Pain Management and Nociception Quiz

Course Information

• 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.
• 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.
  • Central, e.g., spinal cord injury, multiple sclerosis (MS)
  • Peripheral, e.g., diabetic neuropathy, post-surgery neuropathic pain
  • 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.
  • Examples: Fibromyalgia, migraine
• Mixed pain: Both nociceptive and neuropathic, e.g., cancer pain

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, neither protects nor supports repair, often requires treatment.
  • Chronic primary pain: unclear underlying cause
  • Chronic secondary pain: linked to an underlying condition

Multiple Responses to Painful Stimuli

• Spinal withdrawal reflex
• Conscious perception of pain
• Autonomic nervous system (ANS) changes (e.g., increased alertness associated with pain)
• Emotional responses (e.g., fear, depression, anxiety, hopelessness)
• Pain behaviours (e.g., grimacing, limping, avoiding activities)

Perception of Pain

• Pain perception has informational and motivational components (location, intensity, modality)
• Pain perception can be altered, including hyperalgesia (increased sensitivity to painful stimuli) and allodynia (pain in response to non-noxious stimuli).
• Past experience, attention, interpretation, and other contextual factors influence subjective pain experience

Clinical Characterisation of Pain

• Sensations:
  • Paresthesia: pins and needles
  • Dysesthesia: burning sensation
• Other clinical characteristics such as burning, stabbing, electric shock-like (nerve pain) and tenderness, achiness, and stiffness (muscle pain)

Clinical Characterisation of Pain - Visual Analogue Scale

• Visual analogue scale (VAS) used to quantify pain experience

Pain Sensory Receptors = Nociceptors

• Nociceptors: Free peripheral nerve endings of Aδ and C fibres that are excited by noxious or painful stimuli
• Stimuli include mechanical (intense pressure or stretch), thermal (extremes of hot or cold), and chemical stimuli.
• Chemical stimuli can cause or potentially cause tissue damage and release substances that either activate nociceptors directly or sensitize them.
• Examples include bradykinin (BK), prostaglandins (PG), ATP, and H+.

Nociception = Transduction of Painful Stimuli

• Detection of noxious stimuli by nociceptors
• Transduction of electrical signal to the CNS

Pain Fibres (I & II)

• Aδ fibres: Thinly myelinated fibres, speed of conduction ~5-35 m/s, trigger immediate withdrawal, produce sharp, localised, immediate pain
• C fibres: Slow, unmyelinated fibres, speed of conduction 0.5-2.0 m/s, produce dull, diffuse pain (secondary pain), relay information via the thalamus to cortex, limbic system, and hypothalamus, and trigger memory of stimulus.

Pain Pathways

• Conventional pathway is a 3-neuron system
• Primary pain afferent to spinal cord, contralateral spinothalamic tract to thalamus, thalamus to sensory cortex
• Sensory neurons from one side of the body project to the sensory cortex on the contralateral side
• Pain from the face travels in cranial nerves (different pathways)

Nociceptive Fibres in Spinal Cord

• Primary afferent neurons (Aδ and C fibres): transmit from nociceptor to the spinal cord via the dorsal root.
• On entering the spinal cord, they ascend/descend in the tract of Lissauer.
• Synapse with 2nd order neurons in superficial layers (laminae) of the dorsal horn.
  • Aδ fibers – synapse in layers I and V (some synapse in layer II)
  • C fibers – synapse in layer II (substantia gelatinosa)
• 2nd order neurons: Axons cross(decussate), ascend in contralateral spinothalamic tract, synapse with 3rd order neurons in thalamus.
• 3rd order neurons: axons project from thalamus to somatosensory cortex.

Ascending Pain Pathways (Specific & Non-Specific)

• Specific pathways: relay information about a single type of stimulus to specific areas of the cerebral cortex involved in localization and pain perception.
• 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. Involves behavioral responses.

Visceral Pain - Referred Pain

• Visceral pain is poorly localized and felt in areas far away from the stimulus site.
• Peripheral afferent neurons from viscera converge on the same spinothalamic neurons from the same spinal segment as skin afferents
• Brain interprets visceral pain as coming from the area of skin that shares the same pathway.
• Pain is referred to somatic structures, quite far from the internal organ.

Pain - Neurotransmission

• Neurotransmitters involved in pain transmission include glutamate, NMDA, AMPA, and NK1 receptors.
• Inhibitory neurons in the substantia gelatinosa use GABA, opioids, and endocannabinoids to modulate pain.

Modulation of Pain Perception

• Pain perception can be magnified or suppressed (modulation).
• Gate control theory: somatic non-painful signals can inhibit pain signal transmission.
• Descending pathways influence dorsal horn modulation.
• Endogenous opioids play a role.

Pain Modulation: Descending/Analgesic Pathways

• Descending analgesic pathways modulate pain.
• Periaqueductal gray matter and rostroventral medulla involved.
• Endogenous opioid release from descending analgesic pathways bind with opioid receptors on afferent pain fibers inhibiting glutamate and substance p release.

Pain Modulation: Descending Control

• Pain can be modulated by descending pathways originating from the brainstem (e.g., peri-ventricular/per-aqueductal grey matter, rostroventral medulla, including raphe nuclei and locus coeruleus)
• Descending fibers reduce nociceptor transmission through neurotransmitters such as serotonin and noradrenaline.
• Endogenous opioids and endocannabinoids also involved.

Endogenous Opioids

• Neuropeptides associated with analgesic modulation (endorphins, enkephalins, dynorphins, endomorphins, orphanin-FQ/nociceptin)
• Opioid receptors (μ, δ, κ) expressed in the dorsal horn.
• Binding at presynaptic sites inhibits substance P and glutamate release; at postsynaptic sites, reduces depolarisation.

Endocannabinoids

• Anandamide and 2-arachidonylglycerol (2-AG) mediate their analgesic effect via activation of cannabinoid receptors (CB1 and CB2).
• Reduce neurotransmitter release, and attenuate nociceptive responses.

Clinical Characterisation of Pain- Visual Analogue Scale (VAS)

• Visual analogue scale (VAS) used to quantify pain experience.

Case: Spinal Injury

• Mark has a spinal injury and is experiencing neuropathic pain.
• Management includes appropriate pain treatment strategy and consideration of appropriate medications.

Inflammatory Pain

• Inflammatory mediators (e.g., prostaglandins, 5-HT, bradykinin) sensitize pain fibres.
• They don't directly cause pain but sensitize fibres, increasing their response to pain signals

NSAIDs

• Act to inhibit cyclooxygenase (COX) and prostaglandin (PG) production.
• Are anti-inflammatory, analgesic, and anti-pyretic.
  • Examples: Aspirin, ibuprofen, indomethacin

Anti-inflammatory Drugs

• Inflammation is a major cause of pain
• Due to specific inflammatory mediators sensitizing pain fibres.
• Prostaglandins and calcitonin gene-related peptide primarily involved.

COXIBs

• COX-II inhibitors (celecoxib, rofecoxib) developed for protection of gastric mucosa.
• Have similar efficacy to non-selective inhibitors with reduced GI side effects (~50%).

Paracetamol

• Technically not an NSAID; used for fever and pain (not inflammation).
• Mechanism of action unclear but linked to COX II selective inhibition and its major metabolite NAPQI that activates TRPA1 in the spinal cord.

Opioid Analgesics

• Opiate: compounds related to opium poppy (e.g., morphine)
• Opioid: natural or synthetic compounds mimicking opiate-like effects

Endogenous Opioids

• Endorphins, enkephalins, dynorphins, endomorphins, orphanin-FQ/nociceptin
• Main types: μ (MOR), δ (DOR), κ (KOR).

Enkephalinase Inhibitor

• Enkephalinase breaks down enkephalins.
• Thiorphan (active metabolite of racecadotril) used as an anti-diarrheal.
• Research ongoing for enkephalinase inhibitors for pain control.

Opioid Receptors

• Five types of opioid receptor (μ, κ, δ, nociceptin/orphanin FQ, opioid growth factor receptor)
• G-protein-linked.
• Promote opening of K+ channels, reduce neuronal excitability, and inhibit opening of voltage-gated Ca2+ channels.

Case: Low Back Pain

• 39-year-old Ciara with acute lower back pain, treated with diclofenac and physiotherapy, persists with pain
• Determine the appropriate pain management strategy.

OPAL Study

• Opioids showed borderline significance in managing low back/neck pain.

Epidemiology and Public Health Aspects of Pain

• Pain is pervasive and costly in terms of human suffering and economic burden.
• Several risk factors for opioid misuse/addiction exist, including poverty and mental illness; early-onset addiction is common.

Case: Headache

• 29-year-old Shirley with recurrent headaches with visual disturbances, nausea prior to headache onset.
• Determine the appropriate pain management strategy.

Neurogenic Inflammation

• Neurogenic inflammation is due to release of inflammatory mediators (especially neuropeptides) from small-diameter primary afferent C-fibres, causing vasodilation.
• Calcitonin gene-related peptide (CGRP) a key mediator.
• Migraine is an example of neurogenic inflammation. The mechanisms of pain and inflammation are complex.

Phases of Migraine

• Migraine has different phases, including prodrome (early warning signs), aura (sensory disturbances), headache (throbbing pain), and postdrome (symptoms after headache)

Migraine Prevalence Global 2016

• Tension-type headache - 1.89 billion people affected, 7.2M years lived with disability
• Migraine - 1.04 billion people affected, 45.1M years lived with disability

Acute Migraine Treatment

• NSAIDs and/or paracetamol.
• Anti-emetics.
• Triptans (5-HT1 agonists, e.g., frovatriptan, zolmitriptan), ergotamine (ergot alkaloid, 5HT1 agonist).
• Sumatriptan (highly effective but expensive) Ubrogepant and Lasmiditan (5-HT1F agonists)

Migraine-Prophylaxis

• Treatment to prevent migraine attacks, including avoiding triggers.
• Treatments: Beta-adrenoreceptor antagonists, amitriptyline (anti-depressant), topiramate (anti-psychotic), OnabotulinumtoxinA (Botox), and Anti-calcitonin gene-related peptide treatment

Targeting CGRP

• Anti-CGRP receptor antibodies (e.g., erenumab, fremanezumab, galcanezumab, eptinezumab)
• Small molecule CGRP antagonists (e.g., ubrogepant, rimegepant)

Case: Low Back Pain (cont.)

• Determine the appropriate pain management strategy.

Managing Nociplastic Pain

• Exercise therapy is standard therapy.
• Cognitive behavioural therapy (CBT) and mind-body interventions (e.g., mindfulness-based stress reduction (MBSR)) and progressive relaxation may be needed, especially for chronic pain.
• Pharmacotherapy (NSAIDS, duloxetine, tramadol) may be considered in some cases.

Duloxetine

• Serotonin and norepinephrine reuptake inhibitor (SNRI) used in chronic pain.
• Risk of suicide ideation and suicide especially pertinent in young populations

Tramadol

• Racemic mixture of (+)- and (-)-enantiomers.
• (+) Tramadol: μ opioid agonist, inhibits serotonin reuptake
• (-) Tramadol: Inhibits Noradrenaline (NA) reuptake.
• Important to use with caution due to potential for dependence.

Nerve Block

• Injection of local anaesthetic into nerve plexus, used for pain management.
• Potentially including NSAIDs/steroid.
• Locally reduces sodium ion channel activity leading to the inhibition of nerve conduction.

Nerve Block Adverse effects

• Seizures and heart failure at higher doses.

Test your knowledge on the nature of pain, nociceptors, and various types of pain. This quiz covers essential concepts in pain management, including nociceptive and neuropathic pain, as well as the social implications of pain medication use. Perfect for students and professionals in healthcare fields.