Pain: Pathophysiology and Management¶
Chapter 14 | Part 2: Cardinal Manifestations and Presentation of Diseases
KEY CLINICAL POINTS¶
- Pain is both sensation and emotion, serving to protect the body by detecting and localizing tissue-damaging processes
- Peripheral and central sensitization lower nociceptor thresholds and enhance pain transmission, contributing to allodynia and hyperalgesia
- Neuropathic pain results from damage to peripheral or central nociceptive pathways and requires distinct treatment approaches
- Opioids remain the most potent analgesics but require careful patient selection, monitoring, and adherence to CDC guidelines due to addiction and overdose risks
- Multimodal analgesia combining NSAIDs, opioids, antidepressants, and anticonvulsants optimizes pain control while minimizing side effects
1. DEFINITION & OVERVIEW¶
Pain is an unpleasant sensation localized to a part of the body, often described in terms of tissue-destructive processes (stabbing, burning, twisting, tearing, squeezing) and/or bodily or emotional reactions (terrifying, nauseating, sickening). Pain of moderate or higher intensity is accompanied by anxiety and the urge to escape or terminate the feeling. This illustrates the duality of pain: it is both sensation and emotion. The function of the pain sensory system is to protect the body and maintain homeostasis by detecting, localizing, and identifying potential or actual tissue-damaging processes. Because different diseases produce characteristic patterns of tissue damage, the quality, time course, and location of pain provide important diagnostic clues. Acute pain is characteristically associated with behavioral arousal and a stress response consisting of increased blood pressure, heart rate, pupil diameter, and plasma cortisol levels. Local muscle contraction (limb flexion, abdominal wall rigidity) is often present.
2. PERIPHERAL MECHANISMS¶
The peripheral mechanisms of pain involve primary afferent nociceptors, sensitization processes, and nociceptor-induced inflammation.
2.1 The Primary Afferent Nociceptor¶
A peripheral nerve consists of axons from three types of neurons: primary sensory afferents, motor neurons, and sympathetic postganglionic neurons. Primary afferent cell bodies are located in the dorsal root ganglia within the vertebral foramina. Primary afferents are classified by diameter, myelination, and conduction velocity: - A-beta (A β ) fibers: Largest diameter, respond maximally to light touch and moving stimuli; present primarily in skin nerves; do not produce pain in normal individuals - A-delta (A δ ) fibers: Small diameter myelinated axons; respond maximally to intense (painful) stimuli - C fibers: Unmyelinated axons; respond maximally to intense (painful) stimuli A δ and C fiber afferents are present in nerves to skin, deep somatic, and visceral structures. Some tissues (e.g., cornea) are innervated only by A δ and C fiber afferents. The ability to detect painful stimuli is completely abolished when conduction in A δ and C fiber axons is blocked. Individual primary afferent nociceptors can respond to multiple types of noxious stimuli: - Heat - Intense cold - Intense mechanical distortion (pinch) - Changes in pH (especially acidic environment) - Chemical irritants: ATP, serotonin, bradykinin (BK), histamine The TRPV1 receptor (transient receptor potential cation channel subfamily V member 1, also known as vanilloid receptor) mediates perception of noxious stimuli, especially heat, and is activated by heat, acidic pH, endogenous mediators, and capsaicin.
2.2 Sensitization¶
When intense, repeated, or prolonged stimuli are applied to damaged or inflamed tissues, the threshold for activating primary afferent nociceptors is lowered and the frequency of firing is higher for all stimulus intensities. Inflammatory mediators contributing to sensitization: - Bradykinin (BK) - Nerve-growth factor - Prostaglandins (PGs) - Leukotrienes Types of Sensitization: 1. Peripheral Sensitization: Occurs in damaged or inflamed tissues when inflammatory mediators activate intracellular signal transduction in nociceptors, prompting increased production, transport, and membrane insertion of chemically gated and voltage-gated ion channels. This increases excitability of nociceptor terminals and lowers threshold for activation by mechanical, thermal, and chemical stimuli. 2. Central Sensitization: Occurs when activity generated by nociceptors during inflammation enhances excitability of nerve cells in the dorsal horn of the spinal cord. Clinical Manifestations of Sensitization: - Allodynia: Normally innocuous stimuli produce pain - Hyperalgesia: Increased pain intensity in response to the same noxious stimulus - Tenderness and soreness Example: Sunburned skin, where severe pain can be produced by a gentle slap or warm shower. Silent Nociceptors: A large proportion of A δ and C fiber afferents innervating viscera are completely insensitive in normal tissue—they cannot be activated by known mechanical or thermal stimuli and are not spontaneously active. In the presence of inflammatory mediators, these afferents become sensitive to mechanical stimuli, explaining how normally insensitive deep structures can become sources of severe pain and tenderness under pathologic conditions.
2.3 Nociceptor-Induced Inflammation¶
Primary afferent nociceptors are not simply passive messengers but play an active role in tissue protection through a neuroeffector function. Polypeptide mediators released from peripheral terminals when activated: - Substance P (11-amino-acid peptide) - Calcitonin gene-related peptide (CGRP) - Cholecystokinin Biologic Activities of Substance P: - Potent vasodilator - Causes mast cell degranulation - Chemoattractant for leukocytes - Increases production and release of inflammatory mediators Depletion of substance P from joints reduces severity of experimental arthritis.
3. CENTRAL MECHANISMS¶
Central mechanisms involve spinal cord processing, referred pain patterns, ascending pathways, and pain modulation circuits.
3.1 The Spinal Cord and Referred Pain¶
Primary afferent nociceptor axons enter the spinal cord via the dorsal root and terminate in the dorsal horn of the spinal gray matter. The terminals contact spinal neurons that transmit pain signals to brain sites involved in pain perception. Neurotransmitters released at primary afferent terminals: - Glutamate: Rapidly excites second-order dorsal horn neurons - Substance P and CGRP: Produce slower, longer-lasting excitation Convergence-Projection Hypothesis of Referred Pain: Each primary afferent contacts many spinal neurons, and each spinal neuron receives convergent inputs from many primary afferents. All spinal neurons receiving input from viscera and deep musculoskeletal structures also receive input from skin. Convergence patterns are determined by the spinal segment of the dorsal root ganglion supplying afferent innervation. Because spinal neurons are most often activated by skin inputs, activity evoked by input from deep structures is often mislocalized to a corresponding skin region. Example: Afferents supplying the central diaphragm are derived from C3-C4 dorsal root ganglia, which also supply shoulder and lower neck skin. Therefore, inflammation near the central diaphragm is often reported as shoulder discomfort.
3.2 Ascending Pathways for Pain¶
Most spinal dorsal horn neurons activated by primary afferent nociceptors send their axons to the contralateral thalamus via the spinothalamic tract, located in the anterolateral white matter of the spinal cord. Path of Spinothalamic Tract: - Spinal cord → lateral edge of medulla → lateral pons and midbrain → thalamus The spinothalamic pathway is crucial for pain sensation in humans; interruption produces permanent deficits in pain and temperature discrimination. Thalamic Projections and Cortical Processing: 1. Somatosensory Cortex Projection: - Mediates sensory-discriminative aspects of pain - Location, intensity, and quality of pain 2. Anterior Cingulate and Insular Cortex Projections: - Subserve affective/unpleasant emotional dimension of pain - Produces suffering and exerts potent control of behavior - Fear is a constant companion of pain Lesions to frontal cortex areas activated by painful stimuli can diminish emotional impact of pain while preserving ability to localize and recognize stimuli as painful.
3.3 Pain Modulation¶
Pain produced by injuries of similar magnitude is remarkably variable in different situations and individuals. Athletes have sustained serious fractures with only minor pain, and Beecher's World War II survey revealed soldiers unbothered by injuries that would produce agonizing pain in civilians. Factors Affecting Pain Perception: - Placebo effect: Suggestion of pain relief can have significant analgesic effect - Nocebo effect: Expectation of worsening pain can increase perceived intensity - Attention and psychological variables Descending Pain-Modulation Circuit: A circuit with links to hypothalamus, midbrain, and medulla selectively controls spinal dorsal horn pain-transmission neurons. Human brain-imaging studies implicate this circuit in pain-relieving effects of attention, suggestion, and opioid analgesics. Endogenous Opioid System: - Component structures contain opioid receptors and are sensitive to opioid drugs - Contain endogenous opioid peptides (enkephalins, β -endorphin) - Activated by suggestion of pain relief or intense emotion directed away from injury - Endogenous opioids released following surgical procedures and placebo administration Pain-Facilitating Circuits: Both pain-inhibiting and pain-facilitating neurons in the medulla project to spinal pain-transmission neurons. Because pain-transmission neurons can be activated by modulatory neurons, pain signals can theoretically be generated without peripheral noxious stimulus. This provides a framework for understanding how psychological factors contribute to chronic pain.
4. NEUROPATHIC PAIN¶
Lesions of peripheral or central nociceptive pathways typically result in loss or impairment of pain sensation. Paradoxically, damage to or dysfunction of these pathways can also produce pain.
4.1 Causes and Characteristics¶
Causes of Neuropathic Pain: - Damage to peripheral nerves (e.g., diabetic neuropathy) - Damage to primary afferents (e.g., herpes zoster infection) - Damage to CNS (trauma or vascular injury to spinal cord, brainstem, or thalamus) Characteristic Features: - Unusual burning, tingling, or electric shock-like quality - May occur spontaneously without stimulus - May be triggered by very light touch - Sensory deficit co-extensive with area of pain on examination - Hyperpathia: Greatly exaggerated pain response to innocuous or mild nociceptive stimuli - Allodynia: Lightest moving stimulus evokes exquisite pain Neuropathic pain is often severe and resistant to standard pain treatments. Topical 5% lidocaine patch is effective for postherpetic neuralgia with prominent allodynia.
4.2 Mechanisms¶
Multiple mechanisms contribute to neuropathic pain: 1. Peripheral Mechanisms: - Damaged primary afferents become highly sensitive to mechanical stimulation - May generate impulses without stimulation - Increased density of sodium channels in damaged nerve fiber - Damaged afferents may develop sensitivity to norepinephrine 2. Central Mechanisms: - Spinal cord pain-transmission neurons cut off from normal input may become spontaneously active Both central and peripheral nervous system hyperactivity contribute to neuropathic pain.
4.3 Sympathetically Maintained Pain (Complex Regional Pain Syndrome)¶
Patients with peripheral nerve injury may develop spontaneous pain in or beyond the region innervated by the nerve. Characteristics: - Burning quality pain - Begins after delay of hours to days or weeks - Swelling of the extremity - Periarticular bone loss - Arthritic changes in distal joints - Early: Pain may be relieved by sympathetic block - Damaged primary afferent nociceptors acquire adrenergic sensitivity Classification: - CRPS Type I (Reflex Sympathetic Dystrophy): Similar clinical picture without obvious nerve injury - CRPS Type II (Causalgia/Posttraumatic Neuralgia): Occurs after identifiable nerve injury Causes of CRPS: - Fractures - Soft tissue trauma - Myocardial infarction - Stroke CRPS Type I typically resolves with symptomatic treatment; persistent cases often reveal evidence of peripheral nerve injury on detailed examination. Signs of sympathetic hyperactivity should be sought in patients with post-traumatic pain and inflammation.
5. TREATMENT OF ACUTE PAIN¶
The ideal treatment for any pain is to remove the cause. While treatment can be initiated immediately, efforts to establish underlying etiology should always proceed as treatment begins. Sometimes treating the underlying condition does not immediately relieve pain, and rapid analgesia is essential for conditions such as postoperative states, burns, trauma, cancer, and sickle cell crisis.
5.1 Aspirin, Acetaminophen, and NSAIDs¶
These drugs are used for similar problems and may have similar mechanisms of action. All compounds inhibit cyclooxygenase (COX), and except for acetaminophen, all have anti-inflammatory actions at higher dosages. Indications: - Mild to moderate headache - Pain of musculoskeletal origin - Most commonly used analgesics (available without prescription) Pharmacokinetics: - Well absorbed from gastrointestinal tract - Minimal side effects with occasional use Side Effects and Risks: - Gastric irritation (most severe with aspirin): Erosion, ulceration, bleeding, perforation - Aspirin irreversibly acetylates platelet COX, interfering with coagulation - Risk factors for GI bleeding: Older age, history of GI disease - Nephrotoxicity with chronic use - Blood pressure elevation in some individuals - Acetaminophen: Hepatotoxic at high doses but rarely causes gastric irritation, does not affect platelet function COX-2 Selective Drugs: - Similar analgesic potency with less gastric irritation - No difference in nephrotoxicity risk - Significant benefit for postoperative pain (no effect on blood coagulation) - Nonselective COX inhibitors (especially aspirin) contraindicated postoperatively - Associated with increased cardiovascular risk (CV death, MI, stroke, heart failure, thromboembolic events) - Class effect of NSAIDs (excluding aspirin) Parenteral NSAIDs: - Ketorolac and diclofenac - Sufficiently potent and rapid onset to supplant opioids for many patients with acute severe headache and musculoskeletal pain
Nonnarcotic Analgesics: Usual Doses and Intervals¶
| Generic Name | Dose (mg) | Interval | Comments |
|---|---|---|---|
| Acetylsalicylic acid | 650 PO | q4h | Enteric-coated preparations available |
| Acetaminophen | 650 PO | q4h | Side effects uncommon |
| Ibuprofen | 400 PO | q4-6h | Available without prescription |
| Naproxen | 250-500 PO | q12h | Lowest cardiovascular risk among NSAIDs; slightly higher GI bleeding incidence |
| Fenoprofen | 200 PO | q4-6h | Contraindicated in renal disease |
| Generic Name | Dose (mg) | Interval | Comments |
|---|---|---|---|
| Indomethacin | 25-50 PO | q8h | Gastrointestinal side effects common |
| Ketorolac | 15-60 IM/IV | q4-6h | Available for parenteral use |
| Celecoxib | 100-200 PO | q12-24h | Useful for arthritis |
5.2 Opioid Analgesics¶
Opioids are the most potent pain-relieving drugs currently available, with the broadest range of efficacy and most reliable treatment for rapid pain relief. Mechanism: - Produce analgesia by actions in CNS - Activate pain-inhibitory neurons - Directly inhibit pain-transmission neurons - Most act at µ -receptor Side Effects: - Nausea, vomiting - Pruritus - Sedation - Constipation (virtually universal) - Respiratory depression (uncommon at standard doses but life-threatening) - All reversible with naloxone Respiratory Depression Monitoring: - Primarily manifests as reduced respiratory rate - Typically accompanied by sedation - Fall in oxygen saturation represents critical level requiring immediate intervention - Monitoring devices with capnography or pharyngeal air flow can detect apnea onset - Maintain ventilatory assistance until respiratory depression resolves - Naloxone should be readily available Important Considerations: - Synergistic respiratory depression with other CNS depressants - Benzodiazepine co-administration particularly dangerous; avoid especially in outpatient setting - Great variability among patients in effective doses - Most common error: Prescribing inadequate dose - Titration required for optimal dose and interval Normeperidine Toxicity: - Metabolite of meperidine - At doses >1 g/day: Hyperexcitability and seizures (not reversible with naloxone) - Accumulation increased in renal failure - Routine use of meperidine not recommended
Narcotic Analgesics: Usual Doses and Intervals¶
| Generic Name | Parenteral Dose (mg) | PO Dose (mg) | Comments |
|---|---|---|---|
| Codeine | 30-60 q4h | 30-60 q4h | Nausea common |
| Oxycodone | — | 5-10 q4-6h | Usually available with acetaminophen or aspirin |
| Generic Name | Parenteral Dose (mg) | PO Dose (mg) | Comments |
|---|---|---|---|
| Oxycodone extended-release | — | 10-40 q12h | Oral extended-release; high potential for misuse |
| Morphine | 5 q4h | 30 q4h | — |
| Morphine sustained release | — | 15-60 bid to tid | Oral slow-release preparation |
| Hydromorphone | 1-2 q4h | 2-4 q4h | Shorter acting than morphine sulfate |
| Levorphanol | 2 q6-8h | 4 q6-8h | Longer acting; absorbed well PO |
| Methadone | 5-10 q6-8h | 5-20 q6-8h | Long half-life; respiratory depression may persist after analgesia; start £40 mg/d; escalate no more than every 3 days |
| Meperidine | 50-100 q3-4h | 300 q4h | Poorly absorbed PO; normeperidine toxic metabolite; routine use not recommended |
| Butorphanol | — | 1-2 q4h | Intranasal spray |
| Fentanyl | 25-100 mg/h | — | 72-h transdermal patch |
| Buprenorphine | 5-20 mg/h | — | 7-day transdermal patch |
| Buprenorphine | 0.3 q6-8h | — | Parenteral administration |
| Tramadol | — | 50-100 q4-6h | Mixed opioid/adrenergic action |
5.3 Patient-Controlled Analgesia (PCA)¶
PCA uses a microprocessor-controlled infusion device delivering: - Baseline continuous dose of opioid - Preprogrammed additional doses when patient pushes button Applications: - Postoperative pain management (most extensive use) - Any hospitalized patient with persistent severe pain - Short-term home care for intractable pain (e.g., metastatic cancer) Important Principles: - PCA delivers small, repeated doses to maintain pain relief - Pain must first be controlled with loading dose before transitioning to PCA - Bolus doses: Morphine 1 mg, hydromorphone 0.2 mg, or fentanyl 10 µ g - Lockout period after each demand dose (typically starting at 10 min) - Limit on total dose delivered per hour - Continuous basal infusion may increase respiratory depression risk without improving efficacy
5.4 Routes of Opioid Administration¶
New routes of administration extend opioid analgesic usefulness: Spinal Administration: - Catheter placed intrathecally or epidurally - Regional analgesia with relatively low total doses - Intrathecal morphine dose: 0.1-0.3 mg (vs. 5-10 mg IV for similar analgesia) - Minimizes sedation, nausea, respiratory depression - Applications: Labor and delivery, postoperative pain - Continuous intrathecal delivery via implanted systems for cancer-related pain Alternative Routes: - Intranasal: Butorphanol - Rectal - Transdermal: Fentanyl, buprenorphine (steady plasma levels) - Oral mucosal: Fentanyl Peripherally Acting Opioid Antagonists: - Alvimopan (Entereg): Oral, restricted to intestinal lumen - Methylnaltrexone (Rellistor): Subcutaneous, no CNS penetration - Bind peripheral µ -receptors - Reverse peripheral opioid effects without affecting CNS analgesia - Alvimopan: Reduces duration of postoperative ileus - Methylnaltrexone: Relieves opioid-induced constipation
5.5 Opioid and COX Inhibitor Combinations¶
When used in combination, opioids and COX inhibitors have additive or synergistic effects. Lower doses of each achieve same pain relief with reduced dose-related side effects. Risk of Fixed-Ratio Opioid-Acetaminophen Combinations: - Dose escalation due to increased pain severity or tolerance may lead to toxic acetaminophen levels - Acetaminophen-related hepatotoxicity uncommon but significant cause of liver failure - Many practitioners avoid opioid-acetaminophen combinations to prevent excessive acetaminophen exposure with dose escalation
6. TREATMENT OF CHRONIC PAIN¶
Managing patients with chronic pain is intellectually and emotionally challenging. Sensitization of the nervous system can occur without obvious precipitating cause (e.g., fibromyalgia, chronic headache). In many patients, chronic pain becomes a distinct disease.
6.1 Assessment and Evaluation¶
Factors Causing, Perpetuating, or Exacerbating Chronic Pain: 1. Disease that is characteristically painful without cure: - Arthritis - Cancer - Chronic daily headaches - Fibromyalgia - Diabetic neuropathy 2. Secondary perpetuating factors (persist after disease resolved): - Damaged sensory nerves - Sympathetic efferent activity - Painful reflex muscle contraction (spasm) 3. Psychological conditions (can exacerbate or cause pain) History Red Flags for Emotional Disturbance: - Pain in multiple unrelated sites - Recurrent separate pain problems from childhood/adolescence - Pain onset during emotional trauma (loss of parent/spouse) - History of physical or sexual abuse - Past or present substance abuse Screening for Depression: - Most common emotional disturbance in chronic pain patients - Ask about mood, appetite, sleep patterns, daily activity - Beck Depression Inventory useful screening tool - Major depression is common, treatable, and potentially fatal Physical Examination Focus: - Guarding of painful area - Avoidance of certain movements/postures - Deep tenderness (muscle, ligamentous structures, joints) - Trigger points in chronic myofascial pain (firm bands/knots in muscle) - Evidence of neuropathic component: Sensory impairment, allodynia, weakness, muscle atrophy, loss of deep tendon reflexes - Signs of sympathetic involvement: Diffuse swelling, skin color/temperature changes, hypersensitive skin and joint tenderness Guiding Principle: Assess both emotional and somatic causal and perpetuating factors before initiating therapy. Addressing issues together improves compliance and assures patients that psychological evaluation does not question validity of complaint.
6.2 Treatment Principles¶
Treatment Planning: - Complete evaluation to identify causative and exacerbating factors - Establish explicit treatment plan with specific, realistic functional goals: - Getting good night's sleep - Being able to go shopping - Returning to work Multidisciplinary Approach May Include: - Medications - Counseling - Physical therapy - Nerve blocks - Surgery Minimally Invasive Procedures: - Image-guided epidural glucocorticoid injection for acute radicular pain - Radiofrequency treatment of facet joints for chronic facet-related back/neck pain - Spinal cord stimulation (electrodes on peripheral nerves, nerve roots, or dorsal columns) - Reserved for patients unresponsive to conservative treatment - Referral to multidisciplinary pain clinic should precede invasive procedures
6.3 Antidepressant Medications¶
Tricyclic Antidepressants (TCAs): Nortriptyline and desipramine are useful for chronic pain management. Mechanism: - Spectrum of dose-related biologic activities including analgesia - Analgesic effect has more rapid onset and occurs at lower dose than required for depression treatment - Patients without depression obtain pain relief - Evidence suggests TCAs potentiate opioid analgesia Indications Responding to TCAs: - Postherpetic neuralgia - Diabetic neuropathy - Fibromyalgia - Tension headache - Migraine headache - Rheumatoid arthritis - Chronic low back pain - Cancer pain - Central post-stroke pain TCA Side Effects: - Orthostatic hypotension - Drowsiness - Cardiac conduction delay - Memory impairment - Constipation - Urinary retention - Particularly problematic in elderly - Additive to opioid side effects Alternative Antidepressants: - SSRIs (e.g., fluoxetine): Fewer side effects but much less effective for pain - SNRIs (venlafaxine, duloxetine): Retain pain-relieving effects of TCAs with better side effect profile; have largely supplanted TCAs
Antidepressants for Pain Management¶
| Generic Name | 5-HT Uptake | NE Uptake | Sedative Potency | Anticholi nergic Potency | Orthostat ic Hypote nsion | Cardiac Arrhythm ia | Average Dose (mg/d) | Range (mg/d) |
|---|---|---|---|---|---|---|---|---|
| Doxepin | ++ | + | High | Moderate | Moderate | Less | 200 | 75-400 |
| Amitriptyli ne | ++++ | ++ | High | Highest | Moderate | Yes | 150 | 25-300 |
| Imipramin e | ++++ | ++ | Moderate | Moderate | High | Yes | 200 | 75-400 |
| Nortriptyli ne | +++ | ++ | Moderate | Moderate | Low | Yes | 100 | 40-150 |
| Desiprami ne | +++ | ++++ | Low | Low | Low | Yes | 150 | 50-300 |
| Venlafaxi ne | +++ | ++ | Low | None | None | No | 150 | 75-400 |
| Duloxetin e | +++ | +++ | Low | None | None | No | 40 | 30-60 |
Painful Conditions Responding to Tricyclic Antidepressants¶
| Condition | Evidence Level |
|---|---|
| Postherpetic neuralgia | Controlled trials demonstrate analgesia |
| Diabetic neuropathy | Controlled trials demonstrate analgesia |
| Fibromyalgia | Controlled trials demonstrate analgesia |
| Tension headache | Controlled trials demonstrate analgesia |
| Migraine headache | Controlled trials demonstrate analgesia |
| Rheumatoid arthritis | Controlled studies indicate benefit but not analgesia |
| Chronic low back pain | Controlled studies indicate benefit but not analgesia |
| Cancer | Clinical evidence |
| Central post-stroke pain | Clinical evidence |
6.4 Anticonvulsants and Antiarrhythmics¶
Primarily useful for neuropathic pain. First-Generation Agents: - Phenytoin (Dilantin) and carbamazepine (Tegretol): First shown to relieve trigeminal neuralgia - Particularly helpful for pains with lancinating (brief, shooting, electric shock-like) quality Newer Anticonvulsants (Calcium Channel Alpha-2-Delta Subunit Ligands): - Gabapentin (Neurontin) - Pregabalin (Lyrica) - Effective for broad range of neuropathic pains - Favorable side effect profile; often used as first-line agents - Sedation common with high doses required for pain relief Antiarrhythmics: - IV lidocaine can provide transient analgesia for various neuropathic pains - Relief typically lasts only hours after cessation - Oral mexiletine poorly tolerated (frequent GI adverse effects) Note: Gabapentin up to 1800 mg/d is FDA-approved for postherpetic neuralgia. Antidepressants, anticonvulsants, and antiarrhythmics have not been FDA-approved for pain treatment.
Anticonvulsants and Antiarrhythmics for Pain¶
| Generic Name | PO Dose (mg) | Interval | Comments |
|---|---|---|---|
| Carbamazepine | 200-300 | q6h | Rare aplastic anemia, GI irritation, hepatotoxicity |
| Oxcarbazepine | 300 | bid | Similar to carbamazepine |
| Gabapentin | 600-1200 | q8h | Dizziness, GI irritation; useful in trigeminal neuralgia |
| Pregabalin | 150-600 | bid | Similar to gabapentin; dry mouth, edema |
6.5 Cannabinoids¶
Widely used for analgesic properties. Evidence: - Modest analgesic effects with small increases in pain threshold - Variable reductions in clinical pain intensity - More consistently reduces unpleasantness of pain experience - In cancer pain: Can lessen chemotherapy-associated nausea and vomiting
6.6 Chronic Opioid Therapy¶
Long-term opioid use is accepted for malignant disease pain. For chronic noncancer pain, opioids may be the only option providing meaningful relief for many patients. Considerations Before Starting: - Explore other options first - Explain limitations and risks to patient - Some degree of tolerance and physical dependence likely with long-term use - Opioid-induced hyperalgesia may worsen pain in some individuals - Risk of addiction small but increases with dose escalation and treatment duration Mixed Agonist-Antagonist Opioids: - Butorphanol and buprenorphine - May worsen pain by inducing abstinence syndrome in patients physically dependent on other opioids Long-Acting Formulations: - Levorphanol, methadone, extended-release morphine/oxycodone, transdermal fentanyl - Sustained analgesic blood levels - Potentially minimize peak-related sedation - Reduce rebound pain from rapid plasma concentration fall - Extended-release formulations approved primarily for patients already taking other opioids - Should not be first-line opioids Opioid Prescribing Challenges: - OxyContin introduction (late 1990s) followed by dramatic rise in ED visits and deaths - Drug-induced deaths now second leading cause of death in Americans (after motor vehicle fatalities) - 2011: Office of National Drug Control Policy established approach including PDMPs - 2016: CDC Guidelines for Prescribing Opioids for Chronic Pain - 2019, updated 2022: HHS Task Force on chronic pain best practices Guideline Recommendations: 1. When to initiate or continue opioids for chronic pain 2. Opioid selection, dosage, duration, follow-up, and discontinuation 3. Assessing risk and addressing harms of opioid use
Guidelines for Selecting and Monitoring Patients Receiving Chronic Opioid Therapy (COT) for Chronic Noncancer Pain¶
| Category | Recommendations |
|---|---|
| Patient Selection | (cid:127) Conduct history, physical examination, and appropriate testing including substance abuse risk assessment (cid:127) Consider COT trial if pain is moderate/severe with adverse impact on function/quality of life and benefits outweigh harms (cid:127) Document benefit-to-harm evaluation before and during COT |
| Category | Recommendations |
|---|---|
| Informed Consent | (cid:127) Obtain informed consent with continuing discussion of goals, expectations, risks, and alternatives (cid:127) Consider written COT management plan documenting responsibilities and expectations |
| Initiation and Titration | (cid:127) Initial treatment should be therapeutic trial to determine appropriateness (cid:127) Individualize selection, dosing, and titration according to health status, previous opioid exposure, therapeutic goals, and observed harms |
| Monitoring | (cid:127) Reassess periodically with documentation of pain intensity, functioning, therapeutic progress, adverse events, and adherence (cid:127) High-risk patients or those with aberrant behaviors: Periodically obtain urine drug screens (cid:127) Non-high-risk patients: Consider periodic urine drug screens to confirm adherence |
CDC Checklist for Prescribing Opioids for Chronic Pain (Adults ≥ 18 with Chronic Pain ≥ 3 Months, Excluding Cancer/Palliative/End-of-Life)¶
| Phase | Checklist Items |
|---|---|
| When Considering Long-Term Opioid Therapy | (cid:127) Set realistic goals for pain and function based on diagnosis (cid:127) Check that nonopioid therapies tried and optimized (cid:127) Discuss benefits and risks (addiction, overdose) with patient (cid:127) Evaluate risk of harm or misuse; discuss risk factors (cid:127) Check PDMP data (cid:127) Check urine drug screen (cid:127) Set criteria for stopping or continuing opioids (cid:127) Assess baseline pain and function (e.g., PEG scale) (cid:127) Schedule initial reassessment within 1-4 weeks (cid:127) Prescribe short-acting opioids at lowest dosage; match duration to reassessment |
| If Renewing Without Visit | (cid:127) Check return visit scheduled £3 months from last visit |
| When Reassessing at Visit | (cid:127) Continue opioids only after confirming meaningful improvements in pain and function without significant risks (cid:127) Assess pain and function; compare to baseline (cid:127) Evaluate risk of harm or misuse (cid:127) Check for oversedation/overdose risk (if yes: taper dose) (cid:127) Check PDMP (cid:127) Check for opioid use disorder (if yes: refer for treatment) (cid:127) Check nonopioid therapies optimized (cid:127) Determine whether to continue, adjust, taper, or stop opioids (cid:127) Calculate opioid dosage MME (cid:127) If ‡50 MME/day (‡50 mg hydrocodone; ‡33 mg oxycodone): increase follow-up frequency; consider offering naloxone (cid:127) Avoid ‡90 MME/day (‡90 mg hydrocodone; ‡60 mg oxycodone) or carefully justify; consider specialist referral (cid:127) Schedule reassessment at regular intervals (£3 months) |
7. TREATMENT OF NEUROPATHIC PAIN¶
Individualize treatment for patients with neuropathic pain. General principles: move quickly to provide relief and minimize drug side effects.
7.1 Treatment Algorithm¶
First-Line Options: 1. Topical Lidocaine: - 5% lidocaine patches (Lidoderm) - Immediate relief without systemic side effects - Ideal for postherpetic neuralgia with cutaneous hypersensitivity 2. Anticonvulsants: - Gabapentin or pregabalin - Effective for broad range of neuropathic pain - Sedation possible at higher doses 3. Antidepressants: - For elderly or patients requiring high-level mental activity: - SNRIs (venlafaxine, duloxetine) preferred first-line - Alternatives: Nortriptyline, desipramine Second/Third-Line Options: - Opioid medications - Effective for many painful conditions but sedating - Effect tends to lessen over time leading to dose escalation - Occasionally worsens pain Mixed Opioid/Norepinephrine Reuptake Agents: - Tramadol: Relatively weak opioid; sometimes effective when nonopioid analgesics fail - Tapentadol: Stronger opioid with enhanced analgesia from norepinephrine reuptake blockade Combination Therapy: - Drugs of different classes can be used together to optimize pain control No Consensus on First-Line Treatment: Choice depends on individual patient factors including age, cognitive requirements, and side effect profile tolerance.
8. KEY POINTS & CLINICAL PEARLS¶
- Pain serves a protective function and provides diagnostic clues through its quality, time course, and location.
- Sensitization (peripheral and central) is clinically important, contributing to allodynia, hyperalgesia, and the transformation of normally insensitive deep structures into severe pain sources.
- Referred pain occurs due to convergence of visceral and cutaneous afferents on the same spinal neurons (e.g., diaphragm inflammation → shoulder pain).
- Neuropathic pain has characteristic features (burning, tingling, electric shock-like, triggered by light touch) that distinguish it from nociceptive pain and guide treatment selection.
- The descending pain-modulation system explains placebo/nocebo effects and provides the basis for psychological interventions in pain management.
- The most common error in managing severe pain with opioids is prescribing an inadequate dose.
- Respiratory depression from opioids manifests primarily as reduced respiratory rate; oxygen saturation fall indicates critical level requiring immediate intervention.
- Never co-administer benzodiazepines with opioids, especially in outpatient settings, due to synergistic respiratory depression.
- Fixed-ratio opioid-acetaminophen combinations carry hepatotoxicity risk with dose escalation; many practitioners avoid these.
- For chronic pain, assess both emotional and somatic factors before initiating therapy—depression is the most common comorbid condition.
- Extended-release opioid formulations should not be used as first-line opioids; they are approved primarily for patients already taking other opioids.
- For neuropathic pain, topical lidocaine can provide immediate relief without systemic side effects in patients with cutaneous hypersensitivity.
- SNRIs (venlafaxine, duloxetine) have largely supplanted TCAs due to better side effect profiles while retaining pain-relieving efficacy.
- Multimodal analgesia combining different drug classes optimizes pain control while minimizing side effects.
- Constipation should be treated expectantly in all patients receiving opioids; peripherally acting opioid antagonists (alvimopan, methylnaltrexone) can reverse constipation without affecting analgesia.