Pain: From Alarm to Aftermath

Module 01 of 09 · Act I — The Alarm

Nociception & Transduction

Pain is not a single event. It is a process — beginning with the detection of a threat and ending, sometimes, in a self-sustaining disease. This module begins at the beginning: the alarm.

IASP Definition of Pain (2020 revision) "An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage."

Six key notes:

Pain is always a personal experience influenced by biological, psychological, and social factors
Pain and nociception are different phenomena. Pain cannot be inferred solely from activity in sensory neurons
Through their life experiences, individuals learn the concept of pain
A person's report of an experience as pain should be respected
Although pain usually serves an adaptive role, it may have adverse effects on function and social and psychological well-being
Verbal description is only one of several behaviors to express pain; inability to communicate does not negate the possibility that a human or a nonhuman animal experiences pain

Nociception vs Pain

Nociception

The neural process of encoding noxious stimuli
Occurs in the periphery, spinal cord, brainstem, and brain
Can occur without conscious perception (e.g., under general anaesthesia)
Is measurable via physiological markers
Is not pain

Pain

A subjective, conscious experience
Requires cortical processing and awareness
Influenced by context, emotion, culture, memory
Is what the patient says it is
Can occur without identifiable nociceptive input (e.g., phantom limb)

The Four Steps of Nociception

1 · Transduction
Noxious stimulus → electrical signal

→

2 · Transmission
Signal travels to CNS

→

3 · Modulation
Signal altered at spinal/brainstem

→

4 · Perception
Conscious experience of pain

Step 1 — Transduction: The Molecular Alarm

Nociceptors are free nerve endings in peripheral tissues — skin, muscle, joints, viscera, and bone. They are activated by noxious mechanical, thermal, or chemical stimuli. The process of converting these stimuli into electrical signals is transduction.

The Inflammatory Soup

Tissue injury releases a cocktail of mediators that sensitise and activate nociceptors. This is the origin of peripheral sensitisation.

Mediator	Source	Effect on Nociceptor
Protons (H⁺)	Ischaemia, inflammation	Activate ASICs and TRPV1 → direct depolarisation
ATP	Damaged cells	Activates P2X₃ receptors → direct excitation
Bradykinin	Plasma (kinin system)	Activates B₂ receptors → sensitisation
Prostaglandins (PGE₂, PGI₂)	COX pathway	Sensitise nociceptors → hyperalgesia
Substance P	Primary afferents	Neurogenic inflammation, mast cell activation
CGRP	Primary afferents	Vasodilation, neurogenic inflammation
NGF	Inflammatory cells	TrkA activation → long-term sensitisation
Cytokines (TNF-α, IL-1β, IL-6)	Immune cells, glia	Sensitise nociceptors and central neurons
Endothelins	Endothelium	Excite nociceptors via ETA receptors
Serotonin (5-HT)	Platelets, mast cells	Sensitise via 5-HT₃ receptors
Histamine	Mast cells	Itch and nociceptor sensitisation
Lactate	Ischaemia, anaerobic metabolism	Acidosis → nociceptor activation

Key Receptors and Ion Channels

Channel/Receptor	Stimulus	Clinical Relevance
TRPV1 (capsaicin receptor)	Heat >43°C, protons, capsaicin	Target of topical capsaicin; sensitised in inflammation
TRPM8	Cold, menthol	Cold allodynia in neuropathic pain
TRPA1	Mustard oil, cold, irritants	Neurogenic inflammation; target of investigational drugs
ASICs	Acidosis (H⁺)	Ischaemic pain, muscle pain
P2X₃	ATP	Visceral and neuropathic pain; target of investigational drugs
Nav1.7, Nav1.8, Nav1.9	Voltage-gated sodium channels	Nav1.7 gain-of-function → inherited erythromelalgia; loss-of-function → congenital insensitivity to pain
Kv channels	Voltage-gated potassium	Regulate excitability; opened by retigabine (anticonvulsant)
CB1/CB2	Endocannabinoids	Analgesic targets; THC/CBD pharmacology

Nociceptor Types — The Two Fibres

Property	Aδ Fibres	C Fibres
Myelination	Thinly myelinated	Unmyelinated
Conduction velocity	5–30 m/s (fast)	0.5–2 m/s (slow)
Sensation	Sharp, pricking, well-localised ("first pain")	Dull, burning, aching, poorly localised ("second pain")
Diameter	1–5 μm	0.2–1.5 μm
Neurotransmitters	Glutamate	Glutamate, substance P, CGRP
Clinical block order	Blocked before C fibres by pressure/ischaemia	Blocked first by local anaesthetics (smaller diameter)
Receptive field	Smaller, more precise	Larger, diffuse
Silent nociceptors	Rare	Common — recruited in inflammation

✦ Clinical Pearl — Why Local Anaesthetics Work First on C Fibres Local anaesthetics block small, unmyelinated fibres before large, myelinated ones. This is why patients lose pain and temperature before touch and motor function during a spinal or epidural. The order of block: sympathetic → pain/temperature (C and Aδ) → touch/proprioception (Aβ) → motor (Aα).

Silent Nociceptors

Some nociceptors are silent under normal conditions — unresponsive to even noxious mechanical stimuli
They become active only after inflammation or tissue injury ("sleeping" or "silent" nociceptors)
Their recruitment contributes to primary hyperalgesia — increased pain sensitivity at the site of injury
This is one reason pain can be disproportionate to the apparent injury
Silent nociceptors are thought to play a role in visceral pain and functional pain disorders

Transduction — The Takeaway Transduction is the molecular alarm. It is where the body first detects a threat. It is also the target of NSAIDs (reduce prostaglandin synthesis), local anaesthetics (block sodium channels), and topical agents (capsaicin depletes substance P). Understanding this step explains why these drugs work.

Module 02 of 09 · Act I — The Alarm

Transmission — Periphery to CNS

The signal travels from the site of injury, through the dorsal root ganglion, into the dorsal horn of the spinal cord, and up to the brain.

The Dorsal Horn — First Synapse

The dorsal horn of the spinal cord is the first relay station. Primary afferents synapse with second-order neurons. This is where the signal can be amplified, dampened, or redirected — and where sensitisation begins.

Rexed Laminae

Lamina	Location	Function
Lamina I (marginal zone)	Superficial dorsal horn	Nociceptive-specific projection neurons (NS)
Lamina II (substantia gelatinosa)	Superficial dorsal horn	Interneurons; key site of modulation and sensitisation
Lamina III–IV	Nucleus proprius	Wide dynamic range (WDR) neurons; receive Aβ, Aδ, C input
Lamina V	Deep dorsal horn	WDR neurons; visceral and somatic convergence
Lamina VI	Deep dorsal horn	Proprioceptive input
Lamina VII–IX	Ventral horn	Motor neurons (not nociceptive)
Lamina X	Around central canal	Visceral nociception

Second-Order Neuron Types

Type	Input	Output	Role
Nociceptive-specific (NS)	Aδ and C fibres only	Sharp, well-localised pain	Discriminative pain
Wide dynamic range (WDR)	Aβ, Aδ, C fibres	Responds to touch and noxious stimuli	Central sensitisation; allodynia
Low-threshold (LT)	Aβ fibres	Innocuous input	Normally non-nociceptive
NK1R neurons	Substance P, glutamate	Project to parabrachial area	Affective-motivational dimension

The WDR Neuron — Why Allodynia Happens WDR neurons receive input from both low-threshold mechanoreceptors (Aβ) and nociceptors (Aδ/C). Under normal conditions, Aβ input alone does not cause pain. But after central sensitisation, the WDR neuron's threshold drops — and now light touch activates a pain-signalling neuron. This is the mechanism of mechanical allodynia.

Ascending Pathways

Pathway	Origin	Destination	Function
Spinothalamic tract (neospinothalamic)	Lamina I, V	Thalamus (VPL/VPM) → somatosensory cortex	Sensory-discriminative: location, intensity, quality
Spinoreticular tract	Lamina V, VII, VIII	Reticular formation → thalamus → cortex	Arousal, autonomic response, affective dimension
Spinomesencephalic tract	Lamina I, V	PAG, superior colliculus	Activates descending modulation
Spinoparabrachial tract	Lamina I (NK1R neurons)	Parabrachial area → amygdala	Affective-motivational: unpleasantness, fear, avoidance
Spinohypothalamic tract	Lamina I, V	Hypothalamus	Neuroendocrine and autonomic responses
Spinocervical tract	Lamina IV–V	Lateral cervical nucleus → thalamus	Discriminative touch (minor pain role)

The Pain Matrix — Cortical Processing

Pain is not processed in a single "pain centre." It is distributed across a network of cortical and subcortical regions — the pain matrix.

Region	Role
Primary somatosensory cortex (S1)	Sensory-discriminative: location, intensity, quality
Secondary somatosensory cortex (S2)	Pain intensity, attention to pain
Insula	Autonomic integration, interoception, pain intensity
Anterior cingulate cortex (ACC)	Affective-motivational: unpleasantness, suffering
Prefrontal cortex	Cognitive evaluation, reappraisal, placebo analgesia
Amygdala	Fear, anxiety, emotional learning
Thalamus	Relay and modulation; VPL/VPM for sensory, medial for affective
PAG	Descending modulation; opioid-mediated analgesia
Basal ganglia	Motor responses, avoidance learning

✦ The Two Dimensions of Pain Sensory-discriminative (S1, S2, insula): "Where, what, how much?" Affective-motivational (ACC, amygdala): "How bad is it? How much do I hate it?" This distinction explains why two patients with identical injuries can have vastly different pain experiences — and why treatments targeting one dimension may not touch the other.

Visceral Pain — A Different Beast

Poorly localised: lower density of nociceptors on viscera; less cortical representation
Referred: visceral afferents converge on the same second-order neurons as somatic afferents (convergence-projection theory) — e.g., cardiac ischaemia → left arm pain
Associated features: nausea, sweating, hypotension, changes in heart rate
Types: true visceral (from the organ), parietal (from the peritoneum), referred (to somatic structures)
Clinical note: Visceral pain is often poorly responsive to NSAIDs and opioids; it may respond to visceral analgesics (e.g., paracetamol, dipyrone, ketamine, alpha-2 agonists)

The Dorsal Root Ganglion (DRG)

Location: In the intervertebral foramen, just outside the spinal cord
Function: Cell bodies of primary afferent neurons; no synapse here — signals pass through
Clinical relevance: Target for dorsal root ganglion stimulation (DRGS) — a form of neuromodulation for focal neuropathic pain
DRG is a site of: Ectopic firing in neuropathic pain, sympathetic coupling, and immune activation

The Transmission Pathway — At a Glance

From the periphery to the cortex, the nociceptive signal passes through six stations. Each is a potential target for analgesia — and each is a site where the signal can be amplified or dampened.

The Three Sites of Modulation The signal is not simply relayed — it is modulated at three levels: (1) Dorsal horn — gate control, local interneurons, descending inhibition. (2) Brainstem — PAG-RVM descending pathways that can inhibit or facilitate. (3) Cortex — attention, expectation, emotion, and meaning all shape the final experience. This is why the same injury can hurt differently on different days.

✦ Clinical Correlates — Where Drugs Act Periphery: NSAIDs, local anaesthetics, capsaicin. DRG: DRG stimulation, some sodium channel blockers. Dorsal horn: opioids, gabapentinoids, ketamine, alpha-2 agonists, local anaesthetics (neuraxial). Ascending tracts: surgical ablation (rare), spinal cord stimulation. Thalamus & cortex: opioids, TCAs, SNRIs, psychological therapies, neuromodulation. Understanding the pathway is understanding the targets.

Module 03 of 09 · Act I — The Alarm

Modulation & Perception

The brain does not passively receive pain. It modulates it — up or down. This is where the gate control theory lives, and where endogenous opioids do their work.

The Gate Control Theory

Proposed by Melzack and Wall (1965), the gate control theory states that non-noxious input can inhibit nociceptive transmission at the dorsal horn. This is why rubbing a painful area helps.

Aβ activation (touch, pressure, vibration) inhibits WDR neurons → closes the gate
Aδ/C activation (pain) excites WDR neurons → opens the gate
Descending modulation from the brainstem can also close the gate
Clinical applications: TENS, massage, acupuncture, rubbing a bumped elbow

Descending Modulation — The Brain's Own Analgesia

The brainstem contains powerful descending pathways that can suppress nociceptive transmission at the dorsal horn. This is the basis of stress-induced analgesia — the soldier who doesn't feel a wound until the battle is over.

The Key Players

Structure	Role	Neurotransmitter
Periaqueductal grey (PAG)	Receives input from cortex, amygdala, hypothalamus; activates RVM	Opioids (endorphins, enkephalins)
Rostroventromedial medulla (RVM)	Projects to dorsal horn; can inhibit or facilitate	Serotonin, noradrenaline
Nucleus raphe magnus (NRM)	Serotonergic inhibition of dorsal horn	5-HT
Locus coeruleus	Noradrenergic inhibition	Noradrenaline
Dorsolateral funiculus	Descending pathway to dorsal horn	Serotonin, noradrenaline

Descending Inhibition vs Facilitation The RVM can both inhibit and facilitate pain. Under normal conditions, inhibition predominates. In chronic pain states, the balance shifts toward facilitation — the descending system becomes pronociceptive. This is one mechanism of central sensitisation and explains why chronic pain is not just "more acute pain."

Endogenous Opioid System

Peptide	Precursor	Primary Receptor	Location
β-Endorphin	POMC	μ (MOR)	Pituitary, hypothalamus, PAG
Enkephalins	Proenkephalin	δ (DOR)	Dorsal horn, brainstem, adrenal medulla
Dynorphins	Prodynorphin	κ (KOR)	Dorsal horn, hypothalamus, hippocampus
Endomorphins	—	μ (MOR)	Brain, spinal cord
Nociceptin/orphanin FQ	Prepronociceptin	NOP	Brain, spinal cord; modulates pain and stress

Opioid Receptor Effects

Receptor	Effect	Clinical Relevance
μ (MOR)	Analgesia, respiratory depression, euphoria, constipation, dependence	Target of morphine, fentanyl, most opioids
δ (DOR)	Analgesia, mood effects	Investigational targets; may reduce tolerance
κ (KOR)	Analgesia, dysphoria, sedation, diuresis	Target of butorphanol, nalbuphine; dysphoria limits use
NOP	Modulates pain, anxiety, stress	Investigational; complex pharmacology

✦ Why Opioids Work — and Why They Sometimes Don't Exogenous opioids act on the same receptors as endogenous opioids. They inhibit neurotransmitter release (presynaptic) and hyperpolarise neurons (postsynaptic). In neuropathic pain, the system is altered — opioid responsiveness is reduced, and NMDA receptor activation drives central sensitisation. This is why neuropathic pain often requires adjuvants (gabapentinoids, TCAs, SNRIs, ketamine) rather than opioids alone.

Perception — The Conscious Experience

Perception is the final step: the integration of nociceptive input with context, emotion, memory, and expectation. It is subjective, private, and impossible to measure directly.

Sensory-discriminative: location, intensity, quality (S1, S2, insula)
Affective-motivational: unpleasantness, suffering (ACC, amygdala)
Cognitive-evaluative: meaning, threat, catastrophising (prefrontal cortex)
Behavioural: withdrawal, guarding, facial expression, vocalisation

McCaffery's Classic Definition "Pain is whatever the experiencing person says it is, existing whenever he says it does." This remains the most clinically useful definition — because pain cannot be objectively verified, and the patient's report is the gold standard.

Placebo and Nocebo — The Power of Expectation

Placebo analgesia: Real physiological effect — endogenous opioid release, dopamine activation in nucleus accumbens, prefrontal cortex modulation
Nocebo effect: Negative expectations increase pain — hyperalgesia, anxiety, increased side effects
Clinical relevance: How we frame treatment, communicate risk, and set expectations matters. Positive framing can enhance analgesia; negative framing can worsen it
Mechanism: Descending modulation via PAG-RVM pathway; placebo analgesia is partially reversed by naloxone

Module 04 of 09 · Act II — The Response

Classification of Pain

Nociceptive, neuropathic, nociplastic — three mechanistic categories. Each has a different pathophysiology, a different clinical signature, and a different treatment strategy.

The Three Mechanistic Descriptors (IASP) Nociceptive: pain arising from actual or threatened damage to non-neural tissue, due to activation of nociceptors.
Neuropathic: pain caused by a lesion or disease of the somatosensory nervous system.
Nociplastic: pain arising from altered nociception despite no clear evidence of actual or threatened tissue damage or disease of the somatosensory system.

The Three Types — At a Glance

Feature	Nociceptive	Neuropathic	Nociplastic
Cause	Tissue injury/inflammation	Nerve lesion/disease	Altered central processing
Quality	Aching, throbbing, sharp	Burning, shooting, electric	Variable, diffuse, deep
Distribution	Localised to injury	Neuroanatomically plausible	Widespread, non-dermatomal
Sensory signs	Hyperalgesia at site	Allodynia, hyperalgesia, numbness	Hyperalgesia, allodynia
Responds to NSAIDs?	✓ Yes	✗ Poor	✗ Poor
Responds to opioids?	✓ Yes	Partial	✗ Poor
First-line drugs	NSAIDs, paracetamol, opioids	Gabapentinoids, TCAs, SNRIs	Multimodal, neuromodulators
Examples	Post-op, arthritis, trauma	Diabetic neuropathy, PHN, radiculopathy	Fibromyalgia, IBS, chronic low back pain

Neuropathic Pain — Diagnostic Algorithm (NeuPSIG)

The NeuPSIG algorithm grades the certainty of neuropathic pain:

1 · History suggests nerve lesion

→

2 · Pain in neuroanatomically plausible distribution

→

3 · Signs of conduction loss or hypersensitivity

→

4 · Confirmatory test (if needed)

Possible neuropathic pain: Criteria 1 only
Probable neuropathic pain: Criteria 1 + 2 + 3
Definite neuropathic pain: Criteria 1 + 2 + 3 + 4

NeuPSIG Grading — Clinical Use The grading system is designed to enhance diagnostic certainty. A finding of probable neuropathic pain should prompt treatment according to neuropathic pain guidelines. The system is not intended for medico-legal purposes.

Acute vs Chronic Pain

Feature	Acute Pain	Chronic Pain
Duration	<3 months (usually <7 days)	>3 months
Function	Protective, adaptive	Maladaptive, no protective role
Mechanism	Nociceptive (usually)	Nociceptive, neuropathic, or nociplastic
Autonomic features	Tachycardia, hypertension, diaphoresis	Often absent
Psychological	Anxiety	Depression, catastrophising, fear-avoidance
Treatment	Analgesics, treat cause	Multidisciplinary, biopsychosocial
Response to opioids	Usually good	Variable; risk of OIH

Other Classifications

Category	Definition	Example
Somatic	From skin, muscle, bone, joint	Fracture, arthritis
Visceral	From internal organs	Angina, biliary colic
Referred	Perceived at site distant from origin	Cardiac → left arm
Breakthrough	Transient exacerbation on background controlled pain	Cancer pain on stable opioids
Incident	Predictable, movement-related	Post-thoracotomy cough
Phantom	Perceived in absent body part	Post-amputation
Central	From CNS lesion	Post-stroke pain, MS
Peripheral	From PNS lesion	Diabetic neuropathy, radiculopathy

✦ Mixed Pain — The Rule, Not the Exception Most chronic pain is mixed — components of nociceptive, neuropathic, and nociplastic mechanisms coexist. Low back pain with radiculopathy has both nociceptive (disc, facet) and neuropathic (nerve root) components. Treating only one mechanism often fails.

Module 05 of 09 · Act II — The Response

Assessment of Pain

If pain is subjective, how do we measure it? Through self-report, behavioural observation, and — in the uncommunicative patient — physiological surrogates.

The Primacy of Self-Report Pain assessment is always self-assessment, except when the patient cannot communicate (sedated, cognitively impaired, neonates). In those cases, behavioural tools are used — but they are surrogates, not substitutes.

Unidimensional Scales — Acute Pain

Scale	Method	Range	Strengths	Weaknesses
Visual Analogue Scale (VAS)	100 mm line; mark pain intensity	0–100 mm	Validated, quantifiable, sensitive	Requires vision and motor control; not useful in elderly or cognitively impaired
Numerical Rating Scale (NRS)	0–10 verbal or written	0–10	Quick, no equipment, correlates with VAS	Language barriers; unidimensional
Verbal Rating Scale (VRS)	None / Mild / Moderate / Severe	4-point	Simple, good for screening	Lacks discrimination
Faces Pain Scale	Series of faces	0–10	Useful in children ≥5 years, language-independent	Not useful in vision impairment
Wong-Baker FACES	6 faces	0–10	Widely used in paediatrics	Same limitations as Faces

Multidimensional Scales — Chronic Pain

Tool	Dimensions Assessed	Use
McGill Pain Questionnaire (MPQ)	Sensory, affective, evaluative, miscellaneous	Research; comprehensive pain quality assessment
Brief Pain Inventory (BPI)	Pain severity + functional interference	Chronic pain, cancer pain
Leeds Assessment of Neuropathic Symptoms and Signs (LANSS)	Neuropathic features	Screening for neuropathic pain
PainDETECT	Neuropathic features	Neuropathic pain screening
DN4	Neuropathic features	Neuropathic pain diagnosis
Pain Catastrophizing Scale (PCS)	Rumination, magnification, helplessness	Chronic pain; predicts outcomes

Assessment in the Uncommunicative Patient

Sedated, critically ill, or cognitively impaired patients cannot self-report. Behavioural tools are essential.

Tool	Population	Domains
CPOT (Critical-Care Pain Observation Tool)	ICU adults	Facial expression, body movements, muscle tension, compliance with ventilator
BPS (Behavioral Pain Scale)	ICU adults	Facial expression, upper limb movements, compliance with ventilator
PAINAD	Dementia	Breathing, negative vocalisation, facial expression, body language, consolability
FLACC	Children <3 years	Face, Legs, Activity, Cry, Consolability
NIPS (Neonatal Infant Pain Scale)	Neonates	Facial expression, cry, breathing, arms, legs, state of arousal
PIPP (Premature Infant Pain Profile)	Preterm infants	Gestational age, behavioural, physiological

Physiological Surrogates — Emerging Tools

Pupillometry: Pupil dilation reflects sympathetic activation; opioid effects cause miosis
Nociception Level (NOL) index: Multimodal index (heart rate, heart rate variability, photoplethysmography, skin conductance, temperature, accelerometry) — validated for intraoperative nociception monitoring
Analgesia Nociception Index (ANI): Based on heart rate variability; reflects parasympathetic tone
Skin conductance: Reflects sympathetic cholinergic activity
Pupillary Pain Index (PPI): Response to tetanic stimulation

⚠ These are Nociception Monitors, Not Pain Monitors NOL, ANI, and pupillometry measure nociception — the physiological response to noxious stimuli — not pain — the subjective experience. They are useful under general anaesthesia, where the patient cannot report pain. They do not replace self-report in the awake patient.

Functional Assessment in Chronic Pain

Pain interference: BPI, PROMIS Pain Interference
Disability: Oswestry Disability Index (low back), Neck Disability Index
Psychological: Pain Catastrophizing Scale (PCS), Tampa Scale of Kinesiophobia (TSK), PHQ-9 for depression, GAD-7 for anxiety
Sleep: Pittsburgh Sleep Quality Index (PSQI)
Global impression: PGIC (Patient Global Impression of Change)

✦ The Golden Rule of Pain Assessment Ask the patient to describe their pain in their own words. Listen for quality, location, radiation, timing, aggravating/relieving factors, and impact on function and sleep. A number on a scale is useful for tracking — but it does not capture the experience.

Module 06 of 09 · Act II — The Response

Pharmacology of Analgesia

Multimodal analgesia is the standard of care. Different drugs, different mechanisms, different sites — additive or synergistic effects, reduced side effects.

The WHO Analgesic Ladder

The WHO ladder remains the framework for cancer pain management. For non-cancer pain, the principle of multimodal analgesia applies — combining drugs with different mechanisms to maximise efficacy and minimise toxicity.

Non-Opioid Analgesics

Drug	Mechanism	Dose	Key Points
Paracetamol	Central COX inhibition; TRPA1 activation	1 g q6h IV/PO (max 4 g/day; reduce in hepatic impairment)	Opioid-sparing; hepatotoxic in overdose; IV form useful in NPO patients
NSAIDs (ibuprofen, diclofenac, ketorolac)	COX-1/COX-2 inhibition → ↓ prostaglandins	Variable; ketorolac 15–30 mg IV q6h	GI, renal, cardiovascular risks; avoid in CKD, PUD, cardiac disease
COX-2 inhibitors (celecoxib, parecoxib)	Selective COX-2 inhibition	Celecoxib 200 mg PO; parecoxib 40 mg IV	Less GI risk; cardiovascular risk still present
Dipyrone (metamizole)	COX inhibition + central effects	1–2 g IV/PO	Widely used outside US; risk of agranulocytosis (rare)

Opioid Analgesics

Drug	Equianalgesic IV Dose	Duration	Metabolism	Notes
Morphine	10 mg	3–4 h	Hepatic glucuronidation; M6G active (renal)	Histamine release; pruritus; renal accumulation
Fentanyl	100 μg	30–60 min	Hepatic CYP3A4	Rapid onset; chest wall rigidity with fast bolus
Remifentanil	100 μg (bolus)	3–5 min	Plasma esterases	Ultra-short; no accumulation; must transition to longer-acting opioid
Oxycodone	10 mg	3–4 h	Hepatic CYP2D6, CYP3A4	Good oral bioavailability; used in OIH rotation
Hydromorphone	1.5 mg	3–4 h	Hepatic glucuronidation	Potent; used in OIH rotation
Tramadol	100 mg	4–6 h	Hepatic CYP2D6 (active M1)	Weak μ agonist + SNRI; seizure risk; serotonin syndrome
Methadone	1 mg	24–36 h	Hepatic CYP3A4, CYP2B6	μ agonist + NMDA antagonist + SNRI; QT prolongation; complex titration
Buprenorphine	0.3 mg	6–8 h	Hepatic CYP3A4	Partial μ agonist + κ antagonist; ceiling effect on respiratory depression

⚠ Opioid-Induced Hyperalgesia (OIH) A paradoxical state where opioid therapy increases pain sensitivity. Presents with worsening pain despite escalating doses, burning allodynia, and poor functional improvement. Risk factors: high-dose opioids, rapid escalation, renal impairment, psychological stressors. Management: opioid rotation (switching to a different opioid), dose reduction, and addition of adjuvants.

Adjuvant Analgesics

Drug Class	Examples	Mechanism	Indication	Key Side Effects
Gabapentinoids	Gabapentin, pregabalin	α₂δ subunit of voltage-gated Ca²⁺ channels	Neuropathic pain, post-op	Sedation, dizziness, peripheral oedema
Tricyclic antidepressants	Amitriptyline, nortriptyline	Serotonin + noradrenaline reuptake inhibition; NMDA antagonism	Neuropathic pain, chronic pain	Anticholinergic effects, cardiac conduction delay
SNRIs	Duloxetine, venlafaxine	Serotonin + noradrenaline reuptake inhibition	Neuropathic pain, fibromyalgia	Nausea, hypertension, discontinuation syndrome
Ketamine	—	NMDA receptor antagonist	Acute pain, opioid tolerance, OIH	Dissociation, hallucinations, hypertension
Alpha-2 agonists	Clonidine, dexmedetomidine	Presynaptic α₂ receptor activation	Adjuvant in regional, ICU sedation	Bradycardia, hypotension, sedation
Topical agents	Lidocaine 5% patch, capsaicin	Local sodium channel block / TRPV1 depletion	Localised neuropathic pain	Local irritation; capsaicin causes burning
Corticosteroids	Dexamethasone	Anti-inflammatory; perineural	Post-op, cancer pain, nerve compression	Hyperglycaemia, immunosuppression

✦ Multimodal Analgesia — The Evidence Combining paracetamol + NSAID + opioid + regional technique provides superior analgesia with fewer opioid side effects compared to any single agent. This is the foundation of ERAS (Enhanced Recovery After Surgery) protocols. The goal is not to eliminate opioids, but to use them judiciously alongside other modalities.

Local Anaesthetics — Systemic Toxicity (LAST)

Maximum Doses (Single Injection) Lidocaine: 3 mg/kg (7 mg/kg with adrenaline) · Bupivacaine: 2 mg/kg (2.5 mg/kg with adrenaline)

Ropivacaine: ~3 mg/kg · Levobupivacaine: ~2 mg/kg · Always calculate BEFORE injection

LAST — Recognition and Management

Stage	Features
Prodromal	Circumoral tingling, metallic taste, tinnitus, dizziness, visual disturbance
Excitation	Muscle twitching, seizures, hypertension, tachycardia
Depression	CNS depression, coma, bradycardia, hypotension, ventricular arrhythmias, cardiac arrest

Stop injection immediately
Airway, 100% O₂, ventilation
Seizure control: benzodiazepines (midazolam 2–5 mg IV)
Cardiac arrest: Lipid emulsion 20% — 1.5 mL/kg bolus, then 0.25 mL/kg/min infusion; continue CPR; avoid vasopressin, calcium channel blockers, beta-blockers
Cardiopulmonary bypass for refractory cases

Module 07 of 09 · Act II — The Response

Regional Anaesthesia

The most effective analgesic technique available — blocking pain at its source, before it ever reaches the CNS.

Why Regional?

Superior analgesia: Dense block of nociceptive input before central sensitisation occurs
Opioid-sparing: Reduced systemic opioid requirements and side effects
Sympathetic block: Improved perfusion (useful in limb salvage)
Potential to reduce chronic postsurgical pain: Early, effective analgesia may prevent central sensitisation and CPSP development
Facilitates early mobilisation and recovery (ERAS protocols)

Neuraxial Blocks

Technique	Level	Drug	Duration	Key Points
Spinal (subarachnoid)	L2–3, L3–4, L4–5	Bupivacaine 0.5% (heavy/plain)	2–4 h	Rapid onset; profound block; risk of PDPH, hypotension
Epidural	Any level	Bupivacaine 0.125–0.25%	Continuous	Catheter allows titration; slower onset; risk of dural puncture
CSE (combined spinal-epidural)	—	Spinal dose + epidural catheter	Rapid onset + continuous	Best of both; used in obstetrics and major surgery
Caudal	Sacral hiatus	Bupivacaine 0.125–0.25%	2–4 h	Paediatric; perineal/inguinal surgery

Complications of Neuraxial Blocks

Complication	Incidence	Presentation	Management
Post-dural puncture headache (PDPH)	0.5–1% (epidural)	Postural headache 24–48h after	Hydration, caffeine, blood patch
Hypotension	Common	Sympathectomy	Fluids, vasopressors
Urinary retention	Common	Sacral block	Catheterisation if needed
Epidural haematoma	1:150,000–1:200,000	Back pain, progressive deficit	Emergency MRI, decompression
Epidural abscess	1:10,000–1:20,000	Fever, back pain, deficit	Antibiotics, drainage
Nerve injury	Rare	Persistent deficit	Neurology referral, rehabilitation

Peripheral Nerve Blocks

Block	Indication	Key Nerves	Notes
Interscalene	Shoulder surgery	C5–6 roots	Phrenic nerve block (100% ipsilateral hemidiaphragm paralysis) — avoid in severe respiratory disease
Supraclavicular	Upper limb	Brachial plexus trunks	Complete block; pneumothorax risk (rare with ultrasound)
Axillary	Forearm/hand	Brachial plexus cords	Spares musculocutaneous nerve sometimes
Femoral	Knee, femur	Femoral nerve	Quadriceps weakness — falls risk
Adductor canal	Knee (ACL, TKA)	Saphenous nerve	Motor-sparing (preserves quadriceps) — increasingly preferred over femoral
Sciatic	Foot, ankle, below knee	Sciatic nerve	Often combined with femoral/adductor canal
TAP block	Abdominal surgery	T6–L1	Fascial plane block; useful for laparotomy, Caesarean, hernia
Erector spinae plane	Thoracic/abdominal	Dorsal/ventral rami	Fascial plane; emerging evidence; opioid-sparing
Paravertebral	Thoracic surgery, rib fractures	Spinal nerves	Unilateral; comparable to epidural for thoracotomy

Continuous Perineural Catheters (CPNB)

Indication: Prolonged analgesia where single-shot block duration is insufficient — major limb surgery, rib fractures, complex regional pain
Advantages: Avoids rebound pain as single-shot block wears off; allows extended rehabilitation
Infusate: Low-concentration ropivacaine (0.1–0.2%) or bupivacaine (0.1–0.125%) — sensorimotor discrimination; minimal motor block
Complications: Catheter dislodgement, leakage, infection (rare), local anaesthetic toxicity

✦ The Rebound Pain Phenomenon When a single-shot peripheral nerve block wears off, patients may experience severe rebound pain — often worse than expected. This is thought to reflect the sudden return of nociceptive input after a period of complete blockade. Continuous catheters or multimodal analgesia with pre-emptive dosing can mitigate this.

Anticoagulation & Regional Anaesthesia

Drug	Timing for Neuraxial (ASRA)	Timing for Peripheral
LMWH (prophylactic)	≥12 h after last dose	Less risk; still observe guidelines
LMWH (therapeutic)	≥24 h	Consult guidelines
Warfarin	INR ≤1.4	INR ≤1.4
DOACs	72 h (or per renal function)	48–72 h
Clopidogrel	5–7 days	5–7 days
Aspirin	No need to stop (usually)	No need to stop

⚠ Neuraxial Block in Anticoagulated Patients Neuraxial techniques carry higher risk because bleeding occurs in a non-expansive space (spinal canal) — leading to epidural haematoma and potential permanent paralysis. Peripheral blocks are safer as bleeding can decompress into surrounding tissue. Always follow ASRA guidelines and document neurological examination before and after the block.

Module 08 of 09 · Act III — The Aftermath

The Aftermath — Chronic Pain

When the alarm doesn't switch off. Central sensitisation, chronic postsurgical pain, and the transition from acute to chronic — the most important frontier in pain medicine.

The Transition — Acute to Chronic

Acute pain is protective. Chronic pain is a disease. The transition involves peripheral and central sensitisation — maladaptive plasticity that outlives the original injury.

Tissue injury
Nociceptor activation

→

Peripheral sensitisation
Inflammatory soup

→

Central sensitisation
NMDA activation, glia

→

Descending facilitation
RVM pronociceptive

→

Chronic pain
Self-sustaining

Peripheral Sensitisation

Mechanism: Inflammatory mediators (prostaglandins, bradykinin, NGF, cytokines) reduce nociceptor threshold and increase responsiveness
Receptors upregulated: TRPV1, ASICs, Nav1.7, Nav1.8
Effect: Primary hyperalgesia — increased pain at the site of injury
Clinical example: Sunburned skin — normally innocuous warmth becomes painful

Central Sensitisation

Mechanism: Sustained nociceptive input → dorsal horn neurons become hyperexcitable
Key players: NMDA receptor activation, AMPA receptors, glial activation (microglia, astrocytes), proinflammatory cytokines
Effect: Secondary hyperalgesia (spread beyond injury), mechanical allodynia (light touch → pain), wind-up (progressive increase in response to repeated stimuli)
Clinical example: Post-herpetic neuralgia — pain persists long after the rash has healed

The NMDA Receptor — The Central Sensitisation Switch Under normal conditions, the NMDA receptor is blocked by Mg²⁺. Sustained depolarisation removes the Mg²⁺ block, allowing glutamate to activate the receptor. This triggers long-term potentiation (LTP) — a persistent increase in synaptic strength. This is why ketamine (NMDA antagonist) is used for opioid tolerance and OIH.

Chronic Postsurgical Pain (CPSP)

Definition Pain persisting ≥3 months after surgery, excluding other causes, with the pain either continuing from the acute post-op period or developing after a pain-free interval.

Incidence by Procedure

Procedure	CPSP Incidence	Risk Factors
Thoracotomy	30–40%	Intercostal nerve injury, rib retraction, drainage tubes
Mastectomy	20–30%	Axillary dissection, intercostobrachial nerve injury
Inguinal hernia repair	10–20%	Nerve entrapment, mesh, open vs laparoscopic
Amputation	50–80%	Pre-amputation pain, nerve section, phantom limb
Coronary bypass (CABG)	20–30%	Internal mammary harvest, sternotomy
Caesarean section	10–15%	Nerve entrapment, adhesions
Breast surgery (pooled)	35% any severity	Axillary dissection, radiotherapy, younger age

Prevention — The Evidence

Effective acute pain management: Early, sustained analgesia may reduce CPSP incidence
Regional anaesthesia: Epidural, paravertebral, and peripheral nerve blocks reduce CPSP after thoracotomy and major limb surgery
Multimodal analgesia: Ketamine, gabapentinoids, and NSAIDs may reduce central sensitisation
Psychological interventions: Pre-operative education, cognitive-behavioural techniques
Surgical technique: Nerve-sparing approaches reduce CPSP (e.g., intercostobrachial nerve preservation during breast surgery)
Limitations: Evidence is mixed; no single intervention reliably prevents CPSP

Neuropathic Pain — Mechanisms and Management

Mechanism	Location	Clinical Feature
Ectopic firing	Injured nerve	Spontaneous shooting pain
Central sensitisation	Dorsal horn	Allodynia, hyperalgesia
Sympathetic coupling	DRG, nerve	Sympathetically maintained pain (CRPS)
Deafferentation	CNS	Phantom limb pain, anaesthesia dolorosa
Descending facilitation	RVM	Widespread pain, poor opioid response

Pharmacological Management of Neuropathic Pain

Drug	Starting Dose	Titration	Maximum	NNT (approx)
Amitriptyline	10 mg nocte	10 mg weekly	125 mg	~3
Gabapentin	300 mg nocte	300 mg weekly to TDS	3600 mg/day	~6
Pregabalin	75 mg BD	75 mg weekly	600 mg/day	~6
Duloxetine	30 mg OD	30 mg weekly	120 mg/day	~5
Carbamazepine	100–200 mg OD	100–200 mg biweekly	1600 mg/day	~2 (trigeminal neuralgia)
Lidocaine 5% patch	1–3 patches	—	12h on/12h off	~4

⚠ Opioids in Neuropathic Pain Opioids have limited efficacy in neuropathic pain. They should be used only after first-line agents (gabapentinoids, TCAs, SNRIs) have failed, and always with a clear exit strategy. If not effective, wean off — do not escalate indefinitely.

Complex Regional Pain Syndrome (CRPS)

Feature	CRPS Type I	CRPS Type II
Cause	No identifiable nerve injury	Identifiable major nerve injury
Precipitant	Minor trauma, fracture, surgery	Nerve laceration, compression
Symptoms	Disproportionate pain, oedema, colour change, temperature change, sweating, motor changes	Same
Diagnosis	Budapest criteria	Budapest criteria + nerve lesion

Budapest Criteria for CRPS

Continuing pain disproportionate to any inciting event
At least one symptom in three of four categories: sensory, vasomotor, sudomotor/oedema, motor/trophic
At least one sign in two of four categories
No other diagnosis better explains the symptoms

Management

Early recognition — CRPS is easier to treat in the acute phase
Physiotherapy — graded motor imagery, desensitisation, mobilisation
Pharmacological: Gabapentinoids, TCAs, NSAIDs, bisphosphonates, ketamine
Interventional: Sympathetic blocks, spinal cord stimulation (SCS), intrathecal baclofen
Psychological: CBT, pain education

Nociplastic Pain — The Third Descriptor

Definition: Pain arising from altered nociception despite no clear evidence of actual or threatened tissue damage or disease of the somatosensory system
Features: Widespread, disproportionate to examination findings, often with fatigue, sleep disturbance, cognitive fog, and psychological distress
Examples: Fibromyalgia, irritable bowel syndrome, chronic low back pain, temporomandibular disorder, chronic pelvic pain
Mechanism: Central amplification, descending facilitation, altered brain connectivity, neuroinflammation
Treatment: Multidisciplinary — pain education, graded exercise, CBT, SNRIs, gabapentinoids, avoidance of opioids

The Biopsychosocial Model — The Only Model That Explains Chronic Pain Chronic pain is never purely biological. It is shaped by biological (sensitisation, genetics), psychological (catastrophising, anxiety, depression), and social (work, relationships, culture, compensation) factors. Effective treatment addresses all three. This is why multidisciplinary pain programs outperform single-modality interventions.

Interventional Options for Chronic Pain

Intervention	Indication	Mechanism
Epidural steroid injection	Radicular pain, spinal stenosis	Reduce inflammation at nerve root
Facet joint blocks / radiofrequency	Facet-mediated low back pain	Block or denervate medial branch nerves
Spinal cord stimulation (SCS)	Failed back surgery syndrome, CRPS, refractory neuropathic pain	Electrical stimulation of dorsal columns → gate control
Intrathecal drug delivery	Refractory cancer pain, spasticity	Direct delivery of opioids/baclofen to CSF
Nerve blocks / neurolysis	Cancer pain, neuralgia	Temporary or permanent nerve ablation
Dorsal root ganglion stimulation	Focal neuropathic pain	Stimulation at the DRG
Peripheral nerve stimulation (PNS)	Focal peripheral neuropathic pain	Electrical stimulation of peripheral nerve

The Opioid Epidemic — Lessons Learned

Overprescribing: Opioids were marketed as safe for chronic non-cancer pain — a claim not supported by evidence
Consequences: Addiction, overdose deaths, diversion, opioid-induced hyperalgesia
Current approach: Opioid stewardship — risk assessment, prescription monitoring, urine drug screening, functional goals, clear exit strategies
Principles: Opioids are for acute severe pain and cancer pain. For chronic non-cancer pain, they are rarely first-line and should be used with caution, if at all

The Aftermath — A Summary The alarm protects. The response resolves. But when the alarm doesn't switch off — when central sensitisation takes hold, when descending facilitation replaces inhibition, when the pain becomes self-sustaining — we have entered the aftermath. This is chronic pain. It is not "more acute pain." It is a different disease, requiring a different approach: multimodal, multidisciplinary, and grounded in the biopsychosocial model.

Assessment

Self-Assessment

Twenty-five questions across all modules — from basic physiology to advanced clinical reasoning. Click an option to reveal the explanation.

▸ Questions — click to answer