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1. Introduction to Pain
Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage. It is both a physiological protective mechanism and a complex psychological phenomenon.
According to the International Association for the Study of Pain (IASP):
“Pain is an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage.”
Pain is not merely a symptom; it is a multidimensional experience involving:
- Sensory component
- Emotional component
- Cognitive interpretation
- Behavioral response
Effective pain management is essential because uncontrolled pain can:
- Impair recovery
- Increase morbidity
- Cause psychological distress
- Lead to chronic pain syndromes
2. Classification of Pain
Pain can be classified in multiple ways:
A. Based on Duration
1. Acute Pain
- Sudden onset
- Short duration
- Associated with tissue injury
- Protective in nature
Examples: Postoperative pain, trauma, burns
2. Chronic Pain
- Persists >3 months
- May not have identifiable cause
- Often associated with psychological components
Examples: Osteoarthritis, cancer pain, neuropathy
B. Based on Pathophysiology
1. Nociceptive Pain
Caused by activation of nociceptors.
Types:
- Somatic (bone, muscle, skin)
- Visceral (organs)
2. Neuropathic Pain
Caused by nerve injury or dysfunction. Examples:
- Diabetic neuropathy
- Post-herpetic neuralgia
3. Mixed Pain
Combination of nociceptive and neuropathic.
C. Based on Origin
- Cancer pain
- Postoperative pain
- Obstetric pain
- Musculoskeletal pain
- Inflammatory pain
3. Physiology of Pain
Pain transmission occurs in four stages:
- Transduction
- Transmission
- Perception
- Modulation
A. Transduction
Noxious stimulus converts into electrical impulse.
Chemical mediators involved:
- Prostaglandins
- Bradykinin
- Substance P
- Histamine
B. Transmission
Pain signals travel through:
- A-delta fibers (fast, sharp pain)
- C fibers (slow, dull pain)
Pathway: Peripheral nerve → Dorsal horn → Spinothalamic tract → Thalamus → Cortex
C. Perception
Pain is consciously experienced in:
- Somatosensory cortex
- Limbic system
D. Modulation
Descending inhibitory pathways release:
- Endorphins
- Enkephalins
- Serotonin
- Norepinephrine
4. Pain Assessment
Proper assessment is essential for effective management.
A. Pain Scales
1. Numeric Rating Scale (NRS)
0–10 scale
2. Visual Analog Scale (VAS)
Straight line 0–10
3. Wong-Baker Faces Scale
Used in children
4. FLACC Scale
Used in infants
B. Pain History (SOCRATES)
- Site
- Onset
- Character
- Radiation
- Associations
- Time course
- Exacerbating/Relieving factors
- Severity
5. Pharmacological Management of Pain
Pain management follows WHO Analgesic Ladder.
6. WHO Analgesic Ladder
Step 1 – Mild Pain
Non-opioids ± adjuvants
Step 2 – Moderate Pain
Weak opioids + non-opioids
Step 3 – Severe Pain
Strong opioids + non-opioids
7. Non-Opioid Analgesics
A. Paracetamol (Acetaminophen)
Mechanism:
- Inhibits central COX
- Antipyretic & analgesic
Dose:
- 500–1000 mg every 6–8 hours
Advantages:
- Safe in pregnancy
- Minimal GI irritation
Toxicity:
- Hepatotoxicity in overdose
B. NSAIDs
Examples:
- Ibuprofen
- Diclofenac
- Naproxen
- Aspirin
Mechanism:
- Inhibit COX → decrease prostaglandins
Adverse effects:
- Gastritis
- Renal impairment
- Bleeding
C. COX-2 Inhibitors
Example:
- Celecoxib
Advantages:
- Less gastric irritation
Risk:
- Cardiovascular events
8. Opioid Analgesics
Classification
Strong Opioids
- Morphine
- Fentanyl
- Oxycodone
Weak Opioids
- Tramadol
- Codeine
Mechanism
Bind to:
- Mu receptors
- Kappa receptors
- Delta receptors
Result:
- Inhibit pain transmission
- Alter perception
Adverse Effects
- Respiratory depression
- Constipation
- Nausea
- Sedation
- Dependence
9. Adjuvant Analgesics
Used especially in neuropathic pain.
Examples:
- Antidepressants (Amitriptyline, Duloxetine)
- Anticonvulsants (Gabapentin, Pregabalin)
- Corticosteroids
- Muscle relaxants
10. Management of Specific Types of Pain
A. Postoperative Pain
- Multimodal analgesia
- PCA (Patient Controlled Analgesia)
- Regional blocks
B. Cancer Pain
- WHO ladder
- Morphine gold standard
- Radiotherapy for bone pain
C. Neuropathic Pain
First-line:
- Gabapentin
- Pregabalin
- Duloxetine
Opioids less effective
D. Obstetric Pain
- Epidural anesthesia
- Nitrous oxide
- Paracetamol
E. Pediatric Pain
- Weight-based dosing
- Avoid codeine
- Use FLACC scale
11. Non-Pharmacological Management
- Physiotherapy
- Cognitive Behavioral Therapy
- Acupuncture
- TENS
- Relaxation techniques
- Heat & cold therapy
12. Interventional Pain Management
- Nerve blocks
- Epidural injections
- Radiofrequency ablation
- Spinal cord stimulation
13. Multimodal Analgesia
Combination of drugs with different mechanisms to:
- Improve efficacy
- Reduce opioid requirement
- Minimize side effects
14. Opioid Crisis & Safe Prescribing
- Risk assessment
- Prescription monitoring
- Avoid long-term high doses
- Use lowest effective dose
15. Special Populations
A. Elderly
- Reduced renal clearance
- Lower doses required
B. Pregnancy
- Avoid NSAIDs in 3rd trimester
- Paracetamol preferred
C. Renal Failure
- Avoid NSAIDs
- Use fentanyl cautiously
16. Complications of Poor Pain Management
- Chronic pain syndrome
- Depression
- Sleep disorders
- Reduced quality of life
17. Future of Pain Management
- Targeted biologics
- Gene therapy
- Personalized medicine
- Non-addictive analgesics
Part II – Neurobiology, Advanced Pharmacology & Clinical Protocols
1. Advanced Neurobiology of Pain
Pain is not a simple linear pathway — it is a complex neurochemical network involving peripheral receptors, spinal integration, cortical processing, and descending modulation systems.
1.1 Peripheral Sensitization
Occurs when inflammatory mediators lower the activation threshold of nociceptors.
Key Inflammatory Mediators:
- Prostaglandins
- Bradykinin
- Substance P
- TNF-α
- Interleukins (IL-1, IL-6)
- Nerve Growth Factor (NGF)
Mechanism:
- Increased sodium channel expression (Nav1.7, Nav1.8)
- Increased excitability
- Reduced threshold for firing
Clinical Correlation:
- Hyperalgesia
- Allodynia
- Post-surgical pain
1.2 Central Sensitization
Occurs in dorsal horn of spinal cord.
Mechanism:
- NMDA receptor activation
- Increased glutamate release
- Wind-up phenomenon
- Long-term potentiation (LTP)
Result:
- Amplified pain signals
- Persistent pain even after tissue healing
Seen in:
- Fibromyalgia
- Chronic low back pain
- Neuropathic pain
1.3 Pain Pathways (Detailed)
First-Order Neuron
- Peripheral receptor → Dorsal horn
Second-Order Neuron
- Crosses at spinal cord
- Ascends via Spinothalamic tract
Third-Order Neuron
- Thalamus → Somatosensory cortex
Parallel Pathways:
- Spinoreticular (emotional response)
- Spinomesencephalic (modulation)
2. Neurotransmitters in Pain
Excitatory
- Glutamate
- Substance P
- CGRP
Inhibitory
- GABA
- Glycine
- Endorphins
- Enkephalins
- Serotonin
- Norepinephrine
Clinical relevance: Many analgesics act by enhancing inhibitory pathways.
3. Advanced Pharmacology of Analgesics
3.1 Paracetamol – Deep Mechanism
Mechanism:
- Central COX inhibition (COX-3 theory)
- Inhibits prostaglandin synthesis in CNS
- Activates descending serotonergic pathways
Toxicity Mechanism:
- Converted to NAPQI (toxic metabolite)
- Detoxified by glutathione
- Overdose → hepatic necrosis
Antidote:
- N-Acetylcysteine (NAC)
3.2 NSAIDs – Molecular Level
Mechanism:
- Block COX-1 and COX-2
- Reduce prostaglandins (PGE2)
COX-1:
- Gastric protection
- Platelet aggregation
- Renal blood flow
COX-2:
- Inflammation
- Pain
- Fever
Adverse Effects:
- GI bleeding
- Acute kidney injury
- Fluid retention
- Hypertension
Contraindications:
- Peptic ulcer
- CKD
- Heart failure
3.3 Opioids – Advanced Pharmacodynamics
Receptors:
- Mu (μ) → Analgesia, respiratory depression
- Kappa (κ) → Spinal analgesia
- Delta (δ) → Modulation
Cellular Mechanism:
- Gi protein coupled receptor
- ↓ cAMP
- ↓ Calcium influx
- ↑ Potassium efflux
- Hyperpolarization
Tolerance Mechanism:
- Receptor desensitization
- Downregulation
- NMDA activation
Dependence Mechanism:
- Adaptive neurochemical changes
- Withdrawal upon cessation
3.4 Tramadol – Dual Mechanism
- Weak μ agonist
- Serotonin & norepinephrine reuptake inhibition
Risk:
- Seizures
- Serotonin syndrome
3.5 Neuropathic Pain Drugs – Deep Pharmacology
A. Gabapentin / Pregabalin
Mechanism:
- Bind α2δ subunit of voltage-gated calcium channels
- Reduce glutamate release
Indications:
- Diabetic neuropathy
- Postherpetic neuralgia
- Fibromyalgia
Side effects:
- Dizziness
- Weight gain
- Sedation
B. Antidepressants
TCAs (Amitriptyline)
- Block serotonin & norepinephrine reuptake
- Sodium channel blockade
SNRIs (Duloxetine)
- Dual reuptake inhibition
- Better tolerated than TCAs
4. Multimodal Analgesia – Deep Concept
Principle: Use drugs with different mechanisms to achieve additive or synergistic effect.
Example Postoperative Protocol:
- Paracetamol + NSAID + Opioid PRN
- Regional block
Advantages:
- Reduced opioid consumption
- Faster recovery
- Less adverse effects
5. Interventional Pain Management – Advanced
5.1 Nerve Blocks
Types:
- Peripheral nerve blocks
- Epidural blocks
- Paravertebral blocks
Drugs used:
- Lidocaine
- Bupivacaine
- Ropivacaine
Mechanism:
- Sodium channel blockade
- Prevent nerve conduction
5.2 Epidural Analgesia
Indications:
- Labor pain
- Major abdominal surgery
Benefits:
- Excellent analgesia
- Reduced systemic opioid use
Complications:
- Hypotension
- Urinary retention
- Rare neurological injury
5.3 Spinal Cord Stimulation
Mechanism:
- Gate control theory
- Electrical stimulation of dorsal columns
Used in:
- Failed back surgery syndrome
- Complex regional pain syndrome
6. Cancer Pain – Advanced Approach
Types:
- Bone pain
- Visceral pain
- Neuropathic pain
Management:
- WHO ladder
- Bisphosphonates for bone metastasis
- Radiotherapy
- Nerve blocks
Morphine remains gold standard.
7. Chronic Pain Syndromes
A. Fibromyalgia
- Central sensitization
- Treated with SNRIs, pregabalin
B. Complex Regional Pain Syndrome
- Severe neuropathic pain
- Sympathetic block may help
8. Psychological Aspects of Pain
Pain perception influenced by:
- Anxiety
- Depression
- Fear
- Cultural background
Management includes:
- Cognitive behavioral therapy
- Mindfulness
- Biofeedback
9. Ethical and Legal Aspects
- Informed consent
- Opioid agreements
- Prescription monitoring
- Avoid overprescribing
10. Emerging Therapies
- Monoclonal antibodies against NGF
- Gene therapy targeting sodium channels
- Cannabinoids
- Ketamine (NMDA antagonist)
11. Ketamine in Pain
Mechanism:
- NMDA receptor blockade
- Prevents central sensitization
Uses:
- Refractory neuropathic pain
- Opioid-resistant pain
12. Palliative Pain Care
Goals:
- Comfort
- Dignity
- Quality of life
Principles:
- Around-the-clock dosing
- Breakthrough pain management
- Psychological support
Molecular & Genetic Basis of Pain
1. Molecular Basis of Nociception
Pain begins at the molecular level in specialized sensory neurons called nociceptors.
These receptors respond to:
- Mechanical stimuli
- Thermal stimuli
- Chemical stimuli
- Inflammatory mediators
1.1 Ion Channels in Pain Transmission
Ion channels are critical in pain signaling.
A. Voltage-Gated Sodium Channels (Nav)
Important subtypes:
- Nav1.7
- Nav1.8
- Nav1.9
Role:
- Initiate and propagate action potentials
Clinical Relevance:
- Nav1.7 mutation → congenital insensitivity to pain
- Overexpression → chronic pain syndromes
Emerging therapy:
- Selective Nav1.7 blockers under research
B. TRP Channels (Transient Receptor Potential)
Types:
- TRPV1 → activated by heat & capsaicin
- TRPM8 → cold sensation
- TRPA1 → chemical irritants
TRPV1 activation causes:
- Burning pain
- Neurogenic inflammation
Capsaicin cream works by:
- Depleting substance P
- Desensitizing nociceptors
C. Calcium Channels
Particularly:
- N-type calcium channels
Blocked by:
- Ziconotide (intrathecal drug)
Effect:
- Reduces neurotransmitter release
- Used in severe refractory pain
2. Genetic Factors in Pain Sensitivity
Pain perception varies significantly among individuals.
2.1 Genetic Polymorphisms
A. COMT Gene
Encodes catechol-O-methyltransferase.
Low activity variants:
- Increased pain sensitivity
- Reduced dopamine breakdown
B. OPRM1 Gene
Encodes μ-opioid receptor.
Certain variants:
- Alter opioid response
- Affect morphine requirement
C. SCN9A Gene
Encodes Nav1.7 channel.
Mutations cause:
- Erythromelalgia (extreme burning pain)
- Congenital insensitivity to pain
3. Epigenetics & Chronic Pain
Chronic pain involves:
- DNA methylation changes
- Histone modification
- Altered gene expression
Persistent inflammation → long-term gene expression changes → chronic sensitization.
This explains why chronic pain may persist even after tissue healing.
4. Neuroinflammation
Microglia activation in spinal cord releases:
- TNF-α
- IL-1β
- IL-6
These amplify pain signaling.
Microglial inhibitors are being studied as future therapies.
5. Wind-Up Phenomenon
Repeated C-fiber stimulation causes:
- Progressive increase in dorsal horn neuron firing
- NMDA receptor activation
- Central sensitization
Clinically seen in:
- Chronic back pain
- Fibromyalgia
Ketamine blocks this mechanism.
6. Role of Glial Cells
Earlier thought to be passive support cells.
Now known to:
- Modulate pain
- Release inflammatory cytokines
- Contribute to neuropathic pain
Targeting glial activation is an emerging therapeutic strategy.
7. Pain Memory
Chronic pain can create a “memory” in neural circuits.
Mechanism:
- Long-term potentiation (LTP)
- Persistent NMDA activation
Similar to mechanisms involved in learning and memory.
This explains:
- Pain persistence without injury
- Phantom limb pain
8. Sex Differences in Pain
Women often report:
- Higher pain sensitivity
- Greater chronic pain prevalence
Possible mechanisms:
- Hormonal influences (estrogen)
- Immune system differences
- Microglial activation variations
9. Personalized Pain Medicine
Future approach includes:
- Genetic profiling
- Predicting opioid response
- Individualized dosing
- Risk stratification
Precision medicine will reduce:
- Adverse effects
- Addiction risk
- Ineffective treatment
10. Clinical Integration
Understanding molecular pain mechanisms helps in:
- Choosing NMDA antagonists
- Selecting calcium channel blockers
- Deciding adjuvant therapy
- Developing targeted analgesics
Pain is not just symptom — it is a molecular disease process in chronic states.
Ultra-Deep Opioid Pharmacology & Clinical Protocols
This section is written at advanced MBBS / MD / PharmD level depth.
1. Opioid Receptors – Molecular Structure & Function
Opioid receptors are G-protein coupled receptors (GPCRs) located in:
- Brain (periaqueductal gray, thalamus, limbic system)
- Spinal cord (dorsal horn)
- Peripheral sensory neurons
- Gastrointestinal tract
1.1 Types of Opioid Receptors
1. μ (Mu) Receptor
Responsible for:
- Supraspinal analgesia
- Respiratory depression
- Euphoria
- Physical dependence
- Constipation
Subtypes:
- μ1 → analgesia
- μ2 → respiratory depression & GI effects
2. κ (Kappa) Receptor
Produces:
- Spinal analgesia
- Dysphoria
- Sedation
Less respiratory depression compared to μ.
3. δ (Delta) Receptor
Role:
- Modulation of analgesia
- Emotional response to pain
2. Intracellular Signaling Mechanism
When opioid binds:
- Activates Gi protein
- ↓ Adenylate cyclase
- ↓ cAMP
- ↓ Calcium influx (presynaptic)
- ↑ Potassium efflux (postsynaptic)
Result:
- Neuronal hyperpolarization
- Reduced neurotransmitter release (Substance P, glutamate)
3. Pharmacokinetics of Major Opioids
3.1 Morphine
Bioavailability:
- Oral ~30%
Metabolism:
- Hepatic glucuronidation
- Morphine-6-glucuronide (active metabolite)
Half-life:
- 2–4 hours
Renal excretion → caution in CKD.
3.2 Fentanyl
- Highly lipid soluble
- Rapid onset
- Short duration IV
- Transdermal patch available
Advantage:
- No active metabolites
- Safe in renal impairment
3.3 Oxycodone
- Better oral bioavailability
- Used in moderate to severe pain
- Controlled-release formulations available
3.4 Tramadol
Dual action:
- Weak μ agonist
- SNRI effect
Risk:
- Seizures
- Serotonin syndrome
4. Opioid Equianalgesic Dosing
Used to switch between opioids safely.
Example (approximate oral equivalents):
- Morphine 30 mg
- Oxycodone 20 mg
- Hydromorphone 7.5 mg
When rotating: Reduce calculated dose by 25–50% due to incomplete cross-tolerance.
5. Opioid Tolerance
Mechanisms:
- Receptor desensitization
- Receptor internalization
- NMDA receptor activation
- Increased cAMP pathway activity
Clinical Feature:
- Increasing dose required for same effect
Management:
- Dose escalation
- Opioid rotation
- Add NMDA antagonist (ketamine)
6. Opioid Dependence vs Addiction
Physical Dependence
Normal physiological adaptation. Withdrawal occurs if stopped suddenly.
Addiction (Opioid Use Disorder)
Characterized by:
- Craving
- Loss of control
- Continued use despite harm
These are not the same.
7. Opioid Withdrawal
Symptoms:
- Lacrimation
- Rhinorrhea
- Sweating
- Diarrhea
- Muscle pain
- Anxiety
Onset: 6–24 hours (short-acting opioids)
Management:
- Methadone
- Buprenorphine
- Clonidine
8. Opioid-Induced Hyperalgesia
Paradoxical increase in pain sensitivity.
Mechanism:
- NMDA activation
- Central sensitization
Management:
- Reduce dose
- Rotate opioid
- Add ketamine
9. Opioid Adverse Effects – Deep Analysis
9.1 Respiratory Depression
Mechanism:
- Decreased sensitivity of medullary respiratory center to CO₂
Risk factors:
- Elderly
- Renal failure
- Combined sedatives
Antidote:
- Naloxone (0.04–0.4 mg IV)
9.2 Constipation
Mechanism:
- Reduced GI motility
- Increased sphincter tone
Management:
- Routine laxatives
- Methylnaltrexone (peripheral μ antagonist)
9.3 Nausea & Vomiting
Mechanism:
- Chemoreceptor trigger zone stimulation
Usually improves after few days.
9.4 Endocrine Effects
Chronic opioids cause:
- Hypogonadism
- Reduced testosterone
- Decreased libido
10. Opioid Prescribing Protocol (Clinical)
Step 1: Assess Pain
- Type (nociceptive vs neuropathic)
- Severity
- Functional impact
Step 2: Risk Assessment
Screen for:
- Substance abuse history
- Psychiatric disorders
Use tools:
- Opioid risk tool (ORT)
Step 3: Start Low, Go Slow
Initial dose:
- Lowest effective dose
- Immediate release preferred initially
Step 4: Monitoring
Assess:
- Pain relief
- Function improvement
- Adverse effects
- Aberrant behaviors
Step 5: Reassess Regularly
Continue only if:
- Functional benefit
- No serious harm
11. Special Clinical Situations
A. Renal Failure
Avoid:
- Morphine (metabolite accumulation)
Prefer:
- Fentanyl
- Buprenorphine
B. Liver Failure
Use caution:
- Reduced metabolism
- Dose adjustment required
C. Elderly
- Lower starting dose
- Increased sensitivity
- High fall risk
12. Opioid Rotation
Indicated when:
- Poor analgesia
- Severe side effects
- Tolerance
Steps:
- Calculate equivalent dose
- Reduce by 25–50%
- Monitor closely
13. Breakthrough Pain Management
Definition: Transient flare despite controlled baseline pain.
Treatment:
- Short-acting opioid
- 10–15% of total daily dose
14. Palliative Care Opioid Strategy
Principles:
- Around-the-clock dosing
- Oral preferred
- Titrate aggressively
- No maximum dose in cancer pain
Morphine remains gold standard.
15. Buprenorphine – Special Mention
Partial μ agonist.
Advantages:
- Ceiling effect on respiratory depression
- Used in opioid dependence
- Transdermal option
16. Methadone
Unique properties:
- μ agonist
- NMDA antagonist
- Long half-life
Risk:
- QT prolongation
Requires specialist supervision.
Neuropathic Pain – Complete Textbook-Level Chapter
Neuropathic pain is one of the most complex and challenging pain conditions in clinical medicine.
1. Definition
Neuropathic pain is:
Pain caused by a lesion or disease of the somatosensory nervous system.
Unlike nociceptive pain, it does not result from tissue injury alone, but from dysfunction of the nervous system itself.
2. Epidemiology
- Affects approximately 7–10% of the population
- Common in diabetes
- Common in cancer patients
- Increasing due to aging population
3. Causes of Neuropathic Pain
3.1 Peripheral Causes
- Diabetic neuropathy
- Postherpetic neuralgia
- HIV neuropathy
- Alcoholic neuropathy
- Chemotherapy-induced neuropathy
- Traumatic nerve injury
3.2 Central Causes
- Stroke (thalamic pain)
- Multiple sclerosis
- Spinal cord injury
- Parkinson’s disease
4. Pathophysiology – Deep Mechanism
Neuropathic pain develops due to abnormal processing at multiple levels.
4.1 Peripheral Nerve Injury Changes
After nerve injury:
- Ectopic spontaneous discharges occur
- Increased sodium channel expression
- Abnormal impulse generation
This causes:
- Burning pain
- Electric shock sensations
4.2 Central Sensitization
In dorsal horn:
- NMDA receptor activation
- Reduced inhibitory GABA activity
- Glial cell activation
Results in:
- Allodynia
- Hyperalgesia
4.3 Loss of Inhibitory Control
Normally descending pathways inhibit pain.
In neuropathic states:
- Reduced serotonin & norepinephrine inhibition
- Increased excitatory transmission
This explains why SNRIs are effective.
5. Clinical Features
Patients describe:
- Burning pain
- Electric shock sensation
- Tingling (paresthesia)
- Numbness
- Pins and needles
- Hypersensitivity to touch
6. Diagnostic Approach
6.1 Clinical Assessment
History:
- Duration
- Underlying disease
- Character of pain
Examination:
- Sensory deficits
- Allodynia
- Reduced reflexes
6.2 Screening Tools
- DN4 questionnaire
- PainDETECT
- LANSS scale
6.3 Investigations
Depending on cause:
- Blood glucose (diabetes)
- MRI (central causes)
- Nerve conduction studies
7. Management Principles
Important fact:
⚠ Opioids are less effective in neuropathic pain.
First-line drugs are adjuvant agents.
8. First-Line Pharmacological Treatment
8.1 Anticonvulsants
Gabapentin
Mechanism:
- Binds α2δ calcium channel subunit
- Reduces glutamate release
Dose:
- 300 mg at night → titrate up
Side effects:
- Sedation
- Dizziness
Pregabalin
More predictable absorption.
Dose:
- 75 mg twice daily
8.2 Antidepressants
Amitriptyline (TCA)
Mechanism:
- Blocks serotonin & norepinephrine reuptake
Dose:
- 10–25 mg at night
Side effects:
- Dry mouth
- Constipation
- QT prolongation
Duloxetine (SNRI)
Better tolerated.
Dose:
- 30–60 mg daily
Useful in:
- Diabetic neuropathy
- Fibromyalgia
9. Second-Line Drugs
- Tramadol
- Tapentadol
- Topical lidocaine patch
- Capsaicin patch
10. Third-Line & Refractory Options
- Strong opioids (carefully selected cases)
- Ketamine infusion
- Spinal cord stimulation
- Intrathecal pumps
11. Diabetic Neuropathy – Focused Section
Most common cause worldwide.
Mechanism:
- Chronic hyperglycemia
- Microvascular damage
- Oxidative stress
Management:
- Glycemic control
- Duloxetine
- Pregabalin
- Amitriptyline
Avoid NSAIDs (ineffective).
12. Postherpetic Neuralgia
Caused by: Varicella-zoster virus nerve damage.
Treatment:
- Gabapentin
- Lidocaine patch
- Capsaicin
Prevention:
- Early antiviral therapy
- Vaccination
13. Chemotherapy-Induced Neuropathy
Common agents:
- Vincristine
- Cisplatin
- Paclitaxel
Management:
- Dose modification
- Duloxetine
- Supportive care
14. Central Neuropathic Pain
Seen in:
- Stroke
- Multiple sclerosis
- Spinal cord injury
More resistant to treatment.
Often requires:
- Combination therapy
- Interventional techniques
15. Non-Pharmacological Treatment
- Physiotherapy
- TENS
- Cognitive Behavioral Therapy
- Mindfulness
- Occupational therapy
16. Interventional Techniques
- Nerve blocks
- Sympathetic block
- Spinal cord stimulation
Particularly useful in:
- Complex regional pain syndrome
17. Prognosis
Neuropathic pain:
- Often chronic
- Requires long-term management
- Rarely completely cured
Goal: Improve function and quality of life.
18. Key Clinical Pearls
- Burning pain suggests neuropathic origin
- Poor response to NSAIDs
- Combination therapy often needed
- Treat underlying cause
- Titrate slowly to avoid side effects
Comprehensive Cancer Pain & Palliative Pain Management
Cancer pain is one of the most significant causes of suffering worldwide. Effective management is a core responsibility of every clinician.
1. Overview of Cancer Pain
Approximately:
- 30–50% of cancer patients experience pain
- 70–90% in advanced disease
Pain may result from:
- Tumor invasion
- Treatment (chemotherapy, radiation, surgery)
- Metastasis (especially bone)
- Nerve compression
Cancer pain is often multifactorial.
2. Types of Cancer Pain
2.1 Nociceptive Pain
A. Somatic Pain
- Well localized
- Aching, throbbing
- Bone metastasis common cause
B. Visceral Pain
- Poorly localized
- Cramping, deep pressure
- Caused by organ distension
2.2 Neuropathic Cancer Pain
Due to:
- Tumor compressing nerves
- Chemotherapy-induced neuropathy
- Radiation-induced nerve damage
Burning, electric shock-like pain.
2.3 Breakthrough Pain
Definition: Sudden transient flare of pain despite controlled baseline pain.
Types:
- Incident pain (movement related)
- End-of-dose failure
- Spontaneous pain
3. WHO Analgesic Ladder – Foundation
The World Health Organization developed a 3-step ladder:
Step 1 – Mild Pain
Non-opioids ± adjuvants
Examples:
- Paracetamol
- NSAIDs
Step 2 – Moderate Pain
Weak opioids + non-opioids
Examples:
- Tramadol
- Codeine
Step 3 – Severe Pain
Strong opioids + non-opioids
Examples:
- Morphine
- Fentanyl
- Oxycodone
Adjuvants may be added at any step.
4. Morphine in Cancer Pain
Morphine remains the gold standard.
4.1 Dosing Strategy
Start:
- 5–10 mg oral immediate release every 4 hours
Titrate:
- Increase by 30–50% if pain uncontrolled
Once stable:
- Switch to sustained-release formulation
4.2 No Maximum Dose
In cancer pain: There is no ceiling dose for morphine (except side effects).
Dose is limited by:
- Sedation
- Respiratory depression
- Delirium
5. Management of Breakthrough Pain
Use short-acting opioid.
Dose:
- 10–15% of total daily opioid dose
Example: If patient takes 60 mg/day morphine: Breakthrough dose = 6–10 mg immediate release.
6. Bone Metastasis Pain
Very common in:
- Breast cancer
- Prostate cancer
- Lung cancer
Mechanism:
- Osteoclast activation
- Inflammatory mediators
- Microfractures
6.1 Treatment
- Opioids
- NSAIDs
- Bisphosphonates
- Denosumab
- Radiotherapy
Radiotherapy often gives dramatic relief.
7. Adjuvant Drugs in Cancer Pain
7.1 Corticosteroids
Useful in:
- Brain metastasis
- Spinal cord compression
- Liver capsule pain
Reduce:
- Edema
- Inflammation
7.2 Antidepressants & Anticonvulsants
For neuropathic component.
Examples:
- Duloxetine
- Pregabalin
7.3 Muscle Relaxants
For muscle spasm pain.
8. Interventional Techniques
8.1 Nerve Blocks
Example:
- Celiac plexus block (pancreatic cancer pain)
Provides significant visceral pain relief.
8.2 Intrathecal Pumps
Deliver:
- Morphine
- Ziconotide
Indicated when systemic opioids cause severe side effects.
9. Palliative Care Principles
Palliative care focuses on:
- Comfort
- Quality of life
- Symptom control
- Psychosocial support
It is not limited to end-of-life care.
10. Total Pain Concept
Described by Dame Cicely Saunders.
Pain has 4 dimensions:
- Physical
- Psychological
- Social
- Spiritual
Effective cancer pain management addresses all dimensions.
11. End-of-Life Pain Management
Principles:
- Aggressive symptom control
- Around-the-clock dosing
- Anticipatory prescribing
- Family counseling
Sedation may be considered in refractory suffering.
12. Opioid Side Effect Management in Cancer
Constipation
Always prescribe prophylactic laxative.
Nausea
Short-term antiemetics:
- Metoclopramide
- Ondansetron
Delirium
Evaluate for:
- Infection
- Dehydration
- Opioid toxicity
May require dose reduction or rotation.
13. Ethical Considerations
Important principle:
Doctrine of double effect.
If opioid relieves pain but may suppress respiration: It is ethically acceptable if intention is pain relief.
14. Barriers to Cancer Pain Control
- Fear of addiction
- Inadequate training
- Regulatory restrictions
- Cultural beliefs
Education improves outcomes.
15. Multidisciplinary Approach
Cancer pain care team may include:
- Oncologist
- Palliative physician
- Pain specialist
- Psychologist
- Nurse
- Social worker
16. Prognosis & Quality of Life
Adequate pain control:
- Improves sleep
- Improves appetite
- Enhances mobility
- Reduces depression
- Improves dignity
Pain control is a human right.
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