Pain: Pathophysiology and Management¶
Chapter 14 | Part 2 – Cardinal Manifestations & Presentation · Part 2 – Cardinal Manifestations & Presentation · Chapter 14
Key Clinical Points¶
- Pain is a dual experience consisting of both a sensation (tissue-destructive process) and an emotion (anxiety/fear).
- Primary afferent nociceptors (A-delta and C fibers) are required for pain perception; A-beta fibers do not produce pain in normal individuals.
- Sensitization occurs via peripheral inflammation (prostaglandins, bradykinin) and central spinal cord changes, leading to allodynia and hyperalgesia.
- Referred pain results from the convergence of visceral and somatic afferents on the same spinal neurons (convergence-projection hypothesis).
- Neuropathic pain is characterized by burning, tingling, or electric shock-like quality, often with spontaneous occurrence and allodynia.
- CRPS Type I involves no obvious nerve injury; CRPS Type II follows an identifiable nerve injury.
- NSAIDs (COX inhibitors) carry risks: nonselective inhibitors have GI/renal risks; COX-2 inhibitors have cardiovascular risks.
- Opioids act on mu-receptors; respiratory depression is the primary life-threatening risk, reversible with naloxone.
- Patient-Controlled Analgesia (PCA) provides small, repeated doses to maintain relief and allow for titration.
- Chronic pain management requires a multidisciplinary approach addressing both somatic and emotional factors.
DEFINITION & OVERVIEW¶
• Definition: An unpleasant sensation localized to a part of the body. • Dual Nature of Pain: ◦ Sensation: Described as a penetrating or tissue-destructive process (e.g., stabbing, burning, twisting, tearing, squeezing). ◦ Emotion: A bodily or emotional reaction (e.g., terrifying, nauseating, sickening). • Acute Pain Characteristics: ◦ Associated with behavioral arousal and a stress response. ◦ Physiological markers: Increased blood pressure, heart rate, pupil diameter, and plasma cortisol. ◦ Physical signs: Local muscle contraction (e.g., limb flexion, abdominal wall rigidity). • Function of the System: To protect the body and maintain homeostasis by detecting, localizing, and identifying tissue-damaging processes.
The Pain Sensory System¶
• Primary Afferent Nociceptors: Respond to intense stimuli; conduction in A-delta and C fiber axons is required for pain perception. ◦ Aβ fibers: Large diameter, myelinated; respond to light touch/movement; do not produce pain in normal individuals. ◦ Aδ fibers: Small diameter, myelinated; present in skin and deep somatic/visceral structures. ◦ C fibers: Unmyelinated; present in skin and deep somatic/visceral structures. • Sensory Triggers: Nociceptors respond to heat, intense cold, mechanical distortion (pinch), pH changes (acidic), and chemical irritants (ATP, serotonin, bradykinin, histamine). • TRPV1 (Vanilloid Receptor): Mediates perception of heat, acidic pH, endogenous mediators, and capsaicin.
ETIOLOGY & PATHOPHYSIOLOGY¶
• Peripheral Mechanisms: ◦ Silent Nociceptors: Afferents that are insensitive in non-inflamed tissue but become sensitive to mechanical stimuli in the presence of inflammatory mediators (low pH, prostaglandins, bradykinin). ◦ Neuroeffector Function: Release of substance P (11-amino-acid peptide), CGRP, and cholecystokinin. ◦ Substance P Effects: Potent vasodilator, causes mast cell degranulation, acts as a chemoattractant for leukocytes, and increases inflammatory mediator production.
Central Mechanisms¶
• Spinal Cord Processing: ◦ Primary afferents release glutamate (fast) and substance P/CGRP (slow/long-lasting). ◦ Release of potassium (K^+) and synthesis of prostaglandins (PGs) increase sensitivity to bradykinin (BK). • Referred Pain: ◦ Mechanism: Convergence-projection hypothesis. ◦ Process: Visceral and somatic afferents converge on the same spinal neurons → brain cannot distinguish source → pain is projected to a somatic site (e.g., diaphragm inflammation felt as shoulder pain). • Modulation Pathways: ◦ Descending Pathway: From hypothalamus, midbrain, and medulla; controls spinal dorsal horn neurons. ◦ Function: Can enhance or suppress pain; mediates placebo effect and opioid action. ◦ Circuitry: Thalamus projects to somatosensory cortex (discriminative: location, intensity) and anterior cingulate/insular cortex (affective: emotion).
Neuropathic & Sympathetically Maintained Pain¶
• Neuropathic Pain: ◦ Cause: Damage to peripheral or central nociceptive pathways (e.g., diabetic neuropathy, herpes zoster). ◦ Mechanism: Increased density of sodium channels in damaged fibers; spontaneous activity in spinal neurons. • Sympathetically Maintained Pain (CRPS): ◦ Type I: No obvious nerve injury (reflex sympathetic dystrophy). ◦ Type II: Identifiable nerve injury (posttraumatic neuralgia/causalgia). ◦ Mechanism: Damaged nociceptors acquire adrenergic sensitivity and are activated by sympathetic outflow.
CLINICAL FEATURES¶
• General Pain Characteristics: ◦ Intensity ≥ moderate → accompanied by anxiety and urge to escape. • Neuropathic Pain Features: ◦ Quality: Burning, tingling, or electric shock-like. ◦ Timing: Spontaneous occurrence or triggered by light touch. ◦ Hyperpathia: Exaggerated pain response to repeated innocuous stimuli. ◦ Allodynia: Pain from very light moving stimulus (e.g., 5% lidocaine patch used for postherpetic neuralgia). • CRPS Features: ◦ Location: Pain in or beyond the region of nerve innervation. ◦ Signs: Swelling, periarticular bone loss, and arthritic changes in distal joints.
DIFFERENTIAL DIAGNOSIS¶
• Nociceptive vs. Neuropathic: ◦ Nociceptive: Associated with tissue-destructive process and inflammation. ◦ Neuropathic: Burning/tingling, spontaneous occurrence, allodynia, hyperpathia. • CRPS Type I vs. Type II: ◦ Type I: No identifiable nerve injury. ◦ Type II: Identifiable nerve injury (posttraumatic).
DIAGNOSTIC APPROACH¶
- Identify Pain Type: Determine if pain is nociceptive (tissue damage) or neuropathic (nerve damage/dysfunction).
- Assess for Neuropathic Features: Look for burning, tingling, electric shock-like quality, and allodynia → suggests neuropathic pathway.
- Evaluate for Sympathetic Involvement: Identify swelling, periarticular bone loss, and arthritic changes → indicates CRPS.
- Determine Referral: Assess if pain location matches the site of injury or follows a convergence pattern (e.g., diaphragm → shoulder).
MANAGEMENT & TREATMENT¶
- Acute Pain Management: ◦ Primary Goal: Remove the cause; if not possible, use rapid analgesics (postoperative, burns, trauma, cancer).
- Nonnarcotic Analgesics: ◦ Acetylsalicylic acid: 650 mg PO q4h. ◦ Ibuprofen: 400 mg PO q4–6h OR 250–500 mg PO q12h. ◦ Fenoprofen: 200 mg PO q4–6h OR 25–50 mg PO q8h (Contraindicated in renal disease). ◦ Ketorolac: 15–60 mg IM/IV q4–6h OR 100–200 mg PO q12–24h. ◦ Valdecoxib: 10–20 mg PO q12–24h (Removed from U.S. market in 2005).
- Neuropathic Pain Management: ◦ Antidepressants: Tricyclics (e.g., Imipramine) and SNRIs (e.g., Duloxetine). ◦ Anticonvulsants: Carbamazepine (200–300 mg, 300 mg); Gabapentin (600–1200 mg, 150–600 mg). ◦ Topical: 5% lidocaine patch for postherpetic neuralgia with allodynia.
- Opioid Analgesics: ◦ Codeine: 30–60 mg q4h (IM/IV); 5–10 mg q4–6h (PO). ◦ Oxycodone ER: 10–40 mg q12h; 5 mg q4h. ◦ Morphine SR: 15–60 mg bid to tid; 1–2 mg q4h. ◦ Levorphanol: 2 mg q6–8h (IM/IV); 5–10 mg q6–8h (PO). ◦ Meperidine: 50–100 mg q3–4h (IM/IV); 300 mg q4h (PO) [Note: Normeperidine is toxic; not recommended]. ◦ Fentanyl: 25–100 μg/h OR 5–20 μg/h transdermal patch. ◦ Buprenorphine: 0.3 mg q6–8h (IM/IV); 50–100 mg q4–6h (PO).
- Patient-Controlled Analgesia (PCA): ◦ Delivers small, repeated doses to maintain pain relief and allow titration to optimal levels.
- Opioid Safety & Monitoring: ◦ Respiratory Depression: Primary life-threatening risk; treat with Naloxone. ◦ MME Thresholds: ◦ ≥50 M12/day (e.g., ≥50 mg hydrocodone; ≥33 mg oxycodone) → increase follow-up frequency, offer naloxone. ◦ >90 MME/day (e.g., >100 mg hydrocodone; >60 mg oxycodone) → avoid or justify with specialist referral.
Table 1: Drugs for Relief of Pain¶
• Nonnarcotic Analgesics: ◦ Acetylsalicylic acid: 650 mg PO q4h. ◦ Ibuprofen: 400 mg PO q4–6h; 250–500 mg PO q12h. ◦ Fenoprofen: 200 mg PO q4–6h; 25–50 mg PO q8h. ◦ Ketorolac: 15–60 mg IM/IV q4–6h; 100–200 mg PO q12–24h. ◦ Valdecoxib: 10–20 mg PO q12–24h. • Narcotic Analgesics: ◦ Codeine: 30–60 mg q4h (IM/IV); 5–10 mg q4–6h (PO). ◦ Oxycodone ER: 10–40 mg q12h; 5 mg q4h. ◦ Morphine SR: 15–60 mg bid to tid; 1–2 mg q4h. ◦ Levorphanol: 2 mg q6–8h (IM/IV); 5–10 mg q6–8h (PO). ◦ Meperidine: 50–100 mg q3–4h (IM/IV); 300 mg q4h (PO). ◦ Fentanyl: 25–100 μg/h; 5–20 μg/h. ◦ Buprenorphine: 0.3 mg q6–8h (IM/IV); 50–100 mg q4–6h (PO).
Table 2: Conditions Responding to Tricyclic Antidepressants¶
• Conditions: Postherpetic neuralgia, Diabetic neuropathy, Fibromyalgia, Tension headache, Migraine headache, Rheumatoid arthritis, Chronic low back pain, Cancer, Central poststroke pain.
Table 3: Guidelines for Chronic Opioid Therapy (COT)¶
• Patient Selection: Assess risk of substance abuse/addiction; trial if pain is moderate/severe and impacts quality of life. ◦ Informed Consent: Discuss goals, risks, and alternatives. ◦ Initiation & Titration: Individualize based on health status and prior exposure. ◦ Monitoring: Periodically assess pain intensity, function, and adherence (urine drug screens if high risk).
Table 4: CDC Checklist for Prescribing Opioids¶
• Initial Assessment: Set goals; ensure nonopioid therapies optimized; check PDMP/urine drug screens; assess baseline via PEG scale. ◦ Follow-up: Initial reassessment 1–4 weeks; routine ≤3 months. ◦ Dosage Limits (MME): ◦ ≥50 MME/day: Increase follow-up frequency, offer naloxone. ◦ >90 MME/day: Avoid or justify with specialist referral.
KEY PEARLS & CLINICAL TRAPS¶
• Nociception vs. Pain: Nociception is the physiological detection of a stimulus; pain is the subjective experience (sensation + emotion). ◦ Clinical Trap: Do not assume all pain is nociceptive; burning/tingling suggests neuropathic pathways. • The Role of Substance P: Acts as a vasodilator and mediator for mast cell degranulation, contributing to 'secondary activation' and spread of inflammation. • Reflexive Safety: Naloxone is the specific antidote for opioid-induced respiratory depression. • Opioid Stewardship: Follow MME guidelines strictly; ≥50 MME/day requires increased monitoring and naloxone availability. ◦ MME Calculation: ◦ ≥50 MME/day (e.g., ≥50 mg hydrocodone; ≥33 mg oxycodone) → increase follow-up frequency, offer naloxone. ◦ >90 MME/day (e.g., >100 mg hydrocodone; >60 mg oxycodone) → avoid or justify with specialist referral.
Reference Tables¶
TABLE 14-1 Drugs for Relief of Pain¶
Harrison's 22e, p.97
| GENERIC NAME | DOSE, mg | INTERVAL | COMMENTS | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Nonnarcotic Analgesics: Usual Doses and Intervals | |||||||||||
| Acetylsalicylic acid | 650 PO | q4h | Enteric-coated preparations available | ||||||||
| 650 PO | q4h | ||||||||||
| Ibuprofen | 400 PO | q4–6h | Available without prescription | ||||||||
| 250–500 PO | q12h | ||||||||||
| Fenoprofen | 200 PO | q4–6h | Contraindicated in renal disease | ||||||||
| 25–50 PO | q8h | ||||||||||
| Ketorolac | 15–60 IM/IV | q4–6h | Available for parenteral use | ||||||||
| 100–200 PO | q12–24h | ||||||||||
| Valdecoxib | 10–20 PO | q12–24h | Removed from U.S. market in 2005 | ||||||||
| GENERIC NAME | PARENTERAL DOSE, mg | PO DOSE, mg | COMMENTS | ||||||||
| Narcotic Analgesics: Usual Doses and Intervals | |||||||||||
| Codeine | 30–60 q4h | 30–60 q4h | Nausea common | ||||||||
| — | 5–10 q4–6h | ||||||||||
| Oxycodone extended-release | — | 10-40 q12h | Oral extended-release tablet; high potential for misuse | ||||||||
| 5 q4h | 30 q4h | ||||||||||
| Morphine sustained release | — | 15–60 bid to tid | Oral slow-release preparation | ||||||||
| 1–2 q4h | 2–4 q4h | ||||||||||
| Levorphanol | 2 q6–8h | 4 q6–8h | Longer acting than morphine sulfate; absorbed well PO | ||||||||
| 5–10 q6–8h | 5–20 q6–8h | ||||||||||
| Meperidine | 50–100 q3–4h | 300 q4h | Poorly absorbed PO; normeperidine is a toxic metabolite; routine use of this agent is not recommended |
||||||||
| — | 1–2 q4h | ||||||||||
| Fentanyl | 25–100 μg/h | — | 72-h transdermal patch | ||||||||
| 5–20 μg/h | |||||||||||
| Buprenorphine | 0.3 q6–8h | Parenteral administration | |||||||||
| — | 50–100 q4–6h | ||||||||||
| GENERIC NAME | UPTAKE BLOCKADE | SEDATIVE POTENCY |
ANTICHOLINERGIC POTENCY |
ORTHOSTATIC HYPOTENSION |
CARDIAC ARRHYTHMIA |
AVERAGE DOSE, mg/d |
RANGE, mg/d |
||||
| 5-HT | NE | ||||||||||
| Antidepressantsa | |||||||||||
| Doxepin | ++ | + | High | Moderate | Moderate | Less | 200 | 75–400 | |||
| ++++ | ++ | High | Highest | Moderate | Yes | 150 | |||||
| Imipramine | ++++ | ++ | Moderate | Moderate | High | Yes | 200 | 75–400 | |||
| +++ | ++ | Moderate | Moderate | Low | Yes | 100 | |||||
| Desipramine | +++ | ++++ | Low | Low | Low | Yes | 150 | 50–300 | |||
| +++ | ++ | Low | None | None | No | 150 | |||||
| Duloxetine | +++ | +++ | Low | None | None | No | 40 | 30–60 | |||
| GENERIC NAME | PO DOSE, mg | INTERVAL | COMMENTS | ||||||||
| Anticonvulsants and Antiarrythmicsa | |||||||||||
| Carbamazepine | 200–300 | q6h | Rare aplastic anemia, GI irritation, hepatoitoxicity | ||||||||
| 300 | bid | ||||||||||
| Gabapentinb | 600–1200 | q8h | Dizziness, GI irritation; useful in trigeminal neuralgia | ||||||||
| 150–600 | bid |
TABLE 14-2 Painful Conditions That Respond to Tricyclic Antidepressants Postherpetic neuralgia a Diabetic neuropathy a…¶
Harrison's 22e, p.100
- Postherpetic neuralgiaa
Diabetic neuropathya
Fibromyalgiaa
Tension headachea
Migraine headachea
Rheumatoid arthritisa,b
Chronic low back painb
Cancer
Central poststroke pain
TABLE 14-3 Guidelines for Selecting and Monitoring Patients Receiving Chronic Opioid Therapy (COT) for the Treatment of…¶
Harrison's 22e, p.101
- Patient Selection
- • Conduct a history, physical examination, and appropriate testing, including an
assessment of risk of substance abuse, misuse, or addiction.
• Consider a trial of COT if pain is moderate or severe, pain is having an adverse
impact on function or quality of life, and potential therapeutic benefits
outweigh potential harms.
• A benefit-to-harm evaluation, including a history, physical examination, and
appropriate diagnostic testing, should be performed and documented before
and on an ongoing basis during COT. - Informed Consent and Use of Management Plans
- • Informed consent should be obtained. A continuing discussion with the
patient regarding COT should include goals, expectations, potential risks, and
alternatives to COT.
• Consider using a written COT management plan to document patient and
clinician responsibilities and expectations and assist in patient education. - Initiation and Titration
- • Initial treatment with opioids should be considered as a therapeutic trial to
determine whether COT is appropriate.
• Opioid selection, initial dosing, and titration should be individualized according
to the patient’s health status, previous exposure to opioids, attainment of
therapeutic goals, and predicted or observed harms. - Monitoring
- • Reassess patients on COT periodically and as warranted by changing
circumstances. Monitoring should include documentation of pain intensity and
level of functioning, assessments of progress toward achieving therapeutic
goals, presence of adverse events, and adherence to prescribed therapies.
• In patients on COT who are at high risk or who have engaged in aberrant drug-
related behaviors, clinicians should periodically obtain urine drug screens or
other information to confirm adherence to the COT plan of care.
• In patients on COT not at high risk and not known to have engaged in aberrant
drug-related behaviors, clinicians should consider periodically obtaining urine
drug screens or other information to confirm adherence to the COT plan
of care.
TABLE 14-4 Centers for Disease Control and Prevention Checklist for Prescribing Opioids for Chronic Pain
- For Primary Care Providers Treating Adults (18+) with Chronic Pain
≥3 Months, Excluding Cancer, Palliative, and End-of-Life Care - CHECKLIST
- WHEN CONSIDERING LONG-TERM OPIOID THERAPY
• Set realistic goals for pain and function based on diagnosis (e.g., walk around
the block).
• Check that nonopioid therapies tried and optimized.
• Discuss benefits and risks (e.g., addiction, overdose) with patient.
• Evaluate risk of harm or misuse.
• Discuss risk factors with patient.
• Check prescription drug monitoring program (PDMP) data.
• Check urine drug screen.
• Set criteria for stopping or continuing opioids.
• Assess baseline pain and function (e.g., Pain, Enjoyment, General Activity
[PEG] scale).
• Schedule initial reassessment within 1–4 weeks.
• Prescribe short-acting opioids using lowest dosage on product labeling;
match duration to scheduled reassessment.
IF RENEWING WITHOUT A PATIENT VISIT
• Check that return visit is scheduled ≤3 months from last visit.
WHEN REASSESSING AT A PATIENT VISIT
• Continue opioids only after confirming clinically meaningful improvements in
pain and function without significant risks or harm.
• Assess pain and function (e.g., PEG); compare results to baseline.
• Evaluate risk of harm or misuse:
• Observe patient for signs of oversedation or overdose risk. If yes: Taper dose.
• Check PDMP.
• Check for opioid use disorder if indicated (e.g., difficulty controlling use).
If yes: Refer for treatment.
• Check that nonopioid therapies optimized. Determine whether to continue,
adjust, taper, or stop opioids.
• Calculate opioid dosage morphine milligram equivalent (MME).
• If ≥50 MME/day total (≥50 mg hydrocodone; ≥33 mg oxycodone), increase
frequency of follow-up; consider offering naloxone.
• Avoid ≥90 MME/day total (≥90 mg hydrocodone; ≥60 mg oxycodone), or
carefully justify; consider specialist referral.
• Schedule reassessment at regular intervals (≤3 months).