.1016/S0140-6736(23)00404-X. CDC Chronic Pain Survey 60% used a combination of pharmacologic and non-pharmacologic treatments 27% used medications alone 76% self-reported using OTC pain relievers for pain, Prescription non-opioids (31%) Prescription opioids (13.5%) Those using prescription opioids were – Older, – had public insurance, – had more severe pain Managing Nociplastic Pain Chronic low back pain is an example of nociplastic pain Exercise therapy is standard therapy If significant pain persists use cognitive behavioural therapy and mind-body interventions (mindfulness-based stress reduction [MBSR], biofeedback, and progressive relaxation) Pharmacotherapy is second line treatment Only use NSAIDs if they were effective in acute back pain If not use duloxetine or tramadol Duloxetine For patients with chronic low back pain non-responsive to NSAIDs the first choice of drug is duloxetine Serotonin& norepinephrine reuptake inhibitor Risk of suicide ideation and suicide especially in young people  Tramadol Racemic mixture of + and – enantiomers (+) tramadol is a MOR agonist and inhibitor of serotonin re- uptake (-) tramadol is an inhibitor of noradrenaline re-uptake Use with care as there is a potential for dependence Case: Headache Shirley, a 29-year-old woman presents to her GP with a history of headache. She has been taking ibuprofen and paracetamol but they have little effect and the headaches are becoming more frequent. She describes visual disturbances prior to the onset of the headache which is also associated with nausea. The headache is so bad that she has to go to bed for a few hours. What type of headache is this? What type of pain is it? How should it be managed?  NEUROGENIC INFLAMMATION Neurogenic inflammation is due to release of inflammatory mediators (especially neuropeptides) from small- diameter primary afferent C- fibres rather than immune cells causing vasodilation – calcitonin gene-related peptide (CGRP) Migraine is the classic example of neurogenic inflammation CALCITONIN GENE-RELATED PEPTIDE (CGRP) a | Amino acid structure of human α- type calcitonin gene-related peptide (CGRP). b | The CGRP receptor complex, which consists of the two integral membrane proteins calcitonin receptor- like receptor (CALCRL) and receptor activity-modifying protein 1 (RAMP1) and two cytoplasmic proteins, receptor coupling protein (RCP) and the α-subunit of the GS protein (GαS). c | The targets for CGRP-related migraine therapies illustrated in a CGRP-containing trigeminal nerve varicosity that innervates a cerebrovascular smooth muscle cell. 5-HT, 5-hydroxytryptamine receptor. CALCITONIN GENE-RELATED PEPTIDE NEUROGENIC INFLAMMATION PHASES OF MIGRAINE About 30% migraine attacks associated with aura MIGRAINE PREVALENCE GLOBAL 2016 Tension-type headache – 1·89 billion people affected – 7·2 million years lived with disability Migraine – 1·04 billion – 45·1 million years lived with disability  Figure 3 Migraine Tension Headache The Lancet Neurology 2018 17954-976DOI: (10.1016/S1474-4422(18)30322-3)  Figure 4 Global years of life lived with disability (YLD) rate per 100 000 population The Lancet Neurology 2018 17954-976DOI: (10.1016/S1474-4422(18)30322-3) MIGRAINE-CAUSE  ACUTE MIGRAINE-TREATMENT NSAIDS and/or paracetamol Anti-emetic if required Triptans – 5-HT1 agonists Frovatriptan Zolmitriptan Ergotamine (ergot alkaloid) – 5-HT1 agonist – Adverse effects due to activity on other 5-HT receptors, noradrenergic and dopaminergic receptors – Cannot be used in patients with coronary artery disease Sumatriptan, an agonist is very effective but expensive. Ubrogepant (CGRP antagonist) Lasmiditan (5HT1F agonist) MIGRAINE-PROPHYLAXIS Patients with frequent migraines require treatment to prevent attacks Avoid triggers b-adrenoreceptor antagonists Amitriptyline (anti-depressant) Topiramate (anti-psychotic) OnabotulinumtoxinA (Botulinum toxin, Botox) – chronic migraine only Anti-Calcitonin Gene-Related Peptide treatment TARGETING CGRP Anti-CGRP receptor antibodies – Erenumab Anti-CGRP antibodies – Fremanezumab – Galcanezumab – Eptinezumab Small molecule CGRP antagonists – Ubrogepant – Rimegepant LEARNING OUTCOMES I Define and describe pain as a physiological and pathophysiological process Describe the mechanisms of activation of nociceptors Describe ascending pain pathways including specific, non-specific pathways, and areas of higher cortical processing Describe pain modulation at the level of spinal cord and along descending pathways Describe the different types of pain such as referred, primary, secondary, nociceptive, neuropathic and nociplastic LEARNING OUTCOMES II Outline the use of opioids and NSAIDs in nociceptive pain Describe the role of a multi-disciplinary approach to managing nociplastic and chronic pain Describe the mechanism of action and adverse effects of – drugs that target neuropathic pain – drugs that control migraine – local anaesthetics – general anaesthetics Describe the social consequences of misuse and over use of pain medication