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Pain Management Series

Overview

Pain management is one of the most common—and most difficult—challenges in medicine.

Effective treatment requires understanding:

Pain physiology
Pain pathophysiology
Mechanistic classification
Acute vs chronic transitions
Pain syndromes
Pharmacologic targets
Patient-specific risk factors

This series is organized in a structured framework:

Physiology → Classification → Time Course → Syndromes → Drug Classes → Special Populations → Clinical Application

I. Pain Physiology & Pathophysiology

Pain Physiology

See: Pain Physiology

Nociceptors
A-delta vs C fibers
Peripheral transduction
Dorsal horn processing
Substance P
NMDA receptors
Ascending pathways
Descending inhibitory pathways

Pain Pathophysiology

See: Pain Pathophysiology

Peripheral sensitization
Central sensitization
Wind-up phenomenon
Neuroimmune activation
Reduced descending inhibition

II. Types of Pain

Nociceptive Pain

See: Nociceptive Pain

Somatic
Visceral
Inflammatory mediators

Neuropathic Pain

See: Neuropathic Pain

Nerve injury or disease
Ectopic firing
Sodium channel dysfunction

Nociplastic Pain

See: Nociplastic Pain

Central sensitization
Altered nociception
Amplified pain processing

Mixed Pain States

See: Mixed Pain States

Combination of mechanisms
Common in chronic pain

III. Acute vs Chronic Pain

Acute Pain

See: Acute Pain

Protective
Tissue injury driven
Short duration

Chronic Pain

See: Chronic Pain

Persistent beyond normal healing
Nervous system remodeling
Central amplification
Psychosocial interaction

IV. Pain Syndromes

Musculoskeletal Syndromes

Musculoskeletal Pain

Neuropathic Syndromes

Neuropathic Pain Syndromes

Centralized Pain Syndromes

Visceral Pain Syndromes

V. Pharmacologic Drug Classes

Pain pharmacotherapy must match mechanism.

This series will cover the following drug classes:

Anti-Inflammatory Agents

Mechanism:

Decrease prostaglandin-mediated sensitization.

Voltage-Gated Sodium Channel Antagonists

Lidocaine
Suzetrigine (Nav 1.8 selective antagonist)

Mechanism:

Block action potential propagation in nociceptors.

Gabapentinoids

Mechanism:

Bind α2δ calcium channel subunit → decrease glutamate & substance P release.

Serotonin & Norepinephrine Reuptake Inhibitors

Mechanism:

Enhance descending inhibitory pathways.

NMDA Receptor Antagonists

Ketamine

Mechanism:

Reduce central sensitization and wind-up.

Opioid Analgesics

Opioids

Mechanism:

μ-receptor activation → decrease ascending pain transmission.

NK1 Receptor Antagonists (Investigational for Pain)

NK1 Antagonists

Mechanism:

Block Substance P at NK1 receptors.

Clinical role in chronic pain remains limited.

Nerve Growth Factor (NGF) Antibodies

Tanezumab
Fasinumab

Mechanism:

Block NGF-mediated nociceptor sensitization.

Not currently approved due to safety concerns.

Cannabinoids

THC
CBD

Mechanism:

CB1/CB2 receptor modulation (evidence evolving).

VI. Special Populations

See: Special Populations in Pain Management

Elderly
Chronic kidney disease
Liver disease
Pregnancy
History of substance use disorder

VII. Case-Based Clinical Applications

See: Case-Based Clinical Applications

Acute injury
Chronic low back pain
Diabetic neuropathy
Fibromyalgia
High-risk opioid patient

Guiding Clinical Principles

• Pain classification determines therapy • Chronic pain often reflects central amplification • Mechanism-directed prescribing improves outcomes • Opioids are powerful but limited tools • Multimodal therapy reduces risk

Pharm Reference: Pain Drug Reference (Mechanism → Best Use)

Class	Drug	Primary Pain Type(s)	Acute vs Chronic	Best Clinical Use	Key Pearls / Major Cautions
NSAIDs	Ibuprofen	Nociceptive (somatic), inflammatory	Acute + Chronic	MSK pain, OA flares	GI/renal risk; ↑BP; avoid in CKD/dehydration; ceiling effect
NSAIDs	Naproxen	Nociceptive, inflammatory	Acute + Chronic	OA, tendinitis	Similar NSAID risks; longer duration
NSAIDs	Diclofenac	Nociceptive, inflammatory	Acute + Chronic	OA (esp topical)	Higher CV risk; topical has less systemic exposure
NSAIDs	Indomethacin	Nociceptive, inflammatory	Acute	Acute gout/indomethacin-responsive pain	More CNS/GI adverse effects vs many NSAIDs
NSAIDs	Celecoxib	Nociceptive, inflammatory	Acute + Chronic	OA/RA, GI-risk patients	COX-2 selective → less GI ulcer risk; still CV/renal risk

Acetaminophen

Nociceptive (mild), fever/pain

Acute + Chronic

Baseline analgesic, combination therapy

Liver toxicity risk; safer in CKD than NSAIDs; ceiling effect

Corticosteroids	Prednisone	Inflammatory pain syndromes	Acute (bursts)	Radiculitis flares, inflammatory pain	Not an analgesic; treat inflammation; hyperglycemia, mood, BP
Corticosteroids	Methylprednisolone	Inflammatory	Acute	Dose packs/flares	Same steroid cautions; short courses preferred
Corticosteroids	Dexamethasone	Inflammatory, cancer-related edema pain	Acute	Severe inflammation/edema	Potent/long acting; insomnia, hyperglycemia

Na+ Channel Antagonists	Lidocaine	Neuropathic (localized), nociceptive (procedural)	Acute + Chronic	Topical neuropathic pain; procedures; patches	Topical helpful in PHN; systemic toxicity if misused
Na+ Channel Antagonists	Suzetrigine	Nociceptive (acute), mixed (emerging)	Acute (primary)	Oral peripheral analgesia (Nav1.8)	Newer agent; keep as “emerging/updates” section

Antiepileptics	Gabapentin	Neuropathic, mixed	Chronic (± acute adjunct)	DPN, PHN, radicular neuropathic pain	Sedation/dizziness; dose adjust CKD; misuse risk
Antiepileptics	Pregabalin	Neuropathic, nociplastic (some)	Chronic	DPN, PHN, fibromyalgia	Faster onset than gabapentin; CKD dose adjust; edema
Antiepileptics	Carbamazepine	Neuropathic (paroxysmal)	Chronic	Trigeminal neuralgia	Hyponatremia; CBC/LFT monitoring; drug interactions
Antiepileptics	Oxcarbazepine	Neuropathic (paroxysmal)	Chronic	Trigeminal neuralgia alt	Hyponatremia; fewer interactions than carbamazepine
Antiepileptics	Lamotrigine	Neuropathic (selected)	Chronic	Selected neuropathic syndromes	Rash/SJS risk; slow titration

SNRIs	Duloxetine	Neuropathic + nociplastic + chronic MSK	Chronic	DPN, fibromyalgia, chronic back pain/OA pain	Nausea, BP; avoid severe liver disease; taper to stop
SNRIs	Venlafaxine	Neuropathic (some)	Chronic	Neuropathic pain alt	BP/withdrawal; dose-dependent NE effects

TCAs	Amitriptyline	Neuropathic + nociplastic	Chronic	Neuropathic pain, sleep-pain overlap	Anticholinergic/QTc; avoid elderly/high fall risk
TCAs	Nortriptyline	Neuropathic + nociplastic	Chronic	Neuropathic pain with fewer side effects than amitriptyline	Still anticholinergic/QTc; start low, go slow

NMDA Antagonists	Ketamine	Hyperalgesia, severe acute pain; CRPS (selected)	Acute/episodic	Opioid-refractory pain, ED/procedural	Dissociation/HTN; protocols; not routine outpatient
NMDA Antagonists	Methadone	Mixed, neuropathic component (via NMDA)	Chronic (specialist)	Chronic severe pain; OUD overlap	QTc; complex kinetics; high interaction burden

Opioids	Morphine	Nociceptive (severe), cancer pain	Acute + Chronic (selected)	Severe acute pain, palliative/cancer	Constipation/resp depression; avoid in CKD (active metabolites)
Opioids	Oxycodone	Nociceptive (severe)	Acute + Chronic (selected)	Severe acute pain	High misuse risk; constipation; taper planning
Opioids	Hydrocodone	Nociceptive (moderate-severe)	Acute	Short-term acute pain	Often combo APAP → watch total APAP dose
Opioids	Fentanyl	Severe nociceptive; periop	Acute (mostly)	OR/ICU; chronic patches in opioid-tolerant	Patch only opioid-tolerant; fatal if misused
Opioids	Buprenorphine	Mixed; chronic pain with safety advantages	Chronic	Pain + OUD overlap; safer respiratory profile	Partial agonist; precipitated withdrawal risk; specialist comfort
Opioids	Tramadol	Mixed (nociceptive + monoaminergic)	Acute/Chronic (selected)	Short courses; selected chronic	Seizure risk; serotonin syndrome; variable metabolism
Opioids	Tapentadol	Mixed; neuropathic component	Acute + Chronic (selected)	Severe pain with neuropathic component	μ + NE reuptake; still opioid risks

Alpha-2 Agonists	Clonidine	Neuropathic adjunct; withdrawal-related pain	Acute/adjunct	Adjunct analgesia; periop; sympathetic-driven pain	Hypotension/bradycardia; rebound HTN if abrupt stop
Alpha-2 Agonists	Dexmedetomidine	Acute analgesic-sparing (ICU/periop)	Acute	ICU sedation w/ analgesic sparing	Bradycardia/hypotension; monitored settings

Muscle Relaxants	Cyclobenzaprine	Acute MSK spasm pain	Acute	Acute back/neck spasm	Sedating/anticholinergic; avoid elderly
Muscle Relaxants	Tizanidine	Spasticity-related pain; MSK spasm	Acute/Chronic	Spasm/spasticity	Hypotension/sedation; CYP1A2 interactions
Muscle Relaxants	Baclofen	Spasticity pain	Chronic	Neuro spasticity	Withdrawal if abrupt stop; sedation

Topical Analgesics	Topical Lidocaine	Neuropathic (localized)	Chronic	PHN, focal neuropathic pain	Low systemic risk; site reactions
Topical Analgesics	Capsaicin	Neuropathic (localized), some nociplastic	Chronic	Peripheral neuropathic pain	Burning initially; adherence barrier
Topical Analgesics	Topical Diclofenac	Nociceptive inflammatory	Acute + Chronic	OA localized joints	Lower systemic risk than oral NSAIDs

Triptans	Sumatriptan	Migraine/headache syndromes	Acute	Abort migraine	Contra CAD/uncontrolled HTN; medication overuse
Triptans	Rizatriptan	Migraine/headache	Acute	Abort migraine	Same triptan cautions

CGRP Antagonists	Ubrogepant	Migraine/headache	Acute	Abort migraine	No vasoconstriction; CYP interactions
CGRP Antagonists	Rimegepant	Migraine/headache	Acute (± prevention depending use)	Abort migraine	Useful when triptans contraindicated

Botulinum Toxin

OnabotulinumtoxinA

Chronic migraine

Chronic

Prevention (chronic migraine)

Procedure-based; q12 weeks typical

NK1 Antagonists

Aprepitant

Investigational (pain)

N/A

Primarily antiemetic; pain research only

Not established analgesic clinically

NGF Antibodies	Tanezumab	Nociceptive (OA)	Chronic	OA pain (investigational/limited)	Safety concerns (joint damage); not routine
NGF Antibodies	Fasinumab	Nociceptive (OA)	Chronic	OA pain (investigational/limited)	Similar concerns; evolving status

Cannabinoids	THC	Neuropathic (modest), mixed	Chronic (selected)	Adjunct in selected chronic pain	Cognition/anxiety; variability; safety/legal issues
Cannabinoids	CBD	Mixed (variable evidence)	Chronic (selected)	Adjunct	Interaction potential; product variability

Quick interpretation: • Nociceptive pain → NSAIDs/APAP ± short opioid course; topical NSAID for localized OA • Neuropathic pain → gabapentinoids, SNRIs, TCAs, Na+ blockers; opioids often weak long-term • Nociplastic pain → SNRIs/TCAs + exercise/sleep; avoid chronic opioids when possible • Migraine/headache → triptans/gepants acute; botox prevention for chronic migraine