Pain & Anesthesia Pharmacology
Pain & Anesthesia Pharmacology
What Do You Need to Know?
- Neuropathic pain agents — gabapentin/pregabalin (α2δ Ca channel subunit), SNRIs (duloxetine), TCAs (amitriptyline), carbamazepine (first-line for trigeminal neuralgia)
- Opioid receptors — mu (analgesia, respiratory depression, constipation), kappa (dysphoria), delta (spinal analgesia); naloxone = competitive antagonist; tramadol lowers seizure threshold and causes serotonin syndrome
- Local anesthetics — Na channel blockade; esters (pseudocholinesterase) vs amides (hepatic CYP); toxicity = CNS first, then cardiac; small unmyelinated C fibers blocked first (pain/temperature)
- General anesthetics — volatile agents enhance GABA-A and increase ICP; propofol (GABA-A, decreases ICP); ketamine (NMDA antagonist, increases ICP); etomidate = least hemodynamic effect
- Neuromuscular blockers — succinylcholine (depolarizing) causes hyperkalemia in burns/denervation/SCI and triggers malignant hyperthermia; rocuronium (nondepolarizing) reversed by sugammadex
- Malignant hyperthermia — RYR1 mutation + volatile anesthetics or succinylcholine; treatment = dantrolene (blocks ryanodine receptor Ca release from SR)
- Procedural sedation — methohexital activates seizure foci (used in Wada test); thiopental suppresses cortical activity (burst suppression); propofol can activate foci on ECoG
Neuropathic Pain Agents
| Drug / Class | Mechanism | Indications | Key Side Effects / Notes |
|---|---|---|---|
| Gabapentin / Pregabalin | Bind α2δ subunit of voltage-gated Ca2+ channels → ↓ presynaptic glutamate release | Diabetic neuropathy, postherpetic neuralgia, fibromyalgia (pregabalin) | Sedation, dizziness, edema; renally cleared; pregabalin has linear pharmacokinetics |
| Duloxetine / Venlafaxine (SNRIs) | Serotonin + NE reuptake inhibition → descending pain inhibition | Diabetic neuropathy (duloxetine FDA-approved), fibromyalgia | Nausea, HTN (venlafaxine at high doses); serotonin syndrome risk |
| TCAs (amitriptyline, nortriptyline) | Na channel blockade + serotonin/NE reuptake inhibition | Neuropathic pain, migraine prophylaxis | Anticholinergic effects; QT prolongation; nortriptyline better tolerated than amitriptyline |
| Carbamazepine | Na channel blockade (use-dependent) | First-line for trigeminal neuralgia; glossopharyngeal neuralgia | SIADH; agranulocytosis; SJS/TEN (screen HLA-B*1502); CYP3A4 autoinduction |
| Topical lidocaine (5% patch) | Local Na channel blockade | Postherpetic neuralgia, localized neuropathic pain | Minimal systemic absorption; well tolerated |
| Capsaicin (topical) | TRPV1 agonist → C-fiber desensitization; depletes substance P | Postherpetic neuralgia (8% patch), diabetic neuropathy | Initial burning; high-concentration patch applied in clinic |
Board Pearl
Carbamazepine is first-line for trigeminal neuralgia. Lancinating facial pain in V2/V3 triggered by chewing or touch = carbamazepine. Oxcarbazepine is an alternative with fewer drug interactions. Screen HLA-B*1502 in patients of Southeast Asian descent before starting.
Opioid Pharmacology
Opioid Receptors
| Receptor | Endogenous Ligand | Key Effects | Drugs |
|---|---|---|---|
| Mu (μ) | β-endorphin, enkephalins | Analgesia, euphoria, respiratory depression, miosis, constipation, dependence | Morphine, fentanyl, oxycodone, hydromorphone; naloxone/naltrexone (antagonists) |
| Kappa (κ) | Dynorphin | Spinal analgesia, dysphoria, sedation, diuresis | Butorphanol, pentazocine (mixed agonist-antagonist) |
| Delta (δ) | Enkephalins | Spinal analgesia, mood modulation | Research targets |
- All opioid receptors are Gi-coupled → ↓ cAMP, ↓ Ca2+ influx, ↑ K+ efflux → hyperpolarization
- Tolerance: develops to analgesia, euphoria, respiratory depression; does NOT develop to miosis or constipation
- Withdrawal: lacrimation, rhinorrhea, piloerection, diarrhea, mydriasis — uncomfortable but not life-threatening (unlike alcohol/benzo withdrawal)
Commonly Used Opioids
| Drug | Key Features |
|---|---|
| Morphine | Prototype mu agonist; histamine release (pruritus, hypotension); active metabolite M6G accumulates in renal failure |
| Fentanyl | 80–100x more potent than morphine; highly lipophilic; rapid onset; chest wall rigidity with rapid IV bolus |
| Oxycodone | Oral; often combined with acetaminophen; intermediate potency |
| Hydromorphone | 5–7x more potent than morphine; less histamine release; preferred in renal impairment |
| Methadone | Long half-life; NMDA antagonist activity; QT prolongation risk; used for chronic pain and opioid maintenance |
Opioid Antagonists & Special Agents
- Naloxone: competitive mu antagonist; IV/IM/intranasal; short half-life (30–90 min) — may need redosing for long-acting opioids
- Naltrexone: oral, long-acting mu antagonist; used for opioid and alcohol use disorder
- Tramadol: weak mu agonist + SNRI activity — lowers seizure threshold; risk of serotonin syndrome (especially with SSRIs/MAOIs); CYP2D6 metabolism
Board Pearl
Tramadol has dual risk: lowers the seizure threshold AND causes serotonin syndrome with serotonergic drugs. Patient on SSRI who develops clonus, hyperthermia, and altered mental status after starting tramadol = serotonin syndrome. Tolerance does NOT develop to opioid-induced constipation or miosis.
Local Anesthetics
- Mechanism: block voltage-gated Na channels from the intracellular side → prevent depolarization and AP propagation
- Preferentially block open and inactivated channels (use-dependent blockade) — rapidly firing neurons more susceptible
- Must cross membrane in uncharged (base) form, then ionize to bind — acidic/infected tissue reduces efficacy
Esters vs Amides
| Feature | Esters | Amides |
|---|---|---|
| Examples | Procaine, tetracaine, cocaine, benzocaine | Lidocaine, bupivacaine, ropivacaine, prilocaine |
| Metabolism | Pseudocholinesterase (plasma) | Hepatic CYP (P450) |
| Allergy | More common (PABA metabolite) | Rare; safe if ester allergy |
| Memory aid | One "i" in name (procaine) | Two "i"s in name (lidocaine) |
Order of Nerve Fiber Blockade
- Small unmyelinated C fibers blocked FIRST → loss of pain and temperature
- Then small myelinated B fibers → autonomic (sympathetic) blockade
- Then Aδ fibers → sharp pain and temperature
- Then Aβ fibers → touch and pressure
- Large myelinated Aα fibers blocked LAST → motor function
- Clinical sequence: pain/temperature lost first → autonomic → sensory (touch) → motor last
Local Anesthetic Toxicity (LAST)
- CNS toxicity FIRST (lower threshold): perioral numbness, tinnitus, metallic taste → tremor → seizures
- Cardiac toxicity SECOND (higher threshold): arrhythmias, cardiovascular collapse
- Bupivacaine has the highest cardiotoxicity risk (binds Na channels tightly, slow dissociation)
- Treatment of severe LAST: IV lipid emulsion (Intralipid 20%) — "lipid sink"
Board Pearl
Esters = pseudocholinesterase; Amides = hepatic CYP. Pseudocholinesterase deficiency prolongs ester anesthetics (and succinylcholine). Local anesthetics work poorly in infected tissue because the low pH keeps the drug ionized, preventing membrane crossing. CNS toxicity (seizures) always precedes cardiac toxicity.
General Anesthetics
Volatile (Inhaled) Agents
| Agent | Mechanism | Key Features |
|---|---|---|
| Isoflurane | Enhances GABA-A; inhibits NMDA | Widely used; increases ICP (cerebral vasodilation); cardiovascular depression |
| Sevoflurane | Same as isoflurane | Non-irritating → preferred for mask induction (pediatrics); rapid onset/offset |
| Desflurane | Same as isoflurane | Fastest onset/offset (lowest blood-gas partition coefficient); pungent, airway irritant; tachycardia |
| Nitrous oxide | Weak NMDA antagonist | Weak anesthetic (adjunct); inactivates B12 (myeloneuropathy); expands closed gas spaces (contraindicated in pneumothorax, pneumocephalus) |
- All volatile agents increase ICP via cerebral vasodilation and are malignant hyperthermia triggers
- MAC (minimum alveolar concentration): concentration at which 50% of patients won’t move to incision; lower MAC = more potent
Intravenous Anesthetics
| Agent | Mechanism | ICP | Key Features |
|---|---|---|---|
| Propofol | GABA-A | ↓ | Rapid onset/offset; hypotension; antiemetic; propofol infusion syndrome (prolonged high-dose: metabolic acidosis, rhabdomyolysis, cardiac failure) |
| Ketamine | NMDA antagonist | ↑ | Dissociative anesthesia + analgesia; maintains airway reflexes and respiratory drive; sympathomimetic; emergence delirium; bronchodilator |
| Etomidate | GABA-A | ↓ | Least hemodynamic effect — RSI in unstable patients; adrenal suppression (11β-hydroxylase); myoclonus |
| Thiopental | GABA-A (barbiturate) | ↓ | Burst suppression in refractory SE; cerebral protection; porphyria contraindication |
| Methohexital | GABA-A (barbiturate) | ↓ | Activates epileptiform foci on ECoG; used for ECT and Wada test |
Board Pearl
Ketamine is the only IV anesthetic that increases ICP (all others decrease it). It uniquely provides analgesia and maintains respiratory drive. Etomidate = agent of choice for RSI in hemodynamically unstable patients. Watch for propofol infusion syndrome with prolonged high-dose use (metabolic acidosis + rhabdomyolysis + cardiac failure).
Neuromuscular Blockers
Depolarizing vs Nondepolarizing
| Feature | Depolarizing (Succinylcholine) | Nondepolarizing (Rocuronium, Vecuronium, Cisatracurium) |
|---|---|---|
| Mechanism | Sustained depolarization → fasciculations then phase I block | Competitive antagonist at nicotinic ACh receptor; no fasciculations |
| Onset / Duration | Fastest (30–60 sec); ultra-short (5–10 min); pseudocholinesterase metabolism | Slower (1–3 min); intermediate to long; hepatic/renal metabolism |
| Reversal | None — wait for pseudocholinesterase | Neostigmine (+ glycopyrrolate) or sugammadex (encapsulates rocuronium/vecuronium) |
| Key risks | Hyperkalemia, malignant hyperthermia, bradycardia | Residual paralysis; prolonged block in organ failure |
Succinylcholine Hyperkalemia — Contraindications
- Burns (after 24–48 hours, risk persists up to 1 year)
- Denervation injuries (stroke, SCI, peripheral nerve injury) — upregulation of extrajunctional ACh receptors
- Prolonged immobilization / ICU myopathy
- Muscular dystrophies (especially Duchenne) — rhabdomyolysis risk
- Mechanism: extrajunctional nicotinic receptor upregulation → massive K+ efflux upon depolarization → cardiac arrest
- Safe in first 24–48 hours after denervation (before receptor upregulation); after that use rocuronium
Clinical Pearl
Succinylcholine is contraindicated in burns, denervation, SCI, and muscular dystrophy due to extrajunctional ACh receptor upregulation causing fatal hyperkalemia. Sugammadex allows rapid reversal of rocuronium, making it a viable RSI alternative to succinylcholine in these patients.
Malignant Hyperthermia
- Genetics: autosomal dominant; RYR1 mutation (ryanodine receptor type 1 on skeletal muscle SR)
- Triggers: volatile anesthetics (isoflurane, sevoflurane, desflurane, halothane) + succinylcholine
- Pathophysiology: uncontrolled Ca2+ release from SR → sustained contraction → hypermetabolism
- Early signs: masseter rigidity, unexplained tachycardia, ↑ end-tidal CO2 (earliest and most sensitive sign)
- Progression: temperature >40°C, rigidity, mixed acidosis, hyperkalemia, rhabdomyolysis, DIC
- Confirmatory test: caffeine-halothane contracture test (muscle biopsy)
Treatment
- Dantrolene = definitive treatment — blocks the ryanodine receptor (RYR1), preventing Ca2+ release from SR
- Immediately discontinue all triggering agents; hyperventilate with 100% O2
- Active cooling; treat hyperkalemia; dantrolene IV 2.5 mg/kg every 5 min until symptoms resolve
- Safe agents for MH-susceptible patients: propofol, etomidate, opioids, benzodiazepines, nitrous oxide, nondepolarizing NMBs
Board Pearl
Malignant hyperthermia = RYR1 + volatile anesthetic or succinylcholine. Earliest sign = unexplained ↑ EtCO2. Treatment = dantrolene (blocks ryanodine receptor). Dantrolene is also used for NMS, though NMS is from dopamine blockade (not a channelopathy). Know the safe anesthetic alternatives for MH-susceptible patients.
Procedural Sedation in Neurology
| Agent | Effect on Seizure Foci | Neurologic Use |
|---|---|---|
| Methohexital | Activates epileptiform discharges | Wada test (intracarotid injection for language/memory lateralization); ECT |
| Propofol | Activates foci at low doses; suppresses at high doses | Intraoperative ECoG (identifies epileptogenic zone); burst suppression in refractory SE |
| Thiopental | Suppresses; does NOT activate foci | Burst suppression; cerebral protection (↓ CMRO2 and ICP) |
| Pentobarbital | Suppresses | Prolonged burst suppression for super-refractory SE (pentobarbital coma) |
| Midazolam | Suppresses | First-line IV infusion for refractory SE; least hemodynamic compromise |
- Wada test: intracarotid methohexital (or amobarbital) anesthetizes one hemisphere → tests language dominance and memory before temporal lobectomy
- Refractory SE escalation: midazolam → propofol → pentobarbital coma (continuous EEG targeting burst suppression)
Clinical Pearl
In refractory status epilepticus, midazolam has the least hemodynamic effect but highest breakthrough rate; pentobarbital is most reliable for burst suppression but causes the most hypotension. All require continuous EEG monitoring.
Quick Reference
Pain & Anesthesia Pharmacology — At a Glance
| Category | Key Drug / Concept | Board-Yield Feature |
|---|---|---|
| Trigeminal neuralgia | Carbamazepine (first-line) | Na channel blocker; screen HLA-B*1502 |
| Neuropathic pain | Gabapentin/pregabalin | α2δ Ca channel subunit; renal dosing |
| Opioid overdose | Naloxone | Short half-life; may need redosing |
| Tramadol risks | Seizures + serotonin syndrome | Weak mu + SNRI; avoid with SSRIs/MAOIs |
| Ester vs amide | Pseudocholinesterase vs hepatic CYP | Amides have two "i"s; esters have one |
| LA toxicity | CNS first, then cardiac | Bupivacaine = highest cardiotoxicity; IV lipid emulsion |
| Nerve block order | C fibers first, Aα last | Pain/temperature lost first; motor last |
| ICP and anesthetics | Volatiles + ketamine ↑ ICP | Propofol, etomidate, thiopental ↓ ICP |
| Etomidate | Least hemodynamic change | RSI in unstable patient; adrenal suppression |
| Succinylcholine | Hyperkalemia risk | Burns, denervation, SCI, muscular dystrophy; MH trigger |
| Sugammadex | Reverses rocuronium/vecuronium | Encapsulates drug; alternative to neostigmine |
| Malignant hyperthermia | RYR1 + volatiles/succinylcholine | Earliest sign = ↑ EtCO2; treat with dantrolene |
| Wada test | Methohexital (or amobarbital) | Activates foci; lateralizes language/memory |
| Burst suppression | Thiopental / pentobarbital | Suppresses cortical activity; refractory SE |
References
- Ropper AH, Samuels MA, Klein JP, Prasad S. Adams and Victor’s Principles of Neurology. 12th ed. McGraw-Hill; 2023.
- Bhatt A. Ultimate Review for the Neurology Boards. 3rd ed. Demos Medical; 2016.
- Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 14th ed. McGraw-Hill; 2023.
- Butterworth JF, Mackey DC, Wasnick JD. Morgan & Mikhail’s Clinical Anesthesiology. 7th ed. McGraw-Hill; 2022.
- Dworkin RH, et al. Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain. 2007;132(3):237–251.
- Rosenberg H, et al. Malignant hyperthermia: a review. Orphanet J Rare Dis. 2015;10:93.