**Textbook:** Harrison’s Principles of Internal Medicine (21st Edition)  
**Chapter Number & Name:** Chapter 13 – Pain: Pathophysiology and Management  
**Topics Covered:**  
- Pain Sensory System (Peripheral & Central Mechanisms)  
- Pain Modulation  
- Neuropathic Pain  
- Acute Pain Treatment  
- Chronic Pain and Long-Term Management  
**Page Numbers:** 990–1015 (Approx.)  

Pain: Pathophysiology and Management

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INTRODUCTION

• Pain is the most common symptom leading patients to seek medical care.

• Plays a key protective role: detects, localizes, and identifies tissue-damaging processes.

• Dual nature: Both a sensory and emotional experience, usually accompanied by anxiety and the urge to avoid or stop the painful stimulus.

🟡 High-Yield: Acute pain triggers a stress response (↑ BP, ↑ HR, ↑ pupil dilation, ↑ cortisol) and often protective muscle contractions (e.g., limb flexion).

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THE PAIN SENSORY SYSTEM

Pain Definition

• An unpleasant sensation described as stabbing, burning, twisting, squeezing, etc.

• Often causes a strong emotional reaction (fear, nausea, terror).

• Moderate-to-severe pain → anxiety, autonomic changes (↑ BP, HR).

PERIPHERAL MECHANISMS

The Primary Afferent Nociceptor

• Peripheral nerves contain:

  • Aβ fibers: Large, myelinated → respond to light touch; do not produce pain in normal conditions.

  • Aδ fibers: Small, myelinated → respond to intense, potentially damaging stimuli → produce fast pain.

  • C fibers: Unmyelinated → slow, dull, burning pain.

• Nociceptors respond to multiple noxious stimuli (thermal, mechanical, chemical).

  • TrpV1 (vanilloid) receptor: Activated by heat, acidic pH, capsaicin → important in thermal pain detection.

🟡 High-Yield: Blocking conduction in Aδ and C fibers abolishes the ability to feel pain.

Sensitization

• Repeated or intense stimuli → lowered activation threshold for nociceptors → ↑ firing rate.

• Inflammatory mediators (BK, prostaglandins, nerve growth factor, leukotrienes) drive this process.

  • Peripheral sensitization: ↑ excitability of nerve terminals in injured tissues.

  • Central sensitization: ↑ excitability of dorsal horn neurons in the spinal cord.

• Clinical relevance:

  • Allodynia: Pain from normally non-painful stimuli (e.g., a gentle touch).

  • Hyperalgesia: Exaggerated pain response to a noxious stimulus.

  • “Sunburn” example: Light touch or warm water can cause severe pain in sensitized skin.

🔵 Clinical Pearl: Silent nociceptors in deep structures (e.g., viscera) can become activated during inflammation, leading to severe pain in organs normally insensitive to mechanical stimuli.

Nociceptor-Induced Inflammation

• Primary nociceptors release substance P, CGRP, etc., upon activation.

  • Substance P → vasodilation, mast cell degranulation, ↑ inflammatory mediator release.

  • Can worsen or spread local inflammation and pain sensitivity.

![▶️ Video Placeholder: “Mechanisms of Peripheral Sensitization (Illustrative Animation)”]

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CENTRAL MECHANISMS

The Spinal Cord and Referred Pain

• Primary afferent nociceptors enter via the dorsal root → synapse in the dorsal horn.

• Glutamate is the main excitatory neurotransmitter, with substance P and CGRP contributing to prolonged excitation.

• Convergence of visceral and somatic sensory fibers onto the same dorsal horn neurons → Referred Pain.

  • Example: Diaphragmatic irritation perceived as shoulder pain (C3–C5).

🔴 Exam Alert: Referred pain explains why heart ischemia can present as arm or jaw pain. Always consider convergence patterns in diagnosis.

Ascending Pathways for Pain

• Spinothalamic tract: Major contralateral pathway → from spinal cord → thalamus → cortex.

  • Interruption → permanent deficits in pain/temperature sensation.

• Thalamic projections → somatosensory cortex (location, intensity) & cingulate/insular cortex (emotional/unpleasant component).

Pain Modulation

• Pain intensity is not fixed → descending modulatory pathways from brain to spinal cord can enhance or suppress nociceptive signals.

  • Endogenous opioids (enkephalins, β-endorphin) + opioid receptors in midbrain and medulla → powerful analgesic effect.

  • Placebo effect mediated in part by the same descending opioidergic system.

🟡 High-Yield: Emotional states (e.g., battlefield, sports) + suggestion of relief → robust activation of descending pain-inhibitory circuits → significant analgesia.

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NEUROPATHIC PAIN

• Caused by damage or dysfunction in peripheral or central nociceptive pathways.

• Pain often described as burning, tingling, electric shock–like, sometimes triggered by light touch.

• Typically resistant to standard analgesics.

🔵 Clinical Pearl: Neuropathic pain often coexists with a sensory deficit in the same distribution (e.g., diabetic neuropathy, postherpetic neuralgia).

Sympathetically Maintained Pain (Complex Regional Pain Syndrome, CRPS)

• CRPS type II (causalgia): Spontaneous burning pain beyond the area of nerve injury, sometimes with swelling, bone changes.

• Early on, a sympathetic nerve block can relieve pain → suggests abnormal sympathetic–nociceptor coupling.

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TREATMENT OF ACUTE PAIN

🟡 High-Yield: Always treat the underlying cause if possible (e.g., fix a fracture), but rapid analgesia is essential to minimize distress and physiologic stress responses.

Nonopioid Analgesics

• Aspirin, Acetaminophen, NSAIDs

  • Inhibit cyclooxygenase (COX) → reduce prostaglandins → analgesic ± anti-inflammatory effect.

  • Effective for mild-to-moderate pain (headaches, musculoskeletal pain).

  • Side effects: GI irritation, possible renal impairment, ↑ BP, bleeding risk (especially nonselective NSAIDs).

  • COX-2 inhibitors (e.g., celecoxib) → less GI upset but ↑ cardiovascular risk.

Opioid Analgesics

• Most potent analgesics → mainstay for severe acute pain.

• Mechanism: Activate μ-opioid receptors in CNS → inhibit pain-transmission neurons, enhance descending inhibition.

• Common side effects: Nausea, vomiting, sedation, pruritus, constipation; respiratory depression is the most serious.

• Naloxone reverses opioid-induced side effects (especially respiratory depression).

• Patient-Controlled Analgesia (PCA): Allows patients to self-titrate IV opioids with preset limits → improved pain control, reduced risk of overdose.

🔴 Exam Alert: The most frequent mistake is prescribing inadequate opioid doses. Always reassess for adequate analgesia and titrate appropriately.

Opioid + COX Inhibitor Combinations

• Additive or synergistic analgesic effects with different mechanisms → lower doses and fewer side effects.

• Caution: Fixed-dose acetaminophen–opioid combos risk hepatotoxicity if escalated.

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CHRONIC PAIN

• Chronic pain can become a disease in itself, often with complex biologic and psychosocial components.

• Causes: Ongoing pathology (cancer, arthritis), persistent changes (nerve damage), or psychological conditions (depression, anxiety).

• Evaluation:

  • Carefully assess mood, sleep, daily function.

  • Rule out major depression.

  • Look for neuropathic clues (sensory loss, allodynia) or signs of sympathetic overactivity (swelling, color changes).

🔵 Clinical Pearl: A multidisciplinary approach (counseling, PT, medications, interventional procedures) often needed for chronic pain.

TREATMENT OF CHRONIC PAIN

1. Set Realistic Goals: Focus on function improvement (e.g., better mobility, return to work).

2. Multidisciplinary: Combine medications (analgesics, antidepressants, anticonvulsants), physical therapy, psychotherapy, and interventional procedures.

3. Behavioral Approaches: Mood assessment, cognitive-behavioral therapy if indicated.

Antidepressant Medications

• Tricyclic antidepressants (TCAs) (nortriptyline, desipramine) → analgesic at lower doses than needed for depression. Particularly good for neuropathic pain.

  • Side effects: Sedation, orthostatic hypotension, anticholinergic effects → caution in elderly.

• SNRIs (duloxetine, venlafaxine) → also effective for neuropathic pain, with fewer anticholinergic effects.

Anticonvulsants & Antiarrhythmics

• Help with lancinating or neuropathic pains.

  • Carbamazepine, gabapentin, pregabalin → reduce neuronal hyperexcitability in neuropathic pain.

• Systemic lidocaine or mexiletine → less commonly used (transient benefit, GI side effects).

Cannabinoids

• May modestly reduce pain intensity, especially for cancer- or chemotherapy-related pain and nausea. Variable efficacy and legal considerations apply.

Chronic Opioid Therapy

• Controversial for noncancer pain → risk of dependence, tolerance, opioid-induced hyperalgesia.

• If used, follow guidelines for patient selection, informed consent, risk stratification, and continuous monitoring.

• Long-acting opioids (methadone, extended-release morphine or oxycodone) or transdermal fentanyl → stable plasma levels.

  • Watch for sedation, constipation, and possible misuse.

🔵 Clinical Pearl: Opioid Rotation (switching from one opioid to another) can help reduce side effects and maintain analgesia in long-term therapy.

Treatment of Neuropathic Pain

1. Rapid relief + minimize side effects.

2. Topical lidocaine patches: For localized pain (e.g., postherpetic neuralgia with allodynia).

3. Anticonvulsants (gabapentin, pregabalin) or antidepressants (TCAs, SNRIs) → first-line.

4. Opioids → second- or third-line due to tolerance, sedation risk.

5. Mixed mechanism analgesics (tramadol, tapentadol) → partial opioid effect + NE reuptake inhibition.

6. Interventional procedures (e.g., spinal cord stimulation) for refractory cases.

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MERMAID DIAGRAM: BASIC ACUTE PAIN MANAGEMENT ALGORITHM

flowchart LR
    A[Patient in Acute Pain] --> B{Assess Cause & Severity}
    B -- Mild-Moderate --> C[Nonopioid Analgesics ± Adjuncts]
    B -- Severe --> D[Opioids ± Nonopioid]
    D --> E[PCA or IV Bolus if Needed]
    E --> F[Reassess Pain Control]
    F -- Adequate Relief --> G[Continue & Monitor]
    F -- Inadequate Relief --> H[Increase Dose or Add Adjuncts]

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SUMMARY TABLE: COMMON ANALGESICS

Class	Examples	Key Points
Nonopioids	Aspirin, NSAIDs, Acetaminophen	Good for mild-moderate pain, watch GI & renal side effects
Selective COX-2	Celecoxib	↓ GI toxicity vs. NSAIDs but ↑ CV risk
Weak Opioids	Codeine, Tramadol	For moderate pain; Tramadol also ↑ NE/5-HT
Strong Opioids	Morphine, Oxycodone, Hydromorphone	For severe pain; risk of sedation, respiratory depression, tolerance
Mixed Opioid	Tapentadol	Opioid agonist + NE reuptake inhibition
Adjuvant Agents	TCAs (Amitriptyline), SNRIs (Duloxetine)	Neuropathic pain relief, mood elevation
	Anticonvulsants (Gabapentin, Pregabalin)	Neuropathic pain with burning/lancinating characteristics

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REFERENCES (APA Style, Annotated)

• De Vita, M. J., et al. (2018). Association of cannabinoid administration with experimental pain in healthy adults: a systematic review and meta-analysis. JAMA Psychiatry, 75(11), 1118.

  — Summarizes controlled studies on cannabinoids and pain thresholds.

• Dowell, D., et al. (2016). CDC guideline for prescribing opioids for chronic pain—United States, 2016. JAMA, 315(15), 1624–1645.

  — Foundational guideline on opioid prescribing and monitoring.

• Finnerup, N. B., et al. (2015). Pharmacotherapy for neuropathic pain in adults: A systematic review and meta-analysis. Lancet Neurol, 14(2), 162–173.

  — Definitive review of first-line agents for neuropathic pain (TCAs, SNRIs, gabapentinoids).

• Jones, J., et al. (2023). Selective inhibition of NaV1.8 with VX-548 for acute pain. New Engl J Med, 389, 393–404.

  — Discusses emerging sodium-channel blockers for acute pain management.

• U.S. Department of Health and Human Services. (2019). Pain management best practices inter-agency task force report.

  — Multidisciplinary approach recommendations for chronic pain.

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🟡 High-Yield Takeaway:

• Pain is both sensory + emotional; treatment requires a holistic approach.

• Rapid, adequate analgesia is key in acute pain.

• In chronic pain, multidisciplinary strategies + addressing psychosocial factors yield the best outcomes.

[▶️ Video Placeholder: “Patient-Controlled Analgesia (PCA) Setup and Demonstration (Educational Resource)”]

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