Clinical Setting

Pain Management

Acute and chronic pain, nociceptive and neuropathic mechanisms, opioid pharmacology, interventional procedures, neuromodulation, multimodal analgesia, and every scoring tool, drug conversion, and treatment algorithm across the full scope of pain medicine.

01 Pain Neuroanatomy & Physiology

Pain perception is a complex process involving peripheral transduction, spinal cord transmission, supraspinal processing, and descending modulation. Understanding these mechanisms is essential for selecting targeted interventions at every level of the pain pathway.

Peripheral Nociceptors & Primary Afferents

Nociceptors are free nerve endings of primary afferent neurons whose cell bodies reside in the dorsal root ganglia (DRG) or trigeminal ganglion. They respond to noxious mechanical, thermal, or chemical stimuli. Two principal fiber types carry nociceptive information:

Feature	A-delta Fibers	C Fibers
Diameter	2–5 µm (thinly myelinated)	0.4–1.2 µm (unmyelinated)
Conduction velocity	5–30 m/s	0.5–2 m/s
Pain quality	Sharp, well-localized “first pain”	Dull, burning, aching “second pain”
Modality	Mechanical and mechanothermal nociceptors	Polymodal nociceptors (mechanical, thermal, chemical)
Neurotransmitters	Glutamate	Glutamate, substance P, CGRP
Laminar termination	Laminae I and V of dorsal horn	Laminae I and II (substantia gelatinosa)

A-beta fibers (large, myelinated, 30–70 m/s) normally carry innocuous touch but may transmit pain signals after peripheral or central sensitization, contributing to allodynia (pain from normally non-painful stimuli).

Dorsal Horn Processing & Gate Control Theory

The dorsal horn of the spinal cord is the first major relay and processing center for nociceptive input. The Rexed laminae organize sensory processing: Lamina I (marginal zone) receives A-delta and C fibers; Lamina II (substantia gelatinosa) is rich in inhibitory interneurons; Lamina V contains wide dynamic range (WDR) neurons that receive both nociceptive and non-nociceptive input and are critical to central sensitization.

Gate Control Theory (Melzack & Wall, 1965)

Non-nociceptive input via large-diameter A-beta fibers activates inhibitory interneurons in the substantia gelatinosa, which “close the gate” on nociceptive C-fiber transmission to projection neurons. This explains why rubbing an injured area reduces pain, and provides the theoretical basis for transcutaneous electrical nerve stimulation (TENS) and spinal cord stimulation (SCS). Conversely, loss of A-beta input (as in peripheral neuropathy) “opens the gate,” facilitating pain transmission.

Ascending Pain Pathways

Tract	Origin	Decussation	Destination	Function
Spinothalamic (lateral)	Laminae I, V	Ventral white commissure (1–2 levels above entry)	VPL thalamus → S1/S2 cortex	Pain localization, intensity (sensory-discriminative)
Spinoreticular	Laminae VII, VIII	Bilateral	Reticular formation → medial thalamus	Arousal, autonomic responses, affective-motivational
Spinomesencephalic	Laminae I, V	Contralateral	PAG, superior colliculus	Activates descending modulation
Spinohypothalamic	Laminae I, V, X	Bilateral	Hypothalamus	Neuroendocrine and autonomic responses to pain

Descending Modulation

The periaqueductal gray (PAG) receives input from the cortex, hypothalamus, and amygdala, and projects to the rostral ventromedial medulla (RVM). The RVM contains ON cells (facilitate pain) and OFF cells (inhibit pain). Descending pathways travel in the dorsolateral funiculus and release serotonin (5-HT) and norepinephrine (NE) at the dorsal horn, activating enkephalinergic interneurons. This is the mechanism of action of SNRIs (duloxetine, venlafaxine) and TCAs in pain management — they augment descending inhibition by blocking reuptake of 5-HT and NE.

The endogenous opioid system (endorphins, enkephalins, dynorphins) operates at all three levels: peripheral nociceptors, dorsal horn, and PAG/RVM. This explains why exogenous opioids are effective but also why tolerance develops simultaneously across multiple pathways.

Peripheral & Central Sensitization

Peripheral sensitization occurs when tissue injury releases an “inflammatory soup” (bradykinin, prostaglandins, histamine, serotonin, nerve growth factor, H⁺, ATP) that lowers the activation threshold of nociceptors via TRPV1 and sodium channels. This manifests as primary hyperalgesia at the site of injury. NSAIDs and corticosteroids target this mechanism.

Central sensitization is increased excitability of dorsal horn neurons driven by sustained C-fiber input. Key mechanisms include: (1) Wind-up — progressive increase in action potential output of dorsal horn neurons with repetitive C-fiber stimulation at constant intensity, mediated by temporal summation at NMDA receptors; (2) NMDA receptor activation by glutamate/substance P removes the Mg²⁺ block, allowing Ca²⁺ influx and long-term potentiation (LTP); (3) Microglial activation releasing proinflammatory cytokines (TNF-alpha, IL-1beta, IL-6); (4) Loss of inhibitory interneuron function (GABAergic/glycinergic disinhibition).

Clinical Manifestations of Sensitization

Allodynia — pain from a stimulus that does not normally cause pain (e.g., light touch)
Hyperalgesia — increased pain from a stimulus that normally causes pain
Secondary hyperalgesia — increased pain sensitivity in uninjured tissue surrounding the injury (central mechanism)
Wind-up — progressive increase in pain with repetitive stimulation at identical intensity
Temporal summation — increased pain perception when stimuli are repeated at ≥0.3 Hz
Referred pain — pain perceived at a location distant from the source, due to convergence of visceral and somatic afferents on shared WDR neurons

Neuroplasticity in Chronic Pain

Persistent nociceptive input drives structural and functional changes in the CNS: dorsal horn neuron phenotypic switching (A-beta fibers expressing substance P), cortical reorganization (shrinkage of dorsal lateral prefrontal cortex, expansion of pain-processing areas on fMRI), hippocampal volume loss, and alterations in the default mode network. These changes explain why chronic pain behaves as a disease of the nervous system rather than merely a symptom of ongoing tissue damage.

Key Neurotransmitters & Receptors in Pain Processing

Molecule / Receptor	Role in Pain	Pharmacologic Target
Glutamate / NMDA receptor	Primary excitatory NT; NMDA activation critical for wind-up and central sensitization	Ketamine, methadone, memantine, magnesium
Substance P / NK-1 receptor	Released by C fibers; facilitates nociceptive transmission in dorsal horn	Capsaicin depletes substance P; NK-1 antagonists (aprepitant) for CINV
GABA / GABA-A, GABA-B	Primary inhibitory NT in dorsal horn; loss of GABAergic inhibition promotes central sensitization	Baclofen (GABA-B), benzodiazepines (GABA-A); gabapentinoids act on Ca²⁺ channels, not GABA receptors
Serotonin (5-HT)	Descending modulation from RVM; both facilitatory and inhibitory depending on receptor subtype	SNRIs, TCAs, triptans (5-HT1B/1D for migraine)
Norepinephrine (NE)	Descending inhibition from locus coeruleus via alpha-2 receptors in dorsal horn	SNRIs, TCAs, clonidine, dexmedetomidine
Prostaglandin E2 (PGE2)	Peripheral sensitization; lowers nociceptor threshold via EP receptors	NSAIDs block COX-mediated PGE2 synthesis
TRPV1 (vanilloid receptor)	Heat/capsaicin-activated ion channel on C fibers; mediates thermal hyperalgesia	Capsaicin 8% patch (agonist → desensitization/defunctionalization)
Voltage-gated Na⁺ channels (Nav1.7, 1.8, 1.9)	Generate and propagate action potentials in nociceptors; gain-of-function mutations cause erythromelalgia	Carbamazepine, oxcarbazepine, lidocaine, lacosamide

02 Pain Classification & Assessment

Mechanistic Classification

Type	Mechanism	Character	Examples	Treatment Targets
Nociceptive — Somatic	Activation of nociceptors in skin, bone, muscle, joints	Well-localized, sharp, aching, throbbing	Fractures, OA, surgical incisions, muscle strain	NSAIDs, acetaminophen, opioids, local anesthetics
Nociceptive — Visceral	Activation of nociceptors in hollow/solid organs	Diffuse, crampy, pressure, referred	Pancreatitis, bowel obstruction, renal colic, angina	Opioids, antispasmodics, nerve blocks (celiac plexus)
Neuropathic	Lesion or disease of somatosensory nervous system	Burning, shooting, electric, tingling, numbness	DPN, PHN, trigeminal neuralgia, radiculopathy, CRPS-II	Gabapentinoids, SNRIs, TCAs, topical lidocaine, SCS
Nociplastic	Altered nociception without tissue damage or nerve lesion (central sensitization)	Widespread, fluctuating, fatigue, cognitive fog	Fibromyalgia, IBS, tension-type HA, interstitial cystitis	SNRIs, gabapentinoids, exercise, CBT, no opioids

Temporal Classification

Acute pain (<3 months) is a protective mechanism signaling tissue injury; it correlates with identifiable pathology and is expected to resolve with healing. Chronic pain (≥3 months or beyond expected healing time) is a disease state involving maladaptive neuroplasticity and is often dissociated from ongoing tissue damage. Subacute pain (6 weeks–3 months) represents the transitional period where aggressive intervention may prevent chronification.

Unidimensional Pain Scales

Scale	Type	Range	Population	Interpretation
NRS (Numeric Rating Scale)	Patient self-report	0–10	Adults, cognitively intact	0 = no pain; 1–3 mild; 4–6 moderate; 7–10 severe
VAS (Visual Analog Scale)	Patient self-report	0–100 mm line	Adults, research settings	Patient marks a point on a 100 mm line; measured in mm
Wong-Baker FACES	Patient self-report (visual)	0–10 (6 faces)	Children ≥3 years, cognitively impaired adults	Patient selects the face matching their pain level
FLACC	Behavioral observation	0–10	Children 2 months–7 years, nonverbal	Face, Legs, Activity, Cry, Consolability — each 0–2
CPOT	Behavioral observation	0–8	ICU patients, intubated/sedated	Facial expression, body movements, muscle tension, ventilator compliance — each 0–2

Multidimensional Assessment Tools

The McGill Pain Questionnaire (MPQ) assesses four dimensions: sensory (e.g., throbbing, shooting, stabbing), affective (e.g., tiring, sickening, fearful), evaluative (overall intensity), and miscellaneous. The short form (SF-MPQ-2) includes 22 descriptors rated 0–10. The Brief Pain Inventory (BPI) measures pain intensity (4 items: worst, least, average, current pain) and pain interference (7 items: general activity, mood, walking, work, relations, sleep, enjoyment) on 0–10 scales.

PEG Scale (3-Item Screening)

A rapid, validated screening tool for chronic pain assessment in primary care:

P — What number best describes your Pain on average in the past week? (0–10)
E — What number best describes how pain has interfered with your Enjoyment of life? (0–10)
G — What number best describes how pain has interfered with your General activity? (0–10)

Mean score ≥4 suggests clinically significant pain requiring further assessment. Track over time to monitor treatment response (clinically meaningful change ≥1.0 point).

Functional Assessment

Pain intensity scores alone are insufficient. A comprehensive pain evaluation must include: functional status (ADLs, IADLs, employment, mobility), psychological screening (PHQ-9 for depression, GAD-7 for anxiety, PCS for pain catastrophizing), sleep quality, substance use history, and social determinants. Document the “5 A’s” of pain management at each visit: Analgesia, Activity, Adverse effects, Aberrant behavior, and Affect.

03 Terminology & Abbreviations

Term	Definition
Allodynia	Pain from a stimulus that does not normally cause pain
Hyperalgesia	Increased pain from a normally painful stimulus
Hyperpathia	Exaggerated pain response, especially to repetitive stimuli, with increased threshold
Dysesthesia	Unpleasant abnormal sensation, spontaneous or evoked
Paresthesia	Abnormal sensation (tingling, prickling) that is not unpleasant
Analgesia	Absence of pain in response to normally painful stimulation
Anesthesia dolorosa	Pain in an area that is numb or has no sensation
Causalgia	Burning pain after peripheral nerve injury (CRPS Type II)
Deafferentation pain	Pain due to loss of afferent sensory input (e.g., phantom limb, brachial plexus avulsion)
Nociception	Neural process of encoding noxious stimuli (not synonymous with pain)
Central sensitization	Increased excitability of central neurons, leading to amplified pain processing
Wind-up	Progressive increase in dorsal horn neuron output to repetitive C-fiber stimulation
Tolerance	Decreased effect of a drug with repeated use, requiring dose escalation for same effect
Physical dependence	Adaptation producing withdrawal symptoms upon abrupt discontinuation or dose reduction
Addiction (OUD)	Compulsive use despite harm; loss of control; craving; continued use despite consequences
Pseudoaddiction	Drug-seeking behavior driven by undertreated pain (controversial concept)
Breakthrough pain	Transient flare of pain exceeding controlled baseline — spontaneous or incident-related
Equianalgesic dose	Dose of one opioid that provides analgesia equivalent to a reference dose of another
MME	Morphine milligram equivalents — standardized unit for comparing opioid doses
Opioid-induced hyperalgesia (OIH)	Paradoxical increased pain sensitivity caused by opioid exposure

Distinguish tolerance (pharmacologic adaptation — needs more drug for same effect), physical dependence (withdrawal on cessation — expected physiologic response), and addiction/OUD (behavioral disorder with compulsive use). Physical dependence and tolerance are NOT diagnostic of addiction.

Common Abbreviations in Pain Medicine

Abbreviation	Meaning	Abbreviation	Meaning
NRS	Numeric Rating Scale	VAS	Visual Analog Scale
ESI	Epidural Steroid Injection	MBB	Medial Branch Block
RFA	Radiofrequency Ablation	SCS	Spinal Cord Stimulation
DRG	Dorsal Root Ganglion	CRPS	Complex Regional Pain Syndrome
MME	Morphine Milligram Equivalent	ORT	Opioid Risk Tool
PDMP	Prescription Drug Monitoring Program	UDS	Urine Drug Screen
NMDA	N-Methyl-D-Aspartate	SNRI	Serotonin-Norepinephrine Reuptake Inhibitor
TCA	Tricyclic Antidepressant	COX	Cyclooxygenase
PAG	Periaqueductal Gray	RVM	Rostral Ventromedial Medulla
TENS	Transcutaneous Electrical Nerve Stimulation	FBSS	Failed Back Surgery Syndrome
OIH	Opioid-Induced Hyperalgesia	OIAD	Opioid-Induced Androgen Deficiency
ERAS	Enhanced Recovery After Surgery	IDDS	Intrathecal Drug Delivery System

04 Acetaminophen & NSAIDs

Acetaminophen

Mechanism: Centrally acting; proposed mechanisms include inhibition of COX-3 (a splice variant of COX-1 in the CNS), augmentation of descending serotonergic inhibition, and activation of the endocannabinoid system via AM404 metabolite acting on TRPV1 and CB1 receptors. Lacks peripheral anti-inflammatory activity.

Parameter	Detail
Standard dose	650–1000 mg PO/PR q4–6h; IV 1000 mg q6h (650 mg if <50 kg)
Max daily dose (healthy adult)	4000 mg/day (FDA recommends ≤3000 mg/day for OTC use)
Max daily dose (hepatic impairment/alcohol)	≤2000 mg/day
Hepatotoxicity threshold	≥150 mg/kg or ≥7.5 g single ingestion → NAC protocol
Onset / Duration	PO: 30–60 min onset, 4–6 h duration; IV: 5–10 min onset
Advantages	No GI/renal/platelet toxicity; safe in renal failure; pregnancy Category B

IV acetaminophen is frequently ordered perioperatively, but systematic reviews show it provides only 1–2 point NRS reduction and is vastly more expensive than PO ($30–40/dose vs $0.03/dose). Reserve IV for patients who cannot take PO. Onset is NOT significantly faster than oral for most clinical scenarios.

NSAIDs — Mechanism & Classification

NSAIDs inhibit cyclooxygenase (COX), blocking conversion of arachidonic acid to prostaglandins (PGE2, PGI2) and thromboxane A2. COX-1 is constitutive (gastric mucosal protection, platelet aggregation, renal blood flow). COX-2 is inducible at sites of inflammation (also constitutive in kidney and vascular endothelium).

Drug	COX Selectivity	Dose	Half-life	Key Notes
Ibuprofen	Non-selective	200–800 mg PO q6–8h (max 3200 mg/day)	2–4 h	OTC; lowest CV risk among non-selective NSAIDs
Naproxen	Non-selective	250–500 mg PO BID (max 1500 mg/day)	12–17 h	Lowest CV risk of all NSAIDs; preferred in CV patients
Diclofenac	Slightly COX-2 selective	50 mg PO TID or 75 mg BID (max 150 mg/day)	1–2 h	Also available topical (1% gel, 1.5% solution, patch)
Ketorolac	Non-selective (potent)	15–30 mg IV/IM q6h; 10 mg PO q4–6h	5–6 h	Max 5 days total; most potent parenteral NSAID
Meloxicam	Preferential COX-2	7.5–15 mg PO daily	15–20 h	Once daily dosing; intermediate COX-2 selectivity
Celecoxib	Selective COX-2	100–200 mg PO BID (max 400 mg/day)	11 h	Reduced GI risk; sulfonamide allergy caution; PRECISION trial showed non-inferior CV safety to naproxen/ibuprofen
Indomethacin	Non-selective (potent)	25–50 mg PO TID (max 200 mg/day)	4.5 h	Potent; used for gout, hemicrania continua; high GI risk

NSAID Risk Profile

GI: All NSAIDs ↑ risk of ulcers/bleeding (3–5x baseline). Risk factors: age >65, H. pylori, concurrent anticoagulants/corticosteroids, prior GI bleed. Mitigate with PPI co-therapy or COX-2 selective agent
Renal: Prostaglandin-mediated afferent arteriolar dilation is critical in low-flow states. Avoid in CKD stage ≥4, HF, cirrhosis, hypovolemia. Risk of AIN, papillary necrosis, hyperkalemia, sodium/water retention
Cardiovascular: All NSAIDs (except naproxen) increase risk of MI and stroke. COX-2 inhibitors shift prostacyclin/thromboxane balance toward prothrombotic state. Contraindicated post-CABG (black box warning)
Platelet: Aspirin irreversibly inhibits COX-1 in platelets; all other NSAIDs reversibly inhibit — hold 5 half-lives before surgery

Topical NSAIDs

Diclofenac gel 1% (Voltaren): 4g applied QID to affected joint (max 16g/day per joint for lower extremities, 8g/day for upper). Achieves therapeutic tissue concentrations with <5% systemic absorption. NNT of 6.4 for OA knee pain. Preferred in elderly to minimize systemic adverse effects. Diclofenac 1.5% topical solution: 40 drops applied QID; used with dimethyl sulfoxide carrier. Diclofenac epolamine patch (Flector): Applied BID for acute strains/sprains; 180 mg per patch with 10–15 mg delivered over 12 hours.

NSAID Selection Algorithm

No CV/GI/renal risk: Any NSAID (ibuprofen or naproxen preferred for cost and safety data)
High GI risk, low CV risk: Celecoxib OR non-selective NSAID + PPI
High CV risk, low GI risk: Naproxen (lowest CV risk); avoid all NSAIDs if possible post-MI/stroke
High GI + high CV risk: Avoid NSAIDs if possible; if necessary, naproxen + PPI or celecoxib + PPI at lowest dose for shortest duration
CKD stage ≥4 or acute kidney injury: Avoid ALL NSAIDs including topical (minimal but non-zero systemic absorption)
Pregnancy: Avoid after 20 weeks (oligohydramnios risk); contraindicated after 30 weeks (premature ductus arteriosus closure)
Elderly (>65): Topical NSAIDs first-line; if systemic needed, lowest dose, shortest duration, with PPI; Beers criteria caution

05 Neuropathic Pain Agents

First-line agents for neuropathic pain include gabapentinoids, SNRIs, and TCAs. Selection is guided by pain type, comorbidities, side-effect profile, and cost. NNT for ≥50% pain reduction ranges from 3.6 to 7.7 for first-line agents.

Drug	Mechanism	Starting Dose	Titration	Target/Max	Key Considerations
Gabapentin	Binds alpha-2-delta subunit of voltage-gated Ca²⁺ channels; reduces excitatory neurotransmitter release	100–300 mg QHS	Increase by 300 mg q3–7 days; TID dosing	1800–3600 mg/day in 3 divided doses	Nonlinear absorption (bioavailability decreases at higher doses); renal dosing required; sedation, dizziness, edema; schedule V in some states
Pregabalin	Same as gabapentin; linear pharmacokinetics	75 mg BID or 50 mg TID	Increase to 150 mg BID after 1 week; then 300 mg BID after 1 week	300 mg BID (600 mg/day)	Schedule V (DEA); faster onset than gabapentin; approved for DPN, PHN, fibromyalgia, SCI pain
Duloxetine	SNRI; augments descending 5-HT/NE inhibition	30 mg daily × 1 week	Increase to 60 mg daily	60–120 mg daily	Approved DPN, fibromyalgia, chronic MSK pain, OA; avoid in hepatic impairment, CrCl <30; nausea most common SE; discontinuation syndrome
Venlafaxine	SNRI (NE effect ≥150 mg)	37.5 mg daily	Increase by 75 mg q1–2 weeks	150–225 mg daily	NE reuptake inhibition requires ≥150 mg; hypertension at higher doses; less evidence than duloxetine for pain
Amitriptyline	TCA; blocks 5-HT/NE reuptake, Na⁺ channels, NMDA receptors	10–25 mg QHS	Increase by 10–25 mg q1–2 weeks	75 mg QHS (analgesic ceiling)	Strong evidence for neuropathic pain; anticholinergic SEs limit use in elderly; ECG before starting (>50 years); QTc prolongation; weight gain, sedation
Nortriptyline	TCA; less anticholinergic than amitriptyline	10–25 mg QHS	Same as amitriptyline	75 mg QHS	Preferred TCA in elderly due to fewer anticholinergic effects; same efficacy as amitriptyline
Carbamazepine	Na⁺ channel blockade	100 mg BID	Increase by 200 mg q3–7 days	400–1200 mg/day in divided doses	First-line for trigeminal neuralgia (NNT 1.7); HLA-B*1502 testing in Asian patients (SJS risk); autoinduction; drug interactions; CBC/LFT monitoring
Oxcarbazepine	Na⁺ channel blockade	150 mg BID	Increase by 300 mg q1 week	1200–2400 mg/day	Alternative to carbamazepine for trigeminal neuralgia; fewer drug interactions; risk of hyponatremia

Topical Agents for Neuropathic Pain

Lidocaine 5% patch: Apply up to 3 patches for 12 hours on, 12 hours off. Approved for PHN. Minimal systemic absorption. Can be used as first-line in localized neuropathic pain, especially in elderly. Capsaicin 8% patch (Qutenza): Applied for 60 minutes by a healthcare professional; depletes substance P from C fibers via TRPV1 agonism. Approved for PHN; can provide 3 months of relief per application. Pre-treat area with topical lidocaine. Capsaicin 0.025–0.075% cream: OTC; apply TID–QID; requires 2–4 weeks of consistent use for efficacy; burning on initial application is common and often limits adherence.

When combining neuropathic agents, pair medications with different mechanisms (e.g., gabapentinoid + SNRI) to achieve synergistic effect while minimizing dose-dependent side effects of each individual agent. The COMBO-DN trial showed gabapentin + nortriptyline was superior to either agent alone for DPN.

Neuropathic Pain Treatment Algorithm

Evidence-Based Neuropathic Pain Algorithm

First-line (choose based on comorbidities):
- Gabapentin or pregabalin — preferred if anxiety, insomnia, or no depression
- Duloxetine or venlafaxine — preferred if concurrent depression, anxiety, fibromyalgia, or chronic MSK pain
- TCA (amitriptyline/nortriptyline) — effective and cheap; avoid in elderly, cardiac disease, or overdose risk; nortriptyline preferred in elderly for fewer anticholinergic effects
- Topical lidocaine 5% — first-line for localized neuropathic pain, especially PHN in elderly (no systemic effects)
Second-line (if monotherapy fails after adequate trial 4–8 weeks at therapeutic dose):
- Combination therapy: gabapentinoid + SNRI or gabapentinoid + TCA (avoid SNRI + TCA due to serotonin syndrome risk)
- Capsaicin 8% patch (Qutenza) for localized neuropathic pain
- Tramadol (dual mechanism; weak mu agonism + NRI)
Third-line: Strong opioids (morphine, oxycodone) in carefully selected patients; botulinum toxin type A (subcutaneous injection for PHN/DPN — NNT 1.9); lacosamide, lamotrigine (limited evidence)
Fourth-line / Refractory: SCS or DRG stimulation; intrathecal drug delivery; NMDA antagonists (ketamine infusion)

Condition-Specific First-Line Agents

Condition	Preferred First-Line	Notes
Diabetic peripheral neuropathy	Duloxetine, pregabalin, gabapentin	All three FDA-approved for DPN; duloxetine preferred if concurrent depression
Postherpetic neuralgia	Gabapentin, pregabalin, lidocaine 5% patch, capsaicin 8%	Topicals preferred in elderly; prevention with zoster vaccine more effective than treatment
Trigeminal neuralgia	Carbamazepine (NNT 1.7)	Oxcarbazepine as alternative; if refractory → MVD (microvascular decompression) or percutaneous procedures
Central post-stroke pain	Amitriptyline, lamotrigine, pregabalin	Gabapentin less effective for central pain; opioids generally ineffective
Spinal cord injury pain	Pregabalin (FDA-approved), gabapentin, amitriptyline	Pregabalin only gabapentinoid FDA-approved for SCI neuropathic pain
HIV neuropathy	Capsaicin 8% patch, lamotrigine	Gabapentinoids and TCAs show limited efficacy in HIV neuropathy specifically

06 Muscle Relaxants & Adjuvants

Skeletal Muscle Relaxants

Drug	Mechanism	Dose	Key Notes
Cyclobenzaprine	Centrally acting; structurally related to TCAs; reduces tonic somatic motor activity at brainstem	5–10 mg PO TID (or 5 mg QHS for tolerability); ER 15–30 mg daily	Most studied; efficacy best in acute MSK spasm; sedation most common SE; avoid in elderly (Beers list); short-term use (≤2–3 weeks)
Tizanidine	Alpha-2 adrenergic agonist; reduces excitatory input at spinal interneurons	2–4 mg PO TID (max 36 mg/day)	Less sedating than cyclobenzaprine at low doses; monitor LFTs (hepatotoxicity); CYP1A2 substrate — avoid with fluvoxamine, ciprofloxacin; hypotension, dry mouth
Baclofen	GABA-B agonist; inhibits monosynaptic and polysynaptic reflexes at spinal level	5 mg PO TID, titrate by 5 mg q3 days (max 80 mg/day); intrathecal 50–100 mcg test dose	Best evidence for spasticity (MS, SCI, CP); intrathecal baclofen for severe spasticity; abrupt withdrawal → life-threatening syndrome (seizures, hyperthermia, rhabdomyolysis); renal dosing
Methocarbamol	Central sedative effect; poorly understood mechanism	1500 mg PO QID × 2–3 days, then 750–1000 mg TID–QID	Available IV; less sedating; relatively safe in elderly compared to other muscle relaxants
Carisoprodol	Metabolized to meprobamate (barbiturate-like); sedative, anxiolytic	250–350 mg PO TID + QHS	Schedule IV; high abuse potential; produces euphoria; avoid — no evidence of superiority over safer alternatives; withdrawal can be life-threatening
Dantrolene	Direct-acting; blocks Ca²⁺ release from sarcoplasmic reticulum (ryanodine receptor)	25 mg daily, titrate to 100 mg QID	Only direct-acting relaxant; used for spasticity, malignant hyperthermia, NMS; hepatotoxicity — monitor LFTs

NMDA Receptor Antagonists

Ketamine is a non-competitive NMDA receptor antagonist with additional activity at opioid, monoaminergic, and cholinergic receptors. In sub-anesthetic doses (0.1–0.5 mg/kg/h IV infusion), it reduces central sensitization, opioid tolerance, and opioid-induced hyperalgesia without causing dissociative anesthesia.

Sub-Anesthetic Ketamine Indications & Dosing

Acute pain (perioperative): 0.5 mg/kg IV bolus, then 0.1–0.3 mg/kg/h infusion (no need for intubation at these doses)
CRPS: Outpatient infusions 0.5 mg/kg over 4 hours, daily × 5 days; evidence supports short-term benefit
Treatment-resistant chronic pain: 0.1–0.5 mg/kg/h × 4–8 hours; may provide weeks of relief
Opioid-tolerant patients: Perioperative adjunct reduces opioid consumption by 30–50%
Side effects: Dysphoria, vivid dreams, nystagmus, hypertension, tachycardia; co-administer midazolam 1–2 mg for psychomimetic effects

Other Adjuvants

Magnesium sulfate: NMDA receptor antagonist (Mg²⁺ blocks the channel pore); 30–50 mg/kg IV bolus then 10–15 mg/kg/h infusion; perioperative adjunct reduces opioid consumption; monitor for hypotension, loss of deep tendon reflexes. Clonidine: Alpha-2 agonist; 0.1–0.3 mg PO BID or transdermal patch; useful adjunct for neuropathic pain and opioid withdrawal; side effects include hypotension, bradycardia, sedation. Dexmedetomidine: Highly selective alpha-2 agonist; 0.2–0.7 mcg/kg/h IV; used as ICU sedation adjunct with analgesic-sparing properties; procedural sedation for interventional pain procedures.

07 Corticosteroids & Anti-Inflammatory Agents

Systemic Corticosteroids

Agent	Relative Potency	Half-life	Dose / Protocol	Indication
Prednisone	1 (reference)	18–36 h	Taper: 60 mg × 3d → 40 mg × 3d → 20 mg × 3d → 10 mg × 3d; or 1 mg/kg × 5d then taper over 1–2 weeks	Acute radiculopathy, CRPS flares, cluster headache
Methylprednisolone dose pack	1.25	18–36 h	21 tablets: Day 1: 24 mg; Day 2: 20 mg; Day 3: 16 mg; Day 4: 12 mg; Day 5: 8 mg; Day 6: 4 mg	Acute radiculopathy, inflammatory flares; short-course convenience
Dexamethasone	6.67	36–54 h	4–10 mg PO/IV/IM daily × 3–5 days	Severe radiculopathy, cancer pain, spinal cord compression, cerebral edema

Injectable Corticosteroids for Pain Procedures

Agent	Type	Concentration	Common Doses	Notes
Triamcinolone acetonide	Particulate	40 mg/mL	Epidural: 40–80 mg; joint: 20–40 mg (large), 10–20 mg (small)	Most commonly used; long-acting; risk of embolic infarct if injected intra-arterially (transforaminal)
Methylprednisolone acetate	Particulate	40 or 80 mg/mL	Epidural: 40–80 mg; joint: 20–80 mg	Similar to triamcinolone; risk of arachnoiditis with intrathecal injection (contains PEG)
Betamethasone sodium phosphate/acetate	Mixed (particulate + soluble)	6 mg/mL	Epidural: 6–12 mg; joint: 3–6 mg	Smaller particles than triamcinolone; intermediate risk profile
Dexamethasone sodium phosphate	Non-particulate (soluble)	4 or 10 mg/mL	Epidural: 8–10 mg; joint: 4–8 mg	Non-particulate — REQUIRED for cervical transforaminal ESI to avoid embolic stroke; may have shorter duration of effect

For cervical transforaminal epidural steroid injections, use ONLY non-particulate dexamethasone. Particulate steroids (triamcinolone, methylprednisolone) can cause catastrophic embolic stroke via the vertebral or radicular arteries. This recommendation is endorsed by the Multi-Society Pain Workgroup (2015).

Epidural Steroid Injection Frequency Limits

Maximum 3 epidural steroid injections per spinal region per 12-month period
Minimum 2-week interval between injections (some guidelines recommend 4–6 weeks)
No more than 4–6 total epidural steroid injections per year across all regions
Rationale: Cumulative exogenous corticosteroid burden → HPA axis suppression, bone loss, hyperglycemia, immunosuppression
Diabetic patients: Warn of blood glucose elevation for 1–2 weeks post-injection; may need temporary insulin adjustment

08 Opioid Receptor Pharmacology

Opioid Receptor Types & Effects

Receptor	Endogenous Ligand	Location	Effects of Activation	Clinical Relevance
Mu (μ) (MOR)	Beta-endorphin, endomorphins	PAG, RVM, dorsal horn (lamina II), GI tract, nucleus accumbens	Analgesia (supraspinal & spinal), euphoria, respiratory depression, miosis, constipation, pruritus, physical dependence, bradycardia	Primary target of most clinical opioids; mu-1 (analgesia) vs mu-2 (respiratory depression, constipation) subtypes proposed
Kappa (κ) (KOR)	Dynorphin	Dorsal horn, hypothalamus, limbic system	Analgesia (spinal & visceral), sedation, dysphoria, diuresis, miosis	Butorphanol, nalbuphine, pentazocine act here; ceiling effect for respiratory depression; dysphoria limits abuse potential
Delta (δ) (DOR)	Enkephalins (met-, leu-)	Cortex, olfactory bulb, dorsal horn	Analgesia (modulates mu), anxiolysis, antidepressant effects, respiratory depression (minor)	Research target; delta agonists may provide analgesia without dependence; limited clinical agents
NOP/ORL1	Nociceptin/orphanin FQ	Cortex, amygdala, spinal cord	Complex: anti-analgesic supraspinally, analgesic spinally; anxiolysis	Emerging target; nociceptin receptor agonists in development

Opioid Drug Classifications

Classification	Definition	Examples
Full agonist	Binds and fully activates mu receptor; no ceiling for analgesia (ceiling for respiratory depression is death)	Morphine, hydromorphone, fentanyl, oxycodone, hydrocodone, methadone
Partial agonist	Binds mu receptor but produces submaximal activation even at full receptor occupancy; ceiling effect	Buprenorphine (partial mu agonist / kappa antagonist)
Mixed agonist-antagonist	Agonist at one receptor, antagonist at another	Butorphanol (kappa agonist / mu antagonist), nalbuphine (kappa agonist / mu antagonist), pentazocine (kappa agonist / weak mu antagonist)
Full antagonist	Binds receptor without activation; competitively displaces agonists	Naloxone (IV, t½ 30–90 min), naltrexone (PO, t½ 4–12 h)

Signaling & Tolerance Mechanisms

Opioids act via G-protein coupled receptors (GPCRs): Gi/Go activation → (1) inhibition of adenylyl cyclase → decreased cAMP; (2) opening of inwardly rectifying K⁺ channels (GIRK) → hyperpolarization; (3) closing of voltage-gated Ca²⁺ channels → decreased neurotransmitter release. Tolerance develops through receptor phosphorylation by GRK, beta-arrestin recruitment leading to receptor internalization, and NMDA receptor-mediated neuroplasticity. Tolerance develops at different rates for different effects: rapid for euphoria and nausea, moderate for analgesia and sedation, slow for constipation and miosis.

Opioid-Induced Hyperalgesia (OIH)

OIH is a paradoxical state in which opioid exposure increases pain sensitivity. Distinguished from tolerance: in tolerance, the same stimulus hurts the same but the drug works less well (dose escalation helps); in OIH, pain spreads and worsens diffusely despite dose escalation (dose escalation worsens it). Mechanisms include NMDA receptor upregulation, dynorphin release, enhanced descending facilitation from RVM ON cells, and spinal glial activation. Treatment: opioid dose reduction or rotation, NMDA antagonists (ketamine, methadone), and non-opioid multimodal analgesia.

09 Oral Opioids

Drug	Starting Dose (Opioid-Naive)	Onset / Duration	Potency vs Morphine PO	Metabolism	Key Considerations
Morphine IR	15 mg PO q4h (5–10 mg in elderly/renal)	30 min / 3–4 h	1 (reference)	Hepatic glucuronidation: M3G (neuroexcitatory, no analgesia) + M6G (active, 10x potency, renally cleared)	Avoid in renal failure (M6G accumulation → respiratory depression); histamine release; reference standard for equianalgesic dosing
Oxycodone IR	5–10 mg PO q4–6h	15–30 min / 3–6 h	1.5x (30 mg morphine = 20 mg oxycodone)	CYP3A4 (major), CYP2D6 (minor → oxymorphone)	Less histamine release and nausea than morphine; available as single agent or with acetaminophen (Percocet) or ibuprofen
Hydrocodone	5–10 mg PO q4–6h	20–30 min / 4–6 h	1x (equivalent to morphine PO)	CYP2D6 → hydromorphone (active); CYP3A4	Schedule II (reclassified 2014); most prescribed opioid in US; always combined with acetaminophen or ibuprofen until single-entity ER (Zohydro) approved
Hydromorphone IR	2–4 mg PO q4–6h; 0.2–1 mg IV q2–3h	15–30 min PO / 3–4 h	4–5x PO (30 mg morphine = 6–8 mg hydromorphone)	Hepatic glucuronidation → H3G (neuroexcitatory, renally cleared)	Preferred over morphine in renal impairment (no active metabolite, but H3G still accumulates); 5x potency — careful dose calculation
Codeine	15–60 mg PO q4–6h (max 360 mg/day)	30–60 min / 4–6 h	0.15x (200 mg codeine = 30 mg morphine)	CYP2D6 → morphine (active); prodrug	CYP2D6 polymorphisms: ultra-rapid metabolizers (1–7%) → toxic morphine levels; poor metabolizers (5–10%) → no analgesia; BLACK BOX: contraindicated in children <12 and post-tonsillectomy <18
Tramadol	25–50 mg PO q4–6h (max 400 mg/day)	60 min / 4–6 h	0.1x (weak mu agonist)	CYP2D6 → O-desmethyltramadol (active mu agonist, 200x affinity)	Dual mechanism: mu agonism + NE/5-HT reuptake inhibition; seizure risk (especially with SSRIs, TCAs); serotonin syndrome risk; lower abuse potential but dependence occurs; CYP2D6 dependent like codeine
Tapentadol	50–100 mg PO q4–6h (max 600 mg/day)	60 min / 4–6 h	~0.4x	Glucuronidation (no CYP involvement)	Dual mechanism: mu agonism + NE reuptake inhibition (no serotonergic activity — lower serotonin syndrome risk than tramadol); Schedule II; no CYP interactions; less GI side effects

Avoid codeine and tramadol in CYP2D6 ultra-rapid metabolizers (risk of toxicity) and poor metabolizers (no efficacy). The FDA black box warning for codeine and tramadol in children is based on deaths in post-tonsillectomy pediatric patients who were CYP2D6 ultra-rapid metabolizers.

10 Extended-Release & Long-Acting Opioids

ER/LA opioids are reserved for patients requiring continuous around-the-clock analgesia who have already been on stable opioid therapy. The FDA REMS requires prescriber education. Never initiate in opioid-naive patients (exception: specific ER formulations at lowest dose with close monitoring).

Drug	Formulation	Dosing Interval	Abuse-Deterrent	Key Notes
Morphine ER (MS Contin, Kadian)	Tablet (MS Contin); capsule with extended-release beads (Kadian)	q8–12h (MS Contin); q12–24h (Kadian)	No (standard formulations)	Reference LA opioid; convert from total daily IR morphine dose; Kadian capsules can be sprinkled on applesauce (not crushed)
Oxycodone ER (OxyContin)	Abuse-deterrent tablet	q12h	Yes (polyethylene oxide matrix — resists crushing, dissolving, extraction)	Abuse-deterrent reformulation (2010); must be swallowed whole; convert at 1.5:1 morphine:oxycodone ratio
Oxymorphone ER (Opana ER)	Crush-resistant tablet	q12h	Reformulated	3x morphine potency PO; take on empty stomach (food increases levels 50%); original formulation withdrawn (IV abuse)
Hydromorphone ER (Exalgo)	Osmotic tablet (OROS)	q24h	No	OROS delivery system; must swallow whole; ghost tablet in stool (normal); 4–5x morphine potency
Fentanyl transdermal	Patch (12, 25, 37.5, 50, 75, 100 mcg/h)	q72h	No	Only for opioid-tolerant patients (≥60 mg oral morphine/day); 12–24h onset; depot in SC fat; fever/heat ↑ absorption (potentially fatal); conversion: morphine 60 mg/day PO ≈ fentanyl 25 mcg/h patch

Methadone — Unique Pharmacology

Methadone: Special Considerations

Methadone is a full mu agonist with unique properties that set it apart from all other opioids:

NMDA receptor antagonism — may be particularly effective for neuropathic pain and opioid-induced hyperalgesia
Serotonin/NE reuptake inhibition — additional analgesic mechanism
Variable half-life: 8–59 hours (mean ~24 hours) — steady state requires 5–7 days; risk of accumulation and delayed respiratory depression days after dose increase
Non-linear equianalgesic conversion: Ratio to morphine is NOT fixed — increases at higher doses (at ≤90 mg morphine, ratio is 4:1; at 91–300 mg, ratio is 8:1; at >300 mg, ratio is 12:1 or higher)
QTc prolongation: Blocks hERG potassium channels → risk of Torsades de Pointes; ECG at baseline, 30 days, annually, and after dose increase >30–40 mg/day; hold if QTc >500 ms
Drug interactions: CYP3A4, 2B6, 2D6 substrate; many interactions (rifampin, antiretrovirals, benzodiazepines)
No active metabolites — safe in renal failure (not dialyzable)
Inexpensive: ~$30/month vs >$300 for many ER opioids

Methadone dose conversions are the single most dangerous calculation in pain medicine. The morphine-to-methadone ratio is NOT a fixed number; it increases dramatically at higher morphine doses. When rotating to methadone, always use conservative dosing, involve a pain specialist, and titrate slowly (increase no more frequently than every 5–7 days, matching the long half-life).

Levorphanol

Levorphanol is a long-acting mu agonist with NMDA antagonism, NE/5-HT reuptake inhibition, and kappa/delta agonism — similar to methadone but with more predictable pharmacokinetics (t½ 11–16 h). Dose: 2–4 mg PO q6–8h. No QTc prolongation. Useful alternative when methadone is not tolerated or ECG-contraindicated. Limited availability and prescriber familiarity.

11 Opioid Conversion & Rotation

Equianalgesic Dose Table

Opioid	PO Dose (mg)	IV/IM/SC Dose (mg)	PO:IV Ratio	MME Factor (per mg PO)
Morphine	30	10	3:1	1.0
Oxycodone	20	N/A (no IV in US)	—	1.5
Hydrocodone	30	N/A	—	1.0
Hydromorphone	6	1.5	4:1	4.0
Oxymorphone	10	1	10:1	3.0
Codeine	200	120	1.7:1	0.15
Tramadol	300	N/A	—	0.1
Tapentadol	75	N/A	—	0.4
Fentanyl	N/A	0.1 (100 mcg)	—	Patch: 25 mcg/h ≈ 60–90 mg morphine PO/day
Methadone	Variable (see text)	Variable	2:1	Variable: 4–12 depending on total daily morphine dose

Opioid Rotation Methodology

Step-by-Step Opioid Rotation

Calculate total 24-hour dose of current opioid (include all IR breakthrough doses)
Convert to oral morphine equivalents using equianalgesic table
Convert from oral morphine equivalents to new opioid using equianalgesic table
Reduce calculated dose by 25–50% for incomplete cross-tolerance (receptor polymorphisms and differential receptor binding mean prior opioid exposure does not confer full tolerance to the new agent)
Adjust further for clinical variables: age, renal/hepatic function, pain severity, drug interactions
Provide IR breakthrough medication at 10–20% of total 24-hour dose of new opioid, available q1–2h PRN
Reassess in 24–48 hours and titrate as needed

CDC Morphine Milligram Equivalent (MME) Thresholds

The 2022 CDC Clinical Practice Guideline (updated from 2016) recommends:

Before starting opioids, optimize non-opioid therapy and use the lowest effective dose
≥50 MME/day: Exercise caution; reassess evidence of individual benefits and risks; co-prescribe naloxone
≥90 MME/day: Avoid or carefully justify; involves substantial risk of overdose and death
Epidemiologic data: overdose risk at 50–99 MME/day is 3.7x baseline; at ≥100 MME/day, risk is 8.9x baseline

MME thresholds are population-level risk markers, not rigid limits. The 2022 CDC guideline explicitly states that these thresholds should NOT be used as rigid prescribing ceilings, involuntary tapers, or justification for patient abandonment. Individualized assessment of risk vs benefit is always required.

12 Opioid Risk Management

Risk Assessment Tools

Tool	Format	Scoring	Use
ORT (Opioid Risk Tool)	5-item self-report	0–3 low; 4–7 moderate; ≥8 high risk	Pre-prescribing screen for aberrant behavior risk; assesses family/personal history of substance abuse, age, sexual abuse, psychological disease
SOAPP-R (Screener and Opioid Assessment for Patients with Pain — Revised)	24-item self-report	≥18 high risk (sensitivity 0.81, specificity 0.68)	Pre-prescribing; more comprehensive than ORT; validated in chronic pain populations
DIRE (Diagnosis, Intractability, Risk, Efficacy)	Clinician-rated, 4 domains	7–21; higher = better candidate	Clinician assessment of suitability for long-term opioids; factors: diagnosis, intractability, psychological risk, chemical health risk, reliability, social support, efficacy
COMM (Current Opioid Misuse Measure)	17-item self-report	≥9 positive screen	Ongoing monitoring of patients already on opioids for current aberrant behavior

Urine Drug Screening (UDS)

UDS Interpretation Essentials

Immunoassay (screening): Detects drug classes; cross-reactivity common; cannot distinguish specific opioids; confirms/denies presence of broad categories
LC-MS/MS (confirmatory): Identifies specific drugs and metabolites; quantitative; required to resolve unexpected immunoassay results
Frequency: Baseline before starting opioids; at least annually for stable patients; more frequently (quarterly) for higher-risk patients; random testing preferred
Synthetic opioids NOT detected by standard immunoassay: fentanyl, methadone, buprenorphine, tramadol, tapentadol — require specific testing
Common pitfalls: Hydromorphone is a metabolite of hydrocodone (positive for hydromorphone in patient prescribed hydrocodone is expected); oxymorphone is a metabolite of oxycodone; poppy seeds can cause morphine/codeine positive
Expected results: Prescribed medication PRESENT; non-prescribed controlled substances ABSENT; illicit drugs ABSENT

PDMP Checking & Treatment Agreements

Prescription Drug Monitoring Programs (PDMP): Check at initiation and every 1–3 months (mandated by most states). Red flags: multiple prescribers, overlapping prescriptions, early refills, concurrent benzodiazepines. Treatment agreements (opioid contracts): Document informed consent, expectations, monitoring plan, and consequences of non-adherence. Include: single prescriber/pharmacy, UDS consent, pill counts, safe storage, naloxone provision, reasons for taper/discontinuation.

Naloxone Co-Prescribing

Co-prescribe naloxone for patients receiving ≥50 MME/day, concurrent benzodiazepines, history of overdose, history of substance use disorder, or any patient/family requesting it. Intranasal naloxone (Narcan): 4 mg/spray; may repeat in 2–3 minutes. IM auto-injector (Evzio): 2 mg; may repeat. Educate patient and household contacts on recognition of overdose (unresponsive, slow/stopped breathing, blue lips) and naloxone administration.

Opioid Taper Protocols

For chronic opioids when taper is indicated (lack of benefit, adverse effects, aberrant behavior, patient preference):

Gradual taper: Reduce by 10% of total daily dose per month (slowest, best tolerated)
Moderate taper: Reduce by 10–20% every 2–4 weeks
Faster taper (when safety requires): 20–25% reduction every 1–2 weeks; closer monitoring needed
Pause taper if withdrawal symptoms are intolerable; restart non-opioid analgesics before/during taper
The final 20–30% of taper is the hardest — slow down further

Opioid-Induced Adverse Effects

Effect	Mechanism	Tolerance?	Management
Constipation	Mu receptors in enteric plexus → decreased peristalsis, increased water absorption	Minimal/none	Prophylactic senna + docusate; PEG; methylnaltrexone (SC) or naloxegol (PO) for opioid-induced constipation refractory to laxatives (peripheral mu antagonists)
Nausea/vomiting	CTZ stimulation, vestibular sensitization, GI stasis	Yes (days to weeks)	Ondansetron, prochlorperazine, metoclopramide; usually resolves within 1 week
Sedation	Central mu activation	Yes (days)	Reduce dose; opioid rotation; methylphenidate (controversial)
Respiratory depression	Mu-2 receptors in brainstem (pre-Bötzinger complex)	Yes (parallel to analgesia)	Naloxone 0.04–0.4 mg IV q2–3 min; ventilatory support; lowest risk when titrated to effect
Pruritus	Central mu activation (NOT histamine for most opioids)	Yes	Opioid rotation; nalbuphine 2.5–5 mg IV; antihistamines less effective (mechanism is not histamine-mediated)
Endocrinopathy (OIAD)	Hypothalamic suppression of GnRH → hypogonadism; decreased ACTH, GH	No	Testosterone replacement in hypogonadal men on chronic opioids; check testosterone, DHEA-S, cortisol; dose reduction
Sleep-disordered breathing	Central apnea from depressed respiratory drive	Partial	Sleep study; CPAP/ASV; dose reduction

13 Epidural Steroid Injections

Approaches

Approach	Technique	Advantages	Disadvantages / Risks	Best For
Interlaminar (IL)	Midline or paramedian approach through ligamentum flavum into posterior epidural space; loss-of-resistance technique	Bilateral spread; technically simpler; larger epidural volume	No ventral spread; risk of dural puncture; steroid may not reach ventral pathology	Bilateral symptoms; central stenosis; non-focal radiculopathy
Transforaminal (TF)	Oblique approach into neural foramen under fluoroscopy; targets ventral epidural space near the affected nerve root	Targeted delivery; ventral spread; lower steroid volume needed; diagnostic value	Higher risk of vascular uptake (radicular artery); MUST use non-particulate steroid for cervical TF; risk of nerve injury	Unilateral radiculopathy; specific nerve root pathology; post-surgical anatomy
Caudal	Through sacral hiatus into epidural space; uses higher volumes (10–20 mL)	Low risk of dural puncture; easy in post-surgical patients; no midline scarring concern	Less targeted; requires higher volume; may not reach upper lumbar levels	Multi-level lumbar pathology; post-laminectomy; S1 radiculopathy; patients with difficult anatomy

Evidence by Indication

Lumbar radiculopathy (disc herniation): Best evidence; NNT ~3 for short-term relief; TF approach preferred for focal radiculopathy; greatest benefit within 3 months of symptom onset
Lumbar spinal stenosis: Moderate evidence; IL approach with large volume for bilateral spread; benefit is modest and short-lived; SPORT and MILD trials showed limited long-term benefit over conservative care
Axial low back pain (without radiculopathy): Weakest evidence; not recommended as sole intervention; pain generators are likely facet joints, SI joint, or discogenic
Cervical radiculopathy: Good evidence for IL and TF approaches; TF MUST use non-particulate dexamethasone; IL approach preferred when possible to minimize vascular risk

Complications of Epidural Steroid Injections

Dural puncture (1–5%): Post-dural puncture headache (PDPH); positional (worse upright, better supine); treat with caffeine, hydration, epidural blood patch if persistent >24–48 hours
Epidural hematoma (rare, ~1:150,000): Risk increased with anticoagulation; ASRA guidelines for anticoagulant management; emergency MRI and surgical decompression within 8–12 hours if motor deficit
Epidural abscess: Risk factors include immunosuppression, diabetes, recent bacteremia; presents with fever, back pain, progressive neurologic deficit; emergency MRI; IV antibiotics + surgical decompression
Vascular injection (TF approach): Radicular artery penetration with particulate steroid → spinal cord infarction (anterior spinal artery syndrome); use live fluoroscopy with contrast to detect vascular uptake
Steroid side effects: Facial flushing, hyperglycemia (1–2 weeks), HPA suppression, menstrual irregularity, insomnia, weight gain

14 Facet Joint & Medial Branch Interventions

Facet-Mediated Pain Referral Patterns

Level	Referral Pattern
C2–3	Occipital headache, upper cervical pain
C3–4	Posterolateral neck, does not radiate past shoulder
C5–6	Shoulder, suprascapular region (mimics rotator cuff)
C6–7	Interscapular region
L1–2	Groin, lateral hip
L3–4	Posterior thigh (mimics radiculopathy)
L4–5	Gluteal, posterior thigh to knee
L5–S1	Gluteal, posterior thigh, may reach calf (does NOT go below knee typically)

Diagnostic Medial Branch Blocks

Each facet joint is innervated by the medial branch of the dorsal ramus at the same level and one level above (e.g., L4–5 facet requires L3 and L4 medial branch blocks). The dual comparative block paradigm is the gold standard: two separate diagnostic blocks with different local anesthetics (e.g., lidocaine then bupivacaine) on different days. A block is positive if the patient reports ≥80% pain relief with duration consistent with the agent used. Dual blocks reduce false-positive rates from ~40% (single block) to ~15%.

Radiofrequency Ablation (RFA)

Following positive dual diagnostic blocks, conventional radiofrequency ablation denervates the medial branch nerve. Technique: 18–22 gauge RF cannula placed parallel to the nerve course; sensory stimulation at 50 Hz (concordant pain at ≤0.5 V); motor stimulation at 2 Hz (no multifidus contraction below 2.0 V ensures safe distance from ventral ramus). Lesion parameters: 80°C for 60–90 seconds per lesion site. Typically 2–3 lesions per level for adequate coverage.

RFA Outcome Expectations

Success rate: 50–80% of patients achieve ≥50% pain relief after properly selected dual blocks
Duration of relief: 6–12 months (nerves regenerate); can be repeated
Cervical RFA: Similar efficacy; higher technical precision required due to proximity to vertebral artery and spinal cord
Post-procedure: Soreness for 1–2 weeks; neuritis (neuropathic pain at ablation site) in 5–10%; transient worsening before improvement
Contraindications: Active infection, coagulopathy, negative diagnostic blocks, pregnancy, implanted cardiac device (relative)

15 Sacroiliac Joint Interventions

Clinical Diagnosis

SI joint pain accounts for 15–30% of chronic low back pain. Pain is typically unilateral, below L5, maximal at the posterior superior iliac spine (PSIS), and may radiate to the buttock, groin, or posterior thigh (rarely below the knee). At least 3 of 5 provocation tests must be positive for clinical diagnosis:

Test	Technique	Positive Finding
FABER (Patrick) test	Flex, abduct, externally rotate hip; press down on contralateral ASIS and ipsilateral knee	Pain at ipsilateral SI joint
Gaenslen test	Patient supine at table edge; hyperextend one hip off table while flexing contralateral hip to chest	Pain at SI joint of hyperextended side
Compression test	Patient side-lying; downward pressure on iliac crest	Pain at SI joint
Distraction (gapping) test	Patient supine; outward pressure on bilateral ASIS	Pain at SI joint
Thigh thrust (posterior shear)	Patient supine; hip flexed 90°; axial force through femur toward table	Pain at SI joint

SI Joint Injection

Fluoroscopically guided intra-articular injection with local anesthetic ± corticosteroid. Diagnostic value: ≥75% pain relief confirms SI joint as pain generator. Ultrasound-guided injection is an alternative. Therapeutic relief with corticosteroid is typically short-lived (weeks to months).

Lateral Branch Blocks & RFA

The SI joint is innervated by the lateral branches of the S1–S3 dorsal rami and the L5 dorsal ramus. Lateral branch radiofrequency ablation (using conventional, cooled, or pulsed RF techniques) can provide 6–12 months of relief. Cooled RF creates larger lesions (spherical rather than cylindrical) which improves capture of the variable lateral branch anatomy.

SI Joint Fusion

Minimally invasive SI joint fusion (e.g., iFuse implant system) is indicated for SI joint pain that has failed conservative management and at least two positive diagnostic injections. The INSITE and iMIA RCTs demonstrated superiority over non-surgical management at 6 months. Three triangular titanium implants are placed across the SI joint under fluoroscopic guidance.

16 Joint & Soft Tissue Injections

Major Joint Injections

Joint	Approach	Agent	Key Considerations
Knee	Suprapatellar (preferred — larger target, allows aspiration), inferolateral (seated, knee flexed 90°, lateral to patellar tendon), medial midpatellar	Triamcinolone 40 mg + lidocaine 5 mL; or hyaluronic acid (viscosupplementation)	Most common joint injected; limit to 3–4 corticosteroid injections/year; evidence of long-term cartilage loss with repeated steroid (NEJM 2017 trial)
Shoulder — Subacromial	Posterior approach, 2 cm inferior and medial to posterolateral acromion; needle directed anterosuperiorly	Triamcinolone 40 mg + lidocaine 4–5 mL	Impingement, bursitis, rotator cuff tendinopathy; landmark-guided often sufficient; avoid tendon injection
Shoulder — Glenohumeral	Posterior approach (preferred): 2 cm inferior and medial to posterolateral acromion, directed toward coracoid process; anterior approach also used	Triamcinolone 40 mg + lidocaine 3–5 mL	OA, adhesive capsulitis, inflammatory arthritis; accuracy improved with US guidance (68% landmark vs 93% US-guided)
Shoulder — AC joint	Direct superior approach into the AC joint space	Betamethasone 3 mg or triamcinolone 10–20 mg + lidocaine 0.5–1 mL	Small joint; small volume; palpate joint with cross-body adduction to identify
Hip	Anterior approach under fluoroscopy or US guidance (femoral head-neck junction)	Triamcinolone 40–80 mg + lidocaine/bupivacaine + contrast	Always use image guidance (deep joint, proximity to femoral neurovascular bundle); OA, labral tears, AVN

Trigger Point Injections & Dry Needling

Trigger points are hyperirritable taut bands within skeletal muscle that produce local and referred pain. Injection technique: 25–27 gauge needle inserted into the taut band; elicit local twitch response; inject 0.5–1 mL 1% lidocaine or 0.25% bupivacaine. Dry needling uses acupuncture needles without injectate to disrupt the trigger point. Systematic reviews suggest equivalent efficacy between wet and dry needling; the mechanical disruption of the taut band is the key therapeutic element.

Viscosupplementation

Hyaluronic acid (HA) injections: Available as single-injection (Synvisc-One, Gel-One) or 3–5 weekly injection series (Euflexxa, Supartz, Hyalgan). Mechanism: restores synovial fluid viscoelasticity, anti-inflammatory and analgesic properties. Evidence is mixed — AAOS gives a “limited” recommendation; most benefit in mild-moderate knee OA (KL grade 2–3). Contraindicated in avian-derived products if egg allergy.

Platelet-Rich Plasma (PRP)

PRP is autologous blood concentrated to 3–5x baseline platelet count, providing supraphysiologic growth factors (PDGF, TGF-beta, VEGF). Evidence is strongest for knee OA (meta-analyses show superiority to HA at 12 months) and lateral epicondylitis. Weaker evidence for rotator cuff tendinopathy, plantar fasciitis, and Achilles tendinopathy. Not covered by most insurers. Leukocyte-poor PRP preferred for intra-articular use; leukocyte-rich PRP for tendon/soft tissue.

17 Neuromodulation

Spinal Cord Stimulation (SCS)

SCS involves placement of epidural electrodes over the dorsal columns to modulate pain signaling. The original theoretical basis is the gate control theory — electrical stimulation of large-diameter dorsal column fibers “closes the gate” on nociceptive input. Modern mechanisms also involve supraspinal modulation, GABA release in the dorsal horn, and activation of descending inhibition.

Modality	Frequency	Mechanism	Paresthesia	Key Features
Conventional (tonic)	40–100 Hz	Gate control; dorsal column activation	Yes (paresthesia must overlap pain area)	Oldest modality; requires paresthesia mapping during trial; positional variability
High-frequency (HF10)	10,000 Hz (10 kHz)	Uncertain; may involve glial modulation, wide dynamic range neuron inhibition	No (paresthesia-free)	SENZA-RCT: superior to conventional at 24 months; no paresthesia mapping needed; simpler programming
Burst	500 Hz bursts at 40 Hz interburst frequency	Modulates both lateral (sensory-discriminative) and medial (affective) pain pathways	No (paresthesia-free)	SUNBURST trial: non-inferior to tonic; may preferentially target affective pain component
DRG stimulation	20 Hz	Direct stimulation of dorsal root ganglion; modulates primary afferent signaling	Minimal	ACCURATE study: superior to conventional SCS for CRPS and focal neuropathy; precise dermatomal targeting; lead placed in epidural space at target foramen

SCS Trial & Implant Process

Trial phase (4–7 days): Percutaneous leads placed under fluoroscopy; external generator; patient assesses pain relief in daily activities. Trial is successful if ≥50% pain relief with functional improvement and reduced medication use. If successful, proceed to permanent implant with IPG (implantable pulse generator) placed in subcutaneous pocket (buttock or abdomen).

SCS Indications (Evidence-Based)

Failed back surgery syndrome (FBSS): Strongest evidence (PROCESS trial: SCS + CMM superior to CMM alone)
Complex regional pain syndrome (CRPS): Strong evidence (Kemler RCT); DRG stimulation preferred
Painful diabetic peripheral neuropathy: SENZA-PDN trial; HF10 SCS demonstrated superiority to CMM
Chronic angina refractory to medical therapy: European evidence; less used in US
Peripheral vascular disease / critical limb ischemia: Improves microcirculation; European evidence

Intrathecal Drug Delivery (IDDS)

An intrathecal pump delivers medication directly into the CSF, achieving effective concentrations at 1/300th of the systemic dose. Reduces systemic side effects. Agents: morphine (first-line, FDA-approved), ziconotide (N-type Ca²⁺ channel blocker; FDA-approved; non-opioid; NNT 2.6 for cancer pain; side effects: dizziness, nausea, cognitive changes, psychiatric symptoms), baclofen (for spasticity — MS, SCI, CP). The Polyanalgesic Consensus Conference (PACC) algorithm guides intrathecal drug selection. Pump refills every 1–6 months; battery replacement surgery every 5–7 years.

18 Advanced & Emerging Procedures

Sympathetic Nerve Blocks

Block	Target	Technique	Indications	Risks
Stellate ganglion block	Cervicothoracic sympathetic chain (C6–T1)	Anterolateral approach at C6 (Chassaignac tubercle) under fluoroscopy/US; 5–10 mL local anesthetic	Upper extremity CRPS, phantom limb pain, refractory angina, PTSD (investigational), hyperhidrosis	Horner syndrome (expected — confirms successful block), recurrent laryngeal nerve palsy, vertebral artery injection (seizure), pneumothorax, esophageal perforation
Lumbar sympathetic block	L2–L4 sympathetic chain (anterolateral to vertebral body)	Fluoroscopy-guided; needle at anterolateral L2 or L3 body; 15–20 mL local anesthetic	Lower extremity CRPS, peripheral vascular disease, phantom limb pain, hyperhidrosis	Intravascular injection, ureteral injury, genitofemoral neuralgia, hypotension
Celiac plexus block/neurolysis	Celiac plexus at T12–L1 (anterior to aorta)	Posterior bilateral approach or anterior EUS-guided; diagnostic block with local anesthetic; neurolysis with phenol 6–10% or absolute alcohol	Pancreatic cancer pain (NNT 1.6 for neurolysis), chronic pancreatitis, upper abdominal visceral malignancy	Hypotension (sympathectomy), diarrhea (unopposed parasympathetic), pneumothorax, aortic/IVC puncture, paraplegia (artery of Adamkiewicz)
Superior hypogastric plexus block	Superior hypogastric plexus at L5–S1 (anterior to vertebral body)	Bilateral fluoroscopy-guided; 6–8 mL local anesthetic per side	Pelvic visceral pain: endometriosis, pelvic malignancy, interstitial cystitis, chronic pelvic pain	Intravascular injection, discitis, ureteral injury
Ganglion impar block	Ganglion impar (unpaired ganglion at sacrococcygeal junction)	Trans-sacrococcygeal approach under fluoroscopy; 4–6 mL	Perineal pain: coccydynia, vulvodynia, rectal cancer pain	Rectal perforation, infection

Vertebral Augmentation

Vertebroplasty: Percutaneous injection of PMMA bone cement into the fractured vertebral body under fluoroscopy. Kyphoplasty: Balloon tamp inflated first to create a cavity and partially restore height, then PMMA injected. The VERTOS II trial showed vertebroplasty superior to sham for acute (<6 weeks) painful VCFs, while INVEST showed no difference (sham-controlled). FREE trial showed kyphoplasty superior to conservative care. Current consensus: vertebral augmentation is appropriate for painful osteoporotic VCFs refractory to 2–4 weeks of conservative management.

MILD Procedure (Minimally Invasive Lumbar Decompression)

Percutaneous removal of hypertrophied ligamentum flavum and small bone to create space in the lumbar spinal canal for patients with lumbar spinal stenosis and neurogenic claudication. Performed through a 5.1 mm portal under fluoroscopy. The MILD RCT demonstrated statistically significant improvement in ODI and VAS at 12 months vs epidural steroids.

Peripheral Nerve Stimulation (PNS)

Percutaneous placement of stimulating electrodes adjacent to peripheral nerves for localized neuropathic pain. Targets include occipital nerves (chronic migraine), suprascapular nerve (shoulder pain), medial branch of genicular nerves (knee OA), and tibial nerve (foot pain). Sprint PNS system allows 60-day percutaneous stimulation without permanent implant.

Regenerative Medicine

Bone marrow aspirate concentrate (BMAC) and adipose-derived stem cells are under investigation for OA, degenerative disc disease, and tendinopathy. FDA regulations classify minimally manipulated autologous tissue as exempt from premarket approval but restrict “more than minimally manipulated” products. Evidence remains limited; no FDA-approved stem cell therapy for musculoskeletal pain currently exists.

Intradiscal Procedures

Intradiscal electrothermal therapy (IDET): Thermal catheter placed in the annulus fibrosus; heats collagen to 90°C to denature annular nociceptors and seal annular fissures. Evidence is mixed; largely fallen out of favor. Biacuplasty: Bipolar radiofrequency heating of the posterior annulus via two cooled probes; IDEAL study showed modest benefit at 6 months. Intradiscal biologics: PRP and mesenchymal stem cell injections into degenerative discs are investigational; small RCTs show signal of benefit but lack Level I evidence.

The field of interventional pain continues to evolve rapidly. Before offering advanced or emerging procedures, ensure: (1) the patient has failed appropriate conservative management; (2) the diagnosis is supported by validated diagnostic criteria or diagnostic blocks; (3) the procedure has at least moderate-quality evidence for the specific indication; (4) realistic expectations are set regarding outcomes. Avoid offering procedures purely for revenue generation when evidence does not support their use.

19 Low Back Pain

Epidemiology & Natural History

Low back pain (LBP) is the leading cause of disability worldwide (Global Burden of Disease). Lifetime prevalence 80%. Most acute LBP resolves within 6 weeks regardless of treatment. However, 10–15% develop chronic LBP (>12 weeks). Risk factors for chronification: psychosocial (catastrophizing, fear-avoidance, depression, job dissatisfaction), yellow flags, workers’ compensation involvement, baseline disability level.

Red Flags

Red Flags Requiring Urgent Workup

Cauda equina syndrome: Saddle anesthesia, urinary retention/incontinence, fecal incontinence, bilateral leg weakness → emergent MRI and surgical referral
Cancer: History of malignancy, unexplained weight loss, age >50, pain at rest/night, failure to improve after 4–6 weeks
Infection: Fever, IV drug use, immunosuppression, recent spinal procedure, UTI/skin infection
Fracture: Significant trauma, osteoporosis, chronic corticosteroid use, age >70
Vascular: Pulsatile abdominal mass (AAA), tearing/ripping pain

Imaging Criteria

No imaging within the first 6 weeks of acute LBP in the absence of red flags (ACP/ACR Choosing Wisely). Imaging in the first 6 weeks is appropriate only with: progressive neurologic deficit, cauda equina symptoms, suspected cancer/infection/fracture, or failure to improve after adequate conservative trial. MRI is modality of choice; CT myelography if MRI contraindicated.

Disc Herniation — Nerve Root Correlation

Disc Level	Root Affected	Motor Deficit	Sensory Deficit	Reflex Loss	Exam Finding
L1–2	L2	Hip flexion (iliopsoas)	Anterior thigh	None reliably	Reverse SLR positive
L2–3	L3	Knee extension (quadriceps)	Anterior thigh, medial knee	Patellar (L3-4)	Reverse SLR positive
L3–4	L4	Knee extension, ankle dorsiflexion (tibialis anterior)	Medial leg, medial malleolus	Patellar	SLR may be positive
L4–5	L5	Great toe extension (EHL), hip abduction, ankle dorsiflexion	Lateral leg, dorsum of foot, 1st web space	None (medial hamstring)	SLR positive; foot drop
L5–S1	S1	Ankle plantarflexion (gastrocnemius), hip extension, toe walking	Posterior leg, lateral foot, sole	Achilles	SLR positive; cannot toe walk

Pain Generators in Chronic LBP

Discogenic (39%): Internal disc disruption; pain worse with flexion, sitting; diagnosis via provocation discography (controversial). Facet joint (15–30%): Pain with extension, rotation; referral pattern follows affected level; diagnosed by medial branch blocks. Sacroiliac joint (15–30%): See Section 15. Myofascial: Trigger points in paraspinals, quadratus lumborum, piriformis. Failed back surgery syndrome (FBSS): Persistent or recurrent pain after lumbar spine surgery; multifactorial (recurrent herniation, epidural fibrosis, foraminal stenosis, adjacent segment disease, myofascial, psychological); SCS is first-line interventional option (PROCESS trial).

Treatment Algorithm for Chronic Low Back Pain

Stepwise Approach to Chronic LBP Management

Active self-management: Patient education, reassurance, remain active, physical therapy (core stabilization, McKenzie method), weight management, yoga/tai chi (ACP 2017 guideline first-line)
Non-pharmacologic adjuncts: CBT for pain catastrophizing/fear-avoidance, mindfulness-based stress reduction (MBSR), spinal manipulation, acupuncture, massage therapy
Pharmacologic first-line: NSAIDs (ibuprofen 400–600 mg TID or naproxen 500 mg BID × 2–4 weeks); duloxetine if NSAID-contraindicated or neuropathic component; muscle relaxants short-term for acute flares only
Interventional (targeted): Based on identified pain generator — ESI for radiculopathy, MBB/RFA for facet pain, SI joint injection for SI joint pain; diagnostic blocks must precede ablative procedures
Advanced: SCS for FBSS/refractory radiculopathy; intrathecal pump for cancer-related or refractory non-cancer pain; surgical referral for progressive neurologic deficit or structural pathology amenable to correction

The 2017 ACP guideline recommends non-pharmacologic therapies as first-line for chronic LBP: exercise, multidisciplinary rehabilitation, acupuncture, mindfulness-based stress reduction, tai chi, yoga, motor control exercise, progressive relaxation, operant therapy, CBT, and spinal manipulation. Opioids are recommended only as a last resort when other therapies have failed, with shared decision-making and discussion of risks vs modest benefits.

20 Cervical & Headache Pain

Cervicogenic Headache

Cervicogenic headache (CGH) originates from cervical structures and is referred to the head. The trigeminocervical nucleus (convergence of trigeminal afferents with C1–C3 dorsal horn neurons) is the anatomic basis. Most common sources: C2–3 facet joint (innervated by the third occipital nerve, the superficial medial branch of C3 dorsal ramus), atlantoaxial joint, and upper cervical myofascial structures. Diagnostic criteria (ICHD-3): unilateral headache without sideshift, provoked by neck movement or sustained posture, reduced ROM, responds to diagnostic cervical nerve block.

Occipital Neuralgia

Paroxysmal shooting or stabbing pain in the distribution of the greater occipital nerve (GON) (C2 dorsal ramus — medial branch) or lesser occipital nerve (LON) (C2–C3 ventral rami). Tender over the nerve at the nuchal line, 2–3 cm lateral to the occipital protuberance. Treatment: diagnostic/therapeutic GON block (2–3 mL 0.5% bupivacaine + triamcinolone 20–40 mg); if temporary relief, consider pulsed RF of GON or occipital nerve stimulation for refractory cases.

Cervical Radiculopathy

Spurling test: Cervical extension + lateral flexion + axial compression to affected side reproduces radicular arm pain (sensitivity 50%, specificity 86%). Most common levels: C5–6 (C6 root, 25%), C6–7 (C7 root, 60%). Natural history is generally favorable; 75–90% improve with conservative management. Cervical ESI (interlaminar preferred; TF with non-particulate dexamethasone ONLY) for persistent radicular pain. Surgical indications: progressive motor deficit, myelopathy, failure of 6–12 weeks of conservative treatment with persistent radicular symptoms.

Cervical Myelopathy

Compression of the spinal cord by degenerative cervical spondylosis — the most common cause of spinal cord dysfunction in adults >55. Clinical features: gait abnormality (broad-based, spastic), hand clumsiness (difficulty with buttons, handwriting — “myelopathy hand”), Hoffman sign (flicking the middle finger DIP produces thumb/index flexion), Lhermitte sign (electric shock sensation down the spine/limbs with neck flexion), hyperreflexia, Babinski sign, clonus. MRI shows cord compression with possible T2 signal change (myelomalacia). Treatment is primarily surgical decompression (anterior or posterior approach) — this is NOT an interventional pain condition; referral to spine surgery is mandatory for progressive myelopathy.

Cervical myelopathy is a surgical emergency when progressive. High-dose corticosteroid injections and cervical manipulation are contraindicated in the setting of myelopathy. Always examine for upper motor neuron signs before proceeding with cervical interventional pain procedures.

21 Complex Regional Pain Syndrome

Budapest Clinical Diagnostic Criteria (2003, IASP-adopted 2012)

Budapest Criteria for CRPS

Must meet ALL four of the following:

Continuing pain disproportionate to any inciting event
Must report at least one symptom in 3 of 4 categories:
- Sensory: Hyperesthesia and/or allodynia
- Vasomotor: Temperature asymmetry and/or skin color changes and/or skin color asymmetry
- Sudomotor/Edema: Edema and/or sweating changes and/or sweating asymmetry
- Motor/Trophic: Decreased ROM and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nail, skin)
Must display at least one sign at examination in 2 or more categories:
- Sensory: Hyperalgesia to pinprick and/or allodynia to light touch/pressure/joint movement
- Vasomotor: Temperature asymmetry (>1°C) and/or skin color changes/asymmetry
- Sudomotor/Edema: Edema and/or sweating changes/asymmetry
- Motor/Trophic: Decreased ROM and/or motor dysfunction and/or trophic changes
No other diagnosis better explains the signs and symptoms

Type I: No identifiable nerve lesion (formerly reflex sympathetic dystrophy). Type II: Identifiable nerve lesion present (formerly causalgia).

Diagnostic Studies

Three-phase bone scan: Increased uptake in all three phases (flow, blood pool, delayed) on the affected side. Sensitivity is highest in the first 3–6 months. Thermography: >1°C asymmetry. Quantitative sudomotor axon reflex testing (QSART): asymmetric sweat output. Plain radiographs: patchy osteoporosis (Sudeck atrophy) in later stages.

Treatment Ladder

Stage	Interventions	Details
First-line	Physical/occupational therapy, mirror therapy, graded motor imagery (GMI)	PT is the cornerstone; active ROM, desensitization, edema management; mirror therapy (visual feedback of unaffected limb); GMI sequence: laterality recognition → imagined movements → mirror therapy
Pharmacologic	Neuropathic pain agents, corticosteroids, bisphosphonates	Gabapentin/pregabalin, duloxetine, nortriptyline; early corticosteroid burst (prednisone 30 mg/day × 2–4 weeks in acute CRPS); IV bisphosphonates (alendronate, pamidronate) reduce bone pain
Interventional	Sympathetic nerve blocks, SCS/DRG stimulation	Stellate ganglion block (upper limb) or lumbar sympathetic block (lower limb); series of 3–6 blocks; if response to sympathetic blocks → sympathetically maintained pain (SMP); SCS or DRG stimulation for refractory cases
Advanced	Ketamine infusion, intrathecal drug delivery, amputation (last resort)	Sub-anesthetic ketamine infusion (NMDA antagonism addresses central sensitization); intrathecal baclofen for CRPS dystonia; amputation controversial and may trigger CRPS in residual limb

22 Cancer Pain

WHO Analgesic Ladder (1986, Modified)

Step	Pain Severity	Agents	Adjuvants
Step 1	Mild (NRS 1–3)	Non-opioids: acetaminophen, NSAIDs	± adjuvant (gabapentinoids, antidepressants, corticosteroids)
Step 2	Moderate (NRS 4–6)	Weak opioids: tramadol, codeine, hydrocodone low-dose; OR low-dose strong opioid	± non-opioids ± adjuvant
Step 3	Severe (NRS 7–10)	Strong opioids: morphine, oxycodone, hydromorphone, fentanyl, methadone	± non-opioids ± adjuvant
Step 4 (modified)	Refractory	Interventional: neuraxial analgesia, nerve blocks, neurolysis, SCS, intrathecal pumps	All appropriate adjuvants

Breakthrough Cancer Pain (BTcP)

Dose: 10–20% of total 24-hour opioid dose as IR opioid q1–2h PRN. Available q1h for oral, q15–30 min for parenteral. Rapid-onset fentanyl products (TIRF): transmucosal fentanyl citrate (Actiq), fentanyl buccal tablet (Fentora), fentanyl nasal spray (Lazanda) — all restricted to opioid-tolerant patients (≥60 mg oral morphine/day) via TIRF REMS. If >3–4 breakthrough doses per day, increase the around-the-clock dose by 25–50%.

Opioid Rotation for Cancer Pain

Indications: uncontrolled pain despite dose escalation, intolerable side effects (especially cognitive changes, myoclonus from morphine metabolites), suspected OIH, end-organ changes (renal failure requiring switch from morphine). Rotate using equianalgesic table with 25–50% dose reduction for incomplete cross-tolerance; less reduction (25%) for poorly controlled pain.

Interventional Approaches for Cancer Pain

Celiac plexus neurolysis: Pancreatic cancer pain; superior to medical management (NNT 1.6); perform early when pain is difficult to control; see Section 18
Intrathecal drug delivery: Randomized evidence (Smith 2002) showed improved pain control, reduced toxicity, and improved survival with intrathecal morphine vs comprehensive medical management
Palliative radiation: Single fraction (8 Gy) for painful bone metastases; response rate 60–70%; stereotactic body radiation for oligometastases

Bone Metastases Management

Bisphosphonates (zoledronic acid 4 mg IV q3–4 weeks) and denosumab (120 mg SC monthly) reduce skeletal-related events. Radionuclides: Strontium-89, samarium-153, radium-223 (for castration-resistant prostate cancer with bone metastases — improved survival). Radiation: single-fraction 8 Gy equivalent to multi-fraction for pain palliation (meta-analyses). Corticosteroids (dexamethasone 4–8 mg daily) for bone pain with periosteal stretching or perineural edema.

Cancer Pain Emergencies

Emergency	Presentation	Immediate Management
Spinal cord compression	Back pain (90%), progressive weakness, sensory level, bowel/bladder dysfunction	Dexamethasone 10–16 mg IV bolus then 4 mg q6h; emergent MRI entire spine; radiation ± surgical decompression within 24–48 hours
Pathologic fracture	Acute severe bone pain at metastatic site; deformity; inability to bear weight	Immediate imaging; orthopedic consultation for stabilization; IV opioids for acute pain; radiation after fixation
Acute pain crisis	Sudden severe escalation of pain (NRS 8–10); often with visceral or neuropathic features	Rapid opioid titration (IV morphine 2–4 mg q15 min until controlled); identify cause (obstruction, hemorrhage, fracture, infection); consider ketamine adjunct for refractory pain
Malignant bowel obstruction	Nausea/vomiting, colicky abdominal pain, distension	Octreotide 100–600 mcg/day SC to reduce secretions; dexamethasone 8–16 mg IV; hyoscine butylbromide for colic; opioids for continuous pain; nasogastric decompression or venting gastrostomy if refractory; surgery only if single point of obstruction with good functional status

In cancer pain, the goal is comfort, and there is NO maximum dose of opioids. Doses should be titrated to effect. The palliative exception (principle of double effect) permits any dose escalation where the primary intent is symptom relief, even if respiratory depression is a foreseeable but unintended consequence. This is ethically and legally distinct from euthanasia.

23 Fibromyalgia & Central Sensitization

2016 ACR Revised Diagnostic Criteria

Fibromyalgia Diagnostic Criteria (2016 ACR Revision)

Widespread Pain Index (WPI) ≥7 AND Symptom Severity Scale (SSS) ≥5, OR WPI 4–6 AND SSS ≥9
Generalized pain in at least 4 of 5 regions (left upper, right upper, left lower, right lower, axial)
Symptoms present at a similar level for at least 3 months
Diagnosis is valid regardless of other diagnoses (fibromyalgia can coexist with other conditions)

WPI: Count of 19 specified body areas where patient has had pain in the past week (0–19). SSS: Sum of severity scores (0–3 each) for fatigue, waking unrefreshed, and cognitive symptoms, plus number of somatic symptoms (0–3) = total 0–12.

FDA-Approved Pharmacotherapy

Drug	Class	Dose	Mechanism in Fibromyalgia	NNT
Duloxetine	SNRI	60 mg daily (start 30 mg × 1 week)	Augments descending NE/5-HT inhibition	7.2 for ≥50% pain reduction
Pregabalin	Gabapentinoid	150–450 mg/day in divided doses	Alpha-2-delta Ca²⁺ channel modulation; reduces excitatory neurotransmitter release	8.6
Milnacipran	SNRI	50 mg BID (titrate: 12.5 mg ×1d, 25 mg BID ×2d, 50 mg BID)	Stronger NE than 5-HT reuptake inhibition (3:1 ratio); analgesic and fatigue benefits	7.7

Non-Pharmacologic Management

Exercise is the single most effective intervention (stronger evidence than any medication). Aerobic exercise (walking, swimming, cycling) 30 minutes, 3–5 times per week at moderate intensity. Strength training 2 times per week. Start low, progress slowly (“start low, go slow”). Cognitive behavioral therapy (CBT): Addresses catastrophizing, fear-avoidance beliefs, activity pacing; NNT ~4 for clinically meaningful improvement. Sleep optimization: Sleep hygiene, treat comorbid sleep disorders (sleep apnea is common); low-dose amitriptyline 10–25 mg QHS or cyclobenzaprine 5–10 mg QHS for non-restorative sleep.

Opioids should NOT be used for fibromyalgia. Multiple guidelines (ACR, EULAR) recommend against opioids based on: (1) lack of efficacy evidence; (2) opioid-induced hyperalgesia may worsen central sensitization; (3) high rates of opioid misuse in this population. If a patient with fibromyalgia is on chronic opioids, develop a collaborative taper plan while optimizing non-opioid strategies.

Overlap Syndromes

Fibromyalgia frequently co-occurs with other central sensitization syndromes: irritable bowel syndrome (32–77%), tension-type/migraine headache (48–76%), temporomandibular disorder (18–75%), interstitial cystitis (12–21%), chronic fatigue syndrome (21–80%), and vulvodynia. The shared pathophysiology of augmented central pain processing suggests a common neurobiologic mechanism.

Fibromyalgia vs Other Chronic Pain Conditions

Feature	Fibromyalgia	Polymyalgia Rheumatica	Hypothyroidism	Inflammatory Arthritis
Age	20–50 (peak)	>50 (always >50)	Any age	Variable
Lab findings	Normal ESR/CRP, normal CK	Markedly elevated ESR (>40), CRP	Elevated TSH	Elevated ESR/CRP, positive RF/anti-CCP or HLA-B27
Morning stiffness	Variable, non-specific	Severe, >45 min, shoulder/hip girdles	Generalized	>30–60 min, improves with activity
Tender points	Widespread (WPI)	Proximal girdle muscles	Generalized myalgia	Joint-specific
Response to steroids	No improvement	Dramatic response to prednisone 15–20 mg	No (responds to levothyroxine)	Partial response

Fibromyalgia Treatment Algorithm

Step 1 (All patients): Patient education, aerobic exercise (30 min 3–5x/week), sleep hygiene, CBT referral
Step 2 (Persistent symptoms): Add duloxetine 60 mg daily OR pregabalin 75–225 mg BID OR milnacipran 50 mg BID; low-dose amitriptyline 10–25 mg QHS for sleep
Step 3 (Partial response): Combination therapy (SNRI + gabapentinoid); aquatic therapy; acupuncture (EULAR conditional recommendation)
Step 4 (Refractory): Reassess diagnosis; treat comorbid psychiatric conditions; consider low-dose naltrexone (4.5 mg QHS — off-label, emerging evidence); multidisciplinary pain rehabilitation program

24 Perioperative Pain & ERAS

Preemptive & Preventive Analgesia

Preemptive analgesia is administration of analgesics before surgical incision to prevent central sensitization. Preventive analgesia (broader concept) encompasses any perioperative intervention that reduces post-surgical pain beyond the expected duration of the drug. Evidence supports multimodal preventive strategies, not single-agent preemptive dosing.

Multimodal Opioid-Sparing Protocol

Standard Multimodal Perioperative Regimen

Timing	Agent	Dose	Rationale
Preoperative	Acetaminophen	1000 mg PO	Central analgesic (COX-3 inhibition)
Preoperative	Gabapentin	300–600 mg PO	Alpha-2-delta modulation; reduces postoperative opioid consumption by 20–30%; anxiolysis
Preoperative	Celecoxib	200–400 mg PO	COX-2 inhibition; no platelet effect (safe preoperatively)
Intraoperative	Ketorolac	15–30 mg IV at wound closure	Potent parenteral NSAID; synergistic with acetaminophen
Intraoperative	Dexamethasone	4–8 mg IV	Anti-inflammatory; antiemetic; extends block duration
Intra/Postop	Regional anesthesia	Procedure-specific (see below)	Site-specific analgesia; blocks afferent nociceptive transmission
Postoperative	Acetaminophen	1000 mg PO q6h (scheduled)	Maintain central analgesia; avoid PRN dosing
Postoperative	Ibuprofen or celecoxib	400 mg PO q6h or 200 mg PO BID	Anti-inflammatory synergy with acetaminophen
Postoperative (rescue)	Oxycodone	5 mg PO q4h PRN	Reserved for breakthrough pain not controlled by multimodal regimen

Ketamine & Lidocaine Infusions

Ketamine infusion: Bolus 0.5 mg/kg IV at induction, then 0.1–0.25 mg/kg/h intraoperatively and 0.05–0.15 mg/kg/h for 24–48h postoperatively. Indicated for opioid-tolerant patients, major surgery, or chronic pain patients. Reduces opioid consumption by 30–50%. IV lidocaine infusion: Bolus 1–2 mg/kg IV, then 1–2 mg/min (or 1.5 mg/kg/h) intraoperatively and 24–48h postoperatively. Strongest evidence for abdominal surgery (reduces ileus, pain scores, opioid use, length of stay). Monitor for LAST (local anesthetic systemic toxicity); do not exceed 4.5 mg/kg/h.

Regional Blocks by Surgery Type

Surgery	Block	Coverage
Total knee arthroplasty	Adductor canal (saphenous) block + periarticular injection (PAI)	Anterior knee; motor-sparing (preserves quad function for early ambulation)
Total hip arthroplasty	Fascia iliaca block or pericapsular nerve group (PENG) block	Hip joint innervation (femoral, obturator, lateral femoral cutaneous)
Shoulder surgery	Interscalene brachial plexus block	C5–C7 distribution; risk of phrenic nerve palsy (avoid in contralateral diaphragm paresis)
Breast surgery	Pectoral nerve blocks (PECS I/II) or erector spinae plane (ESP) block	Anterior chest wall, axilla
Abdominal surgery (open)	Transversus abdominis plane (TAP) block or rectus sheath block or thoracic epidural	Abdominal wall (T6–L1)
Thoracotomy	Thoracic epidural or paravertebral block or erector spinae plane block	Unilateral or bilateral thoracic dermatomes; epidural is gold standard for thoracotomy
Rib fractures	Serratus anterior plane block or thoracic epidural or paravertebral block	Lateral chest wall; epidural for bilateral fractures

Enhanced Recovery After Surgery (ERAS)

ERAS pathways integrate multimodal analgesia with other perioperative optimizations: preoperative carbohydrate loading, avoidance of prolonged fasting, early ambulation, early oral intake, minimally invasive technique, goal-directed fluid therapy, and early Foley removal. Pain management is a central pillar — opioid-sparing multimodal regimens reduce opioid-related complications (ileus, PONV, urinary retention, sedation) and accelerate recovery.

Opioid-Free Anesthesia (OFA)

An emerging paradigm using combinations of non-opioid analgesics to provide complete intraoperative and postoperative analgesia without any opioid. Typical OFA protocol includes: dexmedetomidine infusion (0.5–1.0 mcg/kg/h), ketamine infusion (0.1–0.3 mg/kg/h), lidocaine infusion (1.5 mg/kg/h), magnesium sulfate (30–50 mg/kg bolus then 10 mg/kg/h), and regional anesthesia. Evidence supports reduced PONV, faster GI recovery, and potentially less chronic postsurgical pain development. Not universally applicable — requires appropriate patient selection and anesthesia team experience.

Prevention of Chronic Postsurgical Pain (CPSP)

CPSP affects 10–50% of surgical patients (highest after thoracotomy, mastectomy, amputation, hernia repair). Risk factors: preoperative pain >1 month, younger age, female sex, psychological vulnerability (anxiety, catastrophizing), genetic predisposition (COMT polymorphisms), intraoperative nerve injury, and severity of acute postoperative pain. Prevention strategies: aggressive multimodal perioperative analgesia, nerve-sparing surgical technique, regional anesthesia, perioperative ketamine (NMDA antagonism reduces central sensitization), gabapentinoid pre-treatment, and early psychological intervention for high-risk patients.

The intensity of acute postoperative pain is the single strongest modifiable predictor of chronic postsurgical pain. Reducing peak pain intensity in the first 48–72 hours with aggressive multimodal analgesia is the most important preventive strategy.

25 Regulatory & Ethical Considerations

DEA Scheduling of Controlled Substances

Schedule	Definition	Pain-Relevant Examples	Prescribing Rules
Schedule I	No accepted medical use, high abuse potential	Heroin, MDMA, psilocybin (cannabis per federal law)	Cannot prescribe; research only
Schedule II	High abuse potential; accepted medical use with severe restrictions	Morphine, oxycodone, hydromorphone, fentanyl, methadone, hydrocodone, amphetamines	Written/e-prescribed Rx; no refills; max 90-day supply (varies by state)
Schedule III	Moderate abuse potential	Buprenorphine, acetaminophen/codeine, ketamine (for compounding)	5 refills in 6 months; phone-in Rx permitted
Schedule IV	Low abuse potential	Tramadol, carisoprodol, benzodiazepines, zolpidem	5 refills in 6 months
Schedule V	Lowest abuse potential	Pregabalin, gabapentin (in some states), cough syrups with small amounts of codeine	Varies by state; OTC in some states

State Prescribing Laws

Significant state-to-state variation in: initial opioid prescription limits (many states limit to 3–7 days for acute pain), PDMP checking requirements (most states mandate at initiation and periodically), continuing education mandates, prescriber-patient relationship requirements, and telemedicine prescribing rules for controlled substances (Ryan Haight Act requires in-person exam for most controlled substance prescriptions, with COVID-era flexibilities under review).

Medical Marijuana

As of 2026, medical marijuana is legal in 38+ states and DC. Common qualifying conditions include chronic pain, cancer, PTSD, epilepsy, and MS. Federal Schedule I status creates tensions: DEA registrants risk licensure; cannot prescribe (can only “certify” or “recommend”); VA physicians cannot recommend; crosses state lines is trafficking. Evidence is strongest for chronic neuropathic pain (NNT 5.6) and chemotherapy-induced nausea. Limited evidence for fibromyalgia, arthritis, headache. Risks: CUD (9% lifetime), impaired driving, psychosis in predisposed, respiratory effects with smoking.

Ethical Considerations

Informed consent for chronic opioids: Must include realistic discussion of benefits (modest, 30% responder rate for chronic non-cancer pain), risks (addiction 8–12% in chronic pain patients, overdose, endocrinopathy, falls, OIH), alternatives, monitoring requirements, and conditions for discontinuation. Palliative exception: In end-of-life care, adequate pain treatment takes priority over the risk of dependence; the principle of double effect permits medications that may hasten death if the primary intent is symptom relief. Equitable pain treatment: Systematic disparities exist — Black and Hispanic patients receive fewer opioid prescriptions and lower doses than White patients for the same conditions; women are more likely to have pain dismissed as psychogenic. Address implicit bias through standardized assessment tools, clinical decision support, and institutional audit.

The DEA X-waiver requirement for prescribing buprenorphine was eliminated in January 2023 (Consolidated Appropriations Act). All DEA-registered practitioners with Schedule III authority can now prescribe buprenorphine for OUD without additional waiver or training requirement, dramatically expanding access to medication-assisted treatment.

Documentation Standards for Chronic Opioid Therapy

Elements to Document at Every Chronic Opioid Visit

Pain assessment: NRS intensity, functional status (PEG score), quality of life impact
5 A’s: Analgesia (pain relief), Activity (functional improvement), Adverse effects, Aberrant behaviors, Affect (mood)
PDMP review: Date checked, findings, any concerns
UDS results: Date obtained, findings, concordance with prescribed medications
Treatment agreement: Confirm in effect; review if any concerns
Naloxone: Prescribed and education provided (document for ≥50 MME or risk factors)
Risk reassessment: Ongoing evaluation of risk-benefit ratio; document clinical rationale for continuation
Non-pharmacologic therapies: Active engagement in PT, psychology, self-management strategies
Exit strategy: Document plan for eventual taper or clearly articulate ongoing need

26 Equianalgesic & MME Conversion Tables

Comprehensive Equianalgesic Table

Opioid	PO (mg)	IV/IM/SC (mg)	PO:IV Ratio	MME Factor	Duration
Morphine	30	10	3:1	1.0	3–4 h (IR)
Oxycodone	20	—	—	1.5	3–6 h (IR)
Hydrocodone	30	—	—	1.0	4–6 h
Hydromorphone	6	1.5	4:1	4.0	3–4 h
Oxymorphone	10	1	10:1	3.0	3–6 h
Codeine	200	120	1.7:1	0.15	4–6 h
Tramadol	300 (approximate)	—	—	0.1	4–6 h
Tapentadol	75	—	—	0.4	4–6 h
Meperidine	300	75	4:1	0.1	2–3 h (avoid — neurotoxic metabolite normeperidine)
Fentanyl IV	—	0.1 (100 mcg)	—	—	0.5–1 h IV; patch 72 h
Fentanyl Transdermal	25 mcg/h patch ≈ 60–90 mg oral morphine/day (use 60 mg for conservative conversion, 90 mg per manufacturer)
Methadone	See variable ratio: ≤30 mg morphine → 2:1; 31–90 mg → 4:1; 91–300 mg → 8:1; >300 mg → 12:1
Levorphanol	4	2	2:1	11.0	6–8 h

Methadone Conversion Table (Morphine → Methadone)

Total Daily Oral Morphine Equivalent (mg)	Morphine:Methadone Ratio	Example (Methadone Daily Dose)
≤30	2:1	30 mg morphine → 15 mg methadone
31–90	4:1	60 mg morphine → 15 mg methadone
91–300	8:1	240 mg morphine → 30 mg methadone
301–600	12:1	480 mg morphine → 40 mg methadone
601–1000	15:1	750 mg morphine → 50 mg methadone
>1000	20:1	1200 mg morphine → 60 mg methadone

ALWAYS apply a 25–50% dose reduction after equianalgesic conversion for incomplete cross-tolerance. For methadone conversions, use the most conservative published ratios and titrate slowly (no more frequently than every 5–7 days). Methadone conversions should ideally be managed by experienced pain or palliative care specialists.

27 Scoring Tools

Numeric Rating Scale (NRS)

Patient rates pain intensity on a scale from 0 (no pain) to 10 (worst imaginable pain). Clinically meaningful change: ≥2 points or ≥30% reduction. Mild: 1–3; Moderate: 4–6; Severe: 7–10. Most widely used pain scale in clinical practice. Limitation: unidimensional (intensity only).

Visual Analog Scale (VAS)

100 mm horizontal line anchored at “no pain” (0 mm) and “worst pain imaginable” (100 mm). Patient marks a point. Distance measured in mm. Clinically meaningful change: ≥13 mm. More sensitive than NRS for detecting small changes (preferred in research).

FLACC Scale (Pediatric/Nonverbal)

Category	0	1	2
Face	No particular expression; smile	Occasional grimace/frown; withdrawn	Frequent/constant frown; clenched jaw; quivering chin
Legs	Normal position; relaxed	Uneasy, restless, tense	Kicking or legs drawn up
Activity	Lying quietly; normal position; moves easily	Squirming, shifting, tense	Arched, rigid, or jerking
Cry	No cry (awake or asleep)	Moans, whimpers; occasional complaint	Crying steadily; screams; frequent complaints
Consolability	Content; relaxed	Reassured by occasional touching/hugging/talking; distractible	Difficult to console or comfort

Total score 0–10. For ages 2 months–7 years and nonverbal patients. Score ≥4 indicates moderate pain requiring intervention.

CPOT (Critical-Care Pain Observation Tool)

Indicator	0	1	2
Facial expression	Relaxed, neutral	Tense (brow lowering, orbit tightening)	Grimacing (all above + eyelid tightly closed)
Body movements	Absence of movements	Protection (slow, cautious, touching pain site)	Restlessness (pulling at tubes, attempting to sit up, thrashing)
Muscle tension (upper extremity)	Relaxed	Tense, rigid	Very tense or rigid
Compliance with ventilator (intubated) OR vocalization (extubated)	Tolerating / talking in normal tone	Coughing but tolerating / sighing, moaning	Fighting ventilator / crying out, sobbing

Total score 0–8. Score ≥3 suggests clinically significant pain. Validated for ICU patients who cannot self-report.

Opioid Risk Tool (ORT)

Risk Factor	Female Score	Male Score
Family history of substance abuse — Alcohol	1	3
Family history of substance abuse — Illegal drugs	2	3
Family history of substance abuse — Prescription drugs	4	4
Personal history of substance abuse — Alcohol	3	3
Personal history of substance abuse — Illegal drugs	4	4
Personal history of substance abuse — Prescription drugs	5	5
Age 16–45	1	1
History of preadolescent sexual abuse	3	0
Psychological disease (ADD, OCD, bipolar, schizophrenia, depression)	2	2

Total: 0–3 low risk; 4–7 moderate risk; ≥8 high risk for aberrant opioid behavior.

SOAPP-R (Screener and Opioid Assessment for Patients with Pain — Revised)

24-item self-report questionnaire; each item scored 0–4 (never to very often). Sample items: “How often do you have mood swings?”; “How often have you felt a need for higher doses of medication?”; “How often have others expressed concern over your use of medication?” Total score ≥18 indicates high risk for aberrant drug behavior. Sensitivity 0.81, specificity 0.68. Administer before initiating chronic opioid therapy. Recheck with COMM (Current Opioid Misuse Measure) during ongoing treatment.

Budapest Criteria for CRPS

See Section 21 for the complete enumeration of the Budapest Clinical Diagnostic Criteria (symptoms in 3 of 4 categories, signs in 2 of 4 categories, no alternative diagnosis).

PEG Scale

See Section 2 for the 3-item PEG rapid screening tool (Pain, Enjoyment, General activity). Score ≥4 suggests clinically significant pain. Minimum clinically important difference is 1.0 point.

DN4 (Douleur Neuropathique en 4 Questions)

Interview Items (patient-reported)	Examination Items (clinician)
1. Does the pain have burning characteristics?	5. Is there hypoesthesia to touch?
2. Does the pain have cold characteristics?	6. Is there hypoesthesia to pinprick?
3. Is the pain associated with electric shocks?	7. Is the pain provoked or increased by brushing (allodynia)?
4. Is the pain associated with tingling, pins and needles, numbness, or itching?

Score ≥4/7 suggests neuropathic pain (sensitivity 83%, specificity 90%). Useful for screening in primary care to determine need for neuropathic pain agents.

28 Abbreviations Master List

Abbreviation	Full Term
AAPM	American Academy of Pain Medicine
ACD	Abuse-Deterrent Formulation
APS	American Pain Society
ASRA	American Society of Regional Anesthesia and Pain Medicine
BPI	Brief Pain Inventory
BTcP	Breakthrough Cancer Pain
CGRP	Calcitonin Gene-Related Peptide
CMM	Comprehensive Medical Management
CNB	Central Neuraxial Block
COMM	Current Opioid Misuse Measure
COX	Cyclooxygenase
CPOT	Critical-Care Pain Observation Tool
CRPS	Complex Regional Pain Syndrome
CSE	Combined Spinal-Epidural
CT	Computed Tomography
DEA	Drug Enforcement Administration
DIRE	Diagnosis, Intractability, Risk, Efficacy
DPN	Diabetic Peripheral Neuropathy
DRG	Dorsal Root Ganglion
EMG	Electromyography
ERAS	Enhanced Recovery After Surgery
ER/LA	Extended-Release / Long-Acting
ESI	Epidural Steroid Injection
ESP	Erector Spinae Plane (block)
EUS	Endoscopic Ultrasound
FBSS	Failed Back Surgery Syndrome
FDA	Food and Drug Administration
FLACC	Face, Legs, Activity, Cry, Consolability
GABA	Gamma-Aminobutyric Acid
GIRK	G-protein Inwardly Rectifying Potassium (channel)
GMI	Graded Motor Imagery
GON	Greater Occipital Nerve
GPCR	G-Protein Coupled Receptor
GRK	G-Protein-Coupled Receptor Kinase
HA	Hyaluronic Acid
HPA	Hypothalamic-Pituitary-Adrenal (axis)
IASP	International Association for the Study of Pain
ICHD	International Classification of Headache Disorders
IDDS	Intrathecal Drug Delivery System
IL	Interlaminar
IPG	Implantable Pulse Generator
IR	Immediate-Release
IV	Intravenous
KL	Kellgren-Lawrence (OA grading)
LA	Local Anesthetic
LAST	Local Anesthetic Systemic Toxicity
LBP	Low Back Pain
LON	Lesser Occipital Nerve
LSS	Lumbar Spinal Stenosis
LTP	Long-Term Potentiation
MAID	Medical Assistance in Dying
MBB	Medial Branch Block
MILD	Minimally Invasive Lumbar Decompression
MME	Morphine Milligram Equivalent
MPQ	McGill Pain Questionnaire
MRI	Magnetic Resonance Imaging
NCS	Nerve Conduction Study
NE	Norepinephrine
NMDA	N-Methyl-D-Aspartate
NNT	Number Needed to Treat
NRS	Numeric Rating Scale
NSAID	Nonsteroidal Anti-Inflammatory Drug
OA	Osteoarthritis
OIAD	Opioid-Induced Androgen Deficiency
OIH	Opioid-Induced Hyperalgesia
ORT	Opioid Risk Tool
OUD	Opioid Use Disorder
PACC	Polyanalgesic Consensus Conference
PAG	Periaqueductal Gray
PAI	Periarticular Injection
PDMP	Prescription Drug Monitoring Program
PDPH	Post-Dural Puncture Headache
PEG	Pain, Enjoyment, General Activity (scale)
PENG	Pericapsular Nerve Group (block)
PHN	Postherpetic Neuralgia
PMMA	Polymethyl Methacrylate
PNS	Peripheral Nerve Stimulation
PRP	Platelet-Rich Plasma
PSIS	Posterior Superior Iliac Spine
QSART	Quantitative Sudomotor Axon Reflex Test
REMS	Risk Evaluation and Mitigation Strategy
RF / RFA	Radiofrequency / Radiofrequency Ablation
RVM	Rostral Ventromedial Medulla
SCI	Spinal Cord Injury
SCS	Spinal Cord Stimulation
SF-MPQ	Short Form McGill Pain Questionnaire
SI	Sacroiliac
SLR	Straight Leg Raise
SMP	Sympathetically Maintained Pain
SNRI	Serotonin-Norepinephrine Reuptake Inhibitor
SOAPP-R	Screener and Opioid Assessment for Patients with Pain — Revised
TAP	Transversus Abdominis Plane (block)
TCA	Tricyclic Antidepressant
TENS	Transcutaneous Electrical Nerve Stimulation
TF	Transforaminal
TIRF	Transmucosal Immediate-Release Fentanyl
TRPV1	Transient Receptor Potential Vanilloid 1
UDS	Urine Drug Screen
US	Ultrasound
VAS	Visual Analog Scale
VCF	Vertebral Compression Fracture
WDR	Wide Dynamic Range (neuron)
WHO	World Health Organization
WPI	Widespread Pain Index