What it is:Pain is subjective by definition, there's no lab test for it, and it always gets classified two ways before you treat it: by mechanism(nociceptive, neuropathic, or musculoskeletal/nociplastic) and by duration(acute, subacute, chronic, or breakthrough). Both classifications change which drug class you reach for.
The core problem:Nociceptive pain comes from real tissue damage activating intact nerves, so it responds to blocking prostaglandins (NSAIDs) or opioid receptors. Neuropathic pain comes from the nerves themselves being damaged or misfiring, so NSAIDs and opioids underperform and you instead need drugs that calm abnormal neuronal excitability: gabapentinoids, TCAs, SNRIs, and sodium-channel blocking anticonvulsants.
What you do about it:Nonpharmacologic therapy and nonopioids first, opioids reserved for pain where benefit clearly outweighs risk (severe acute pain, cancer pain, or when nonopioids fail/are contraindicated), and neuropathic pain gets its own separate algorithm built on co-analgesics rather than the WHO ladder.
The organizing framework for every pain plan is the 5 A's: Analgesia (is pain controlled), Activities (can they function, work, sleep, walk), Adverse effects (are you causing more harm than good), Aberrant use (any signs of misuse), and Affect (mood and pain amplify each other in both directions). You reassess against all five, not just the pain score.
Two separate axes. Mixing them up is the fastest way to pick the wrong drug class.
| Axis | Categories | Why it matters |
|---|---|---|
| Mechanism | Nociceptive (somatic/visceral tissue damage) · Neuropathic (nerve damage/dysfunction) · Musculoskeletal/nociplastic (bone, joint, muscle without clear tissue injury, e.g. fibromyalgia) | Nociceptive responds to NSAIDs/opioids. Neuropathic often doesn't, and needs co-analgesics instead. |
| Duration | Acute <1 month · Subacute 1-3 months · Chronic >3 months · Breakthrough (acute flare on top of controlled chronic pain) | Determines around-the-clock vs PRN dosing and whether opioids are even on the table (CDC guidance is much more restrictive for chronic pain). |
Cancer pain gets graded by a third axis, intensity on a 0-10 numeric rating scale: mild 1-3, moderate 4-6, severe 7-10. That number drives which rung of the treatment ladder you start on.
"Chronic pain" and "cancer pain" are not synonyms, and neither is "severe pain" a synonym for "needs an opioid." A patient can have severe neuropathic pain that responds better to duloxetine than to oxycodone. Match the drug to the mechanism, not just the intensity.
Normal, protective pain (touch something hot, get cut, have surgery) runs through five steps, and almost every drug class targets one of them.
| Step | What happens | Drug target |
|---|---|---|
| Transduction | Nociceptors in skin, muscle, and viscera are activated by mechanical, thermal, or chemical stimuli. Tissue injury releases cytokines/chemokines that sensitize them further. | NSAIDs (block prostaglandin synthesis that sensitizes nociceptors), topical capsaicin/lidocaine |
| Conduction | Large myelinated fibers carry sharp, well-localized pain fast; small unmyelinated fibers carry dull, aching, poorly-localized pain. | Local anesthetics (sodium channel blockade) |
| Transmission | Afferent fibers synapse in the spinal dorsal horn, releasing glutamate and substance P to relay the signal upward. | Gabapentinoids (reduce glutamate/substance P release), opioids at spinal receptors |
| Modulation | GABA, norepinephrine, serotonin, and endogenous opioids can dampen the signal on its way up or on the way back down (descending pathway). | TCAs and SNRIs (boost NE/serotonin in the descending pathway), opioids (mimic endogenous opioids) |
| Perception | The signal reaches cortical structures and becomes "pain." Cognition and mood modulate it here, relaxation and distraction lessen it, anxiety and depression amplify it. | This is why affect is one of the 5 A's, and why CBT/mindfulness are real treatments, not filler |
Neuropathic pain doesn't start with tissue damage, it starts with damaged or dysfunctional nerves in the CNS or PNS, and the circuitry can permanently rewire itself. Several mechanisms overlap:
Every neuropathic co-analgesic class targets one of those broken pieces: gabapentinoidsblock the extra calcium channels, carbamazepine/oxcarbazepineblock the extra sodium channels, TCAs/SNRIsboost the descending inhibitory signal that's failing to keep up, and topical lidocaine/capsaicindesensitize the peripheral nerve endings directly. None of them are "painkillers" in the opioid sense, they're correcting a specific electrical or chemical malfunction.
| Symptoms | Signs | |
|---|---|---|
| Acute | Sharp, dull, throbbing, or shock-like; fluctuates with an identifiable noxious trigger; infants and older adults may present atypically (irritability, withdrawal, confusion instead of verbalized pain) | Tachycardia, hypertension, diaphoresis, mydriasis, pallor. Often no obvious sign at all, there's no lab test for pain. |
| Chronic | Similar quality but can shift character over time (sharp to dull); emotional factors actively lower the pain threshold | Usually no exam findings. Depression, sleep disturbance, and anxiety are common comorbid findings, not separate problems. |
Burning, electric shock-like, tingling, and numbness are the words that should make you think neuropathic, not nociceptive. Four specific features come up constantly and are easy to mix up:
| Term | Definition |
|---|---|
| Allodynia | Pain from a stimulus that shouldn't hurt at all (light touch, a cool breeze, bedsheets) |
| Hyperalgesia | An exaggerated, amplified response to a stimulus that is normally painful |
| Hyperpathia | The threshold to trigger pain is actually higher, but once triggered the response is disproportionately intense and prolonged, especially with repetitive stimulation |
| Paresthesia / dysesthesia | Abnormal sensations (tingling, pins-and-needles, prickling) from nerve compression, damage, or poor blood flow, may occur with or without pain |
Allodynia= normal stimulus becomes painful. Hyperalgesia= painful stimulus becomes more painful. Both are common exam distractors because they sound interchangeable but describe different starting points.
There is no lab test for pain itself. Diagnosis is entirely patient-centered: a structured history plus, for neuropathic pain, a directed exam and labs to find the underlying cause.
OLDCARTS, SOCRATES, SCHOLAR-MAC, and OPQRSTare functionally interchangeable ways to structure the same interview: Onset, Provocation/palliation (what makes it better or worse), Quality (throbbing, burning, aching), Region/radiation, Severity (the 0-10 score), Timing (duration, pattern, change over time).
Beyond history, a neuropathic workup adds a targeted physical exam and labs aimed at finding a treatable cause, not confirming "neuropathic pain" as a diagnosis in itself.
Before or alongside any drug: physical therapy, exercise, weight loss, and electroanalgesia (TENS through fully implanted spinal cord stimulators), plus complementary approaches like acupuncture, Tai chi, yoga, mindfulness, and biofeedback. This isn't a footnote, the 2022 CDC guideline explicitly ranks nonopioid and nonpharmacologic therapy as at least as effective as opioids for most common acute pain(low back pain, minor surgery pain, dental pain, kidney stone pain, episodic migraine) and preferredfor subacute and chronic pain.
Originally built in 1986 for cancer pain, now generalized to acute, chronic, and non-cancer pain, and updated in 2021 to add a fourth rung.
| Step | What's added |
|---|---|
| 1 | Nonopioid analgesics (APAP, NSAIDs) ± adjuvants |
| 2 | Weak/"mild" opioids added for persisting or increasing pain |
| 3 | Strong opioids for moderate-severe pain |
| 4 (2021 addition) | Interventional/nonpharmacologic options: nerve blocks, spinal stimulators, PCA, with explicit step-up and step-down movement rather than a one-way climb |
| Intensity (NRS) | Opioid-naïve | Opioid-tolerant† |
|---|---|---|
| Mild (1-3) | Nonopioid + adjuvant analgesics | Nonopioid + adjuvant; reassess ongoing opioid need, taper if not indicated |
| Moderate (4-6) | Nonopioid + adjuvant + short-acting opioid PRN, titrate q3-4h; ≥4 doses/day → consider adding a long-acting opioid based on the total daily dose | Titrate the short-acting opioid to raise total daily dose 30-50% until relief; ≥4 doses/day → add/increase long-acting opioid |
| Severe (7-10) | Consider hospital or inpatient hospice admission; IV or oral short-acting opioids | |
†Opioid-tolerant = at least 60 mg/day oral morphine equivalents for 7+ days (or codeine 150 mg, transdermal fentanyl 25 mcg/h, hydromorphone 8 mg, methadone 20 mg, oxycodone 30 mg, oxymorphone 20 mg daily equivalents).
For a patient in an acute pain crisis, dose and reassessment interval depend on route and opioid tolerance, not a fixed protocol:
| Status / Route | Dose | Reassess at |
|---|---|---|
| Opioid-naïve, PO | 5-15 mg oral morphine equivalent | 60 min (expected peak) |
| Opioid-naïve, IV | 2-5 mg IV morphine equivalent | 15 min (expected peak) |
| Opioid-tolerant, PO | 10-20% of previous 24h oral dose | 60 min |
| Opioid-tolerant, IV | 10-20% of previous 24h IV dose | 15 min |
If pain is unchanged or worse at reassessment, increase the next dose 50-100%. If improved but not adequately controlled, repeat the same dose. Once adequately controlled, continue that effective dose PRN for 24 hours, then start a scheduled regimen (dosed q3-4h IV, q4h PO). After 2-3 dosing cycles without control, escalate: switch to IV if you'd been titrating PO, maximize adjuvants, consider opioid rotation, and get a pain specialist involved.
Its mechanism is still not fully pinned down: weak COX inhibition, activation of descending serotonergic pathways, and TRPV1/cannabinoid-1 receptor agonism all seem to contribute. What matters clinically is the metabolism. About 90% of a therapeutic dose is safely inactivated by glucuronidation and sulfation. The remaining 5-10% is oxidized to NAPQI, a toxic metabolite that's normally neutralized by binding glutathione and excreted harmlessly. Push the dose past roughly 4 g/dayand glucuronidation/sulfation saturate, shunting more of the dose down the NAPQI pathway, while glutathione stores can't keep up. That mismatch is hepatotoxicity, and alcohol use or interacting drugs (isoniazid, anticonvulsants that deplete glutathione or induce competing pathways) lower the threshold at which it happens. The antidote, N-acetylcysteine, works by resupplying glutathione.
Combination opioid products (Norco, Percocet, Vicodin) and OTC cold/flu remedies (NyQuil, etc.) both routinely contain APAP. A patient scheduling their own APAP around one of these without realizing it is the single most common way people accidentally cross the toxic threshold.
NSAIDs block cyclooxygenase, which reduces the prostaglandins that sensitize nociceptors and drive inflammation. COX-1is constitutively active everywhere (GI mucosal protection, renal blood flow, platelet aggregation), while COX-2is inducible and mostly shows up during inflammation. Selective COX-2 inhibition was supposed to spare the GI tract while still treating inflammation, but it turned out to raise cardiovascular risk instead (rofecoxib and valdecoxib were pulled from the market for exactly that reason).
ACE inhibitor/ARB + diuretic + NSAIDtogether raises acute kidney injury risk by roughly 36%. Each drug independently constricts a different part of renal blood flow regulation (efferent arteriole, volume, afferent arteriole via prostaglandins), and stacking all three removes the kidney's ability to autoregulate. Always ask about OTC NSAID use in a patient on an ACEi/ARB and a diuretic.
Other hard NSAID rules: an adequate trial is about 1 monthbefore calling it ineffective; chronic use risks GI, cardiac, and renal toxicity; ketorolac is capped at 5 daystotal (including any parenteral doses before an oral switch) because the GI bleed and renal failure risk climbs fast beyond that; NSAIDs are contraindicated in the third trimesterof pregnancy because they can cause premature closure of the ductus arteriosus (interestingly, IV NSAIDs are used deliberately for the opposite purpose, closing a patent ductus arteriosus in neonates); and NSAIDs are contraindicated perioperatively around CABG surgery. Topical NSAIDs are preferred over oral for knee or hand osteoarthritis, similar efficacy with far less systemic exposure.
| Drug | Usual adult dosing | Max/day | Notes |
|---|---|---|---|
| Acetaminophen | 325-1000 mg PO/IV q4-6h; peds 10-15 mg/kg/dose q4-6h | 4000 mg (FDA); 3000 mg OTC label; 2000 mg if hepatotoxicity risk | <5% excreted unchanged; regular alcohol use compounds hepatotoxicity risk |
| Ibuprofen | 200-800 mg q6-8h | 3200 mg (up to 2400 mg OTC) | Avoid CrCl <30 (AKI risk) |
| Naproxen | 250-500 mg q12h | 1000 mg (660 mg OTC) | Avoid CrCl <30 |
| Diclofenac (K/Na) | Initial 100 mg then 50 mg TID | 150 mg | Higher CV thrombotic risk than most NSAIDs |
| Meloxicam | 7.5 mg daily | 15 mg | Not recommended eGFR <60 |
| Indomethacin | 20 mg q8h | - | Avoid CrCl <30 |
| Celecoxib | Initial 400 mg then 200 mg day 1, then 200 mg BID | 400 mg | Avoid with severe sulfa allergy (structurally a sulfonamide); consider lower maintenance dose for CV risk |
| Ketorolac (parenteral → oral bridge) | IM 30-60 mg or IV 15-30 mg single dose; then PO 10 mg q4-6h | 120 mg IV/IM day 1; 40 mg PO | Hard 5-day total limitacross all routes combined; avoid eGFR <30 |
Neuropathic pain (7-10% of adults) has its own drug list because NSAIDs and, often, opioids underperform against nerve-generated pain. Four drug families do the real work here: anticonvulsants, TCAs, SNRIs, and topical/local anesthetics.
| Drug | Dosing | Key notes |
|---|---|---|
| Gabapentin | 100-300 mg steps, ↑ q3-5 days by 100-300 mg; median effective dose 1600-2400 mg/day | Blocks the α2δ subunit of voltage-gated Ca²⁺ channels (not a direct channel blocker). Renal dose adjustment required. Federally tracked misuse potential in several states. |
| Gabapentin (Gralise, once daily) | Day 1: 300 mg → titrate weekly to 1800 mg by day 15, with evening meal | Max 1800 mg/day; not interchangeable mg-for-mg with immediate-release gabapentin |
| Gabapentin enacarbil | 600 mg every morning ×3 days, then 600 mg BID | Max 1200 mg/day |
| Pregabalin | Initial 150 mg/day in 2-3 divided doses; ↑ by 300 mg/day at 1 week | Max varies by indication, overall ~600 mg/day; renal adjustment for CrCl <60 |
| Pregabalin CR | Initial 165 mg daily | Max 330 mg/day (DPN) or 330-660 mg/day (PHN) |
| Carbamazepine/CBZ XR | Initial 100 mg BID, ↑ by 100 mg BID; target 300-900 mg/day | Max 1200 mg/day. First-line specifically for trigeminal neuralgia, not general neuropathic pain. Autoinduces its own CYP3A4 metabolism, so titration is a moving target. Monitor CBC, LFTs, sodium. |
| Oxcarbazepine | Initial 150 mg BID, ↑ by 300 mg q3 days; target 300-600 mg BID | Max 1800 mg/day. Better tolerated, fewer interactions than carbamazepine. Also used for trigeminal neuralgia. |
| Lamotrigine | Initial 25 mg daily, ↑ q2wk to 50, 100, 200 mg/day | Max 400 mg/day. Fourth-line, specialist setting only, because of life-threatening rash (Stevens-Johnson syndrome) risk from fast titration. |
| Topiramate/XR | Initial 25 mg daily ×1wk, ↑ 25-50 mg/wk | Target 50 mg BID (migraine) or 200-400 mg/day (neuropathic pain). Fourth-line. Monitor bicarbonate/renal function; causes kidney stones, weight loss, decreased sweating/hyperthermia risk, hyperammonemia. |
Carbamazepine and oxcarbazepine carry risk of Stevens-Johnson syndrome/TEN, and that risk is markedly higher in patients of Asian ancestry with the HLA-B*1502 variant. Screen before starting in that population. All anticonvulsants here also carry an increased risk of suicidal thoughts and behavior, worth a direct counseling mention.
| Class / Drug | Dosing | Key notes |
|---|---|---|
| TCAs: amitriptyline, imipramine (tertiary amines); desipramine, nortriptyline (secondary amines) | Initial 10-25 mg qhs, ↑ 10-25 mg q3-7 days | Max 150 mg/day, but analgesic doses run far below antidepressant doses. Secondary amines cause less anticholinergic burden. QTc prolongation, orthostatic hypotension, arrhythmia risk; doses >100 mg/day linked to sudden cardiac death. Lowers seizure threshold. |
| Duloxetine | Initial 30 mg daily ×1wk (2wk if older adult); target 60 mg daily | Max 120 mg/day, though little added benefit above 60 mg for pain. Avoid eGFR <30 and chronic liver disease. Only SNRI FDA-approved for diabetic peripheral neuropathy, also fibromyalgia and chronic musculoskeletal pain. |
| Milnacipran | Day 1: 12.5 mg; days 2-3: 12.5 mg BID; days 4-7: 25 mg BID; then 50 mg BID; target 100 mg/day | Max 200 mg/day. FDA-approved for fibromyalgia only. |
| Venlafaxine | Initial SA 37.5 mg daily, ↑ ≤75 mg/day q4 days | Max 225 mg/day; needs higher doses to reach true SNRI (dual reuptake) effect. Does not work for post-herpetic neuralgia, a common trap. QTc prolongation risk higher than duloxetine. |
Duloxetine and venlafaxine both treat diabetic peripheral neuropathy, but only venlafaxine fails for PHN, while lidocaine patch, gabapentinoids, and TCAs are the PHN mainstays. Don't assume every SNRI covers every neuropathic syndrome interchangeably.
| Syndrome | Key facts | Preferred agents |
|---|---|---|
| Diabetic peripheral neuropathy | ≥20% of T1DM by 20 years; ≥10-15% of new T2DM, up to 50% by 10 years. Hyperglycemia → oxidative/inflammatory nerve damage. Symmetric numbness/tingling. Duloxetine's benefit takes 4-6 weeks to show. | Duloxetine (FDA-approved), gabapentinoids, TCAs; tight glycemic control (A1c <7) is prevention, not treatment of established pain |
| Post-herpetic neuralgia (PHN) | Most common long-term complication of shingles (VZV reactivation). Unilateral burning/lancinating pain persisting >3 months after the rash resolves. Vaccination cuts shingles incidence ~51% and PHN ~66%, and reduces illness burden even in patients who already developed PHN. | TCAs, gabapentinoids, lidocaine 5% patch. Not venlafaxine. |
| Trigeminal neuralgia | Irritation of the trigeminal nerve (ophthalmic, maxillary, or mandibular branch). Intense, stabbing, electric shock-like pain, more common in women and older adults. | Carbamazepine or oxcarbazepine first-line; gabapentinoids as alternative |
| Neuropathic cancer pain | Occurs in 20-50% of cancer patients overall, up to 80% with advanced disease; caused by tumor, surgery, radiation, or chemotherapy itself. | Venlafaxine/duloxetine first-line specifically for chemo-induced peripheral neuropathy; gabapentinoids, TCAs, opioids as needed; corticosteroids lack good evidence here |
| Drug-induced neuropathy | Isoniazid (give with pyridoxine/B6 to prevent it), metronidazole, nitrofurantoin, phenytoin. Chemo-induced: platinums, taxanes, vinca alkaloids, proteasome inhibitors, thalidomide. | Treat the syndrome as above; prevention (B6 with isoniazid) beats treatment |
| Chronic low back pain | A symptom, not a disease. Multifactorial (injury, arthritis, mood). | NSAIDs, duloxetine for chronic pain; gabapentinoids/TCAs have weaker evidence. Muscle relaxants, opioids, steroids, and benzodiazepines are actively notrecommended. |
| Fibromyalgia | Widespread aching/burning/throbbing pain plus fatigue, stiffness, tenderness, sleep disturbance. Diagnosis of exclusion, cause unknown. | Duloxetine, milnacipran, and pregabalin all carry FDA approval specifically for fibromyalgia |
Two functional families: antispasmodics(baclofen, diazepam, tizanidine, used for spasm from acute musculoskeletal pain) and antispasticity agents(carisoprodol, chlorzoxazone, cyclobenzaprine, metaxalone, methocarbamol, orphenadrine, plus diazepam/tizanidine again, used for spasticity from CNS lesions). Efficacy overall is modest and the evidence base for chronic low back pain specifically is weak, but they're used constantly for acute flares and post-op spasm.
| Drug | Dosing | Key notes |
|---|---|---|
| Baclofen | Initial 5 mg TID, ↑ q3 days; max 80 mg/day | Abrupt discontinuation risks a withdrawal syndrome with hallucinations and seizures, especially with intrathecal pumps. Renal dose adjustment. |
| Carisoprodol | 250-300 mg QID | Active metabolite meprobamate is itself a barbiturate with Schedule IV misuse potential. Metabolized by CYP2C19 (genetically variable). Additive respiratory depression with opioids/BZDs/barbiturates. |
| Chlorzoxazone | 250-500 mg TID-QID, max 750 mg TID-QID | Rare hepatotoxicity; discolors urine. |
| Cyclobenzaprine | Initial 5 mg TID, ↑ to 7.5-10 mg TID; fibromyalgia: 10 mg AM/20 mg HS | Structurally similar to amitriptyline: anticholinergic effects, serotonin syndrome risk, arrhythmia risk. Avoid in closed-angle glaucoma; lower dose in older adults. |
| Diazepam | 2-10 mg 3-4×/day | Long half-life; avoid in older adults and renal/hepatic impairment; withdrawal risk with abrupt stop. |
| Methocarbamol | 1500 mg QID ×2-3 days, then 750-1000 mg QID | Discolors urine. |
| Metaxalone | 800 mg TID-QID | Contraindicated in severe hepatic/renal impairment. |
| Orphenadrine | 100 mg BID | Anticholinergic effects; rare aplastic anemia. |
| Tizanidine | Initial 4 mg, ↑ by 2-4 mg q6-8h; max 36 mg/day | Hypotension and hepatotoxicity risk; tablets and capsules are not bioequivalent; withdrawal syndrome with abrupt discontinuation. |
The whole point of a topical is local effect with minimal systemic drug exposure, which matters most when CNS side effects from an oral agent are the limiting factor.
| Agent | Use | Application | Notes |
|---|---|---|---|
| Capsaicin cream | Localized neuropathic/musculoskeletal pain | 3-4×/day, scheduled, 2-4 weeks for full effect | Works by desensitizing TRPV1-expressing nerve endings after transient burning; the burning decreaseswith continued scheduled use, so don't let early burning cause discontinuation. |
| Capsaicin 8% patch (Qutenza) | PHN | 1-4 patches, 60 min (PHN) or 30 min (DPN), repeat no sooner than q3mo, max 4 patches | Pretreat with topical anesthetic; monitor BP (transient rise during application). |
| Diclofenac 1% gel (Voltaren) | OA of knees/hands | Lower extremity 4 g QID (max 16 g/day); upper extremity 2 g QID (max 8 g/day); total max 32 g/day | Carries the same black box warnings as oral NSAIDs despite only ~6% systemic absorption. Use the dosing card. |
| Diclofenac patch (Flector) | Acute minor strain/sprain | 1 patch to most painful area BID | <1% systemic exposure after 4 days of repeated use. |
| Lidocaine 5% patch (Lidoderm) | PHN (FDA-approved) | 1-3 patches, 12h on / 12h off, max 3 at once | Sodium channel blocker; may be cut to fit; caution with severe hepatic impairment; apply to intact skin only. |
Both lidocaine 5% patch and capsaicin 8% patch carry FDA approval specifically for post-herpetic neuralgia, which is why PHN shows up so often paired with "topical" answer choices on exams. Cannabis/CBD and ketamine are both listed as emerging options for chronic/neuropathic pain, but dosing, route, and monitoring are still unstandardized, don't reach for either as a default.
| Category | Behavior | Examples |
|---|---|---|
| Full agonist | Fully stimulates the mu receptor, no ceiling effect | Morphine, fentanyl, oxycodone, hydrocodone, hydromorphone, methadone |
| Partial agonist | Stimulates below the maximal level; high affinity/slow dissociation makes it act like an antagonist once bound | Buprenorphine |
| Antagonist | Blocks the receptor, produces no analgesia itself | Naloxone, naltrexone |
| Mixed agonist-antagonist | Stimulates one receptor subtype while blocking another; ceiling effect on analgesia; can precipitate withdrawal in opioid-dependent patients | Nalbuphine, butorphanol, pentazocine |
| Agent | Typical dosing | Equianalgesic (mg) | What makes it distinct |
|---|---|---|---|
| Morphine | PO 5-30 mg q4h; IV 5-15 mg q4h | 25 PO / 10 IV | First-line for moderate-severe pain. Active metabolites (M6G) accumulate in renal impairment, avoid or reduce dose at CrCl ≤30. Orthostatic hypotension risk if hypovolemic. |
| Hydromorphone | PO 2-4 mg q4-6h; IV 0.5-2 mg q4h | 7.5 PO / 1.5 IV | More potent than morphine, fewer AEs (notably less pruritus), but otherwise no real advantage. Same renal caution as morphine. |
| Oxycodone | IR 5-15 mg q4-6h; CR 10-20 mg q12h | 15-30 | PO only. Faster onset (10-15 min) than morphine. Metabolized by CYP3A4/2D6, BBW for concomitant CYP3A4 inhibitors → overdose risk. |
| Hydrocodone | PO 5-10 mg q4-6h (usually with APAP) | - | Mostly seen in combination products (Norco, Vicodin, Lortab); ER monotherapy (Hysingla) exists but is PO only. BBW for CYP3A4 inhibitor interaction. |
| Codeine | PO 15-60 mg q4-6h | - | Prodrug activated by CYP2D6 to morphine; weak on its own. Contraindicated <12 years oldand in post-tonsillectomy/adenoidectomy patients <18, because CYP2D6 ultra-rapid metabolizers can convert enough morphine to cause fatal respiratory depression. |
| Fentanyl | IV 25-50 mcg/h; patch 25 mcg/h q72h | 0.125 IV; variable transdermal | Far more potent, fast onset IV. Transdermal is never for opioid-naïve or acute pain, only for chronic pain in patients already opioid-tolerant (≥60 mg oral MME/day for ≥1 week). Takes a full day to reach steady state after application. |
| Methadone | PO 2.5-10 mg q8-12h, ↑ by 2.5 mg/dose weekly | Variable, drops with rising prior opioid dose | NMDA antagonist + kappa/delta agonist + serotonin/NE reuptake inhibitor, useful for chronic and neuropathic-component pain. Unpredictable half-life (8-59h). BBW: do not initiate if QTc >500 ms.Never titrate more often than weekly. |
| Meperidine | IM 50-150 mg q3-4h | 75 | Active metabolite normeperidine accumulates in renal impairment, causing tremor, myoclonus, seizures. Contraindicated with MAOIs (serotonin syndrome/hyperpyrexia). No advantage over morphine; largely abandoned outside single-dose, short-term use. |
| Buprenorphine | IM/slow IV 0.3 mg q6h; transdermal weekly patch; SL for OUD | 0.3 | Partial agonist with such high receptor affinity it behaves like an antagonist, can precipitate withdrawal in opioid-dependent patients. Used for pain and, combined with naloxone, for OUD, historically requiring a special DEA waiver to prescribe. |
| Tramadol | PO 50-100 mg q4-6h | - | Weak mu agonist plus serotonin/NE reuptake inhibition; prodrug activated by CYP2D6 (200× more active metabolite). Higher seizure-threshold risk than most opioids. Same pediatric/post-tonsillectomy contraindication as codeine. |
| Tapentadol | PO 50-100 mg q4-6h | - | Weak mu agonist plus norepinephrine reuptake inhibition (no serotonin component, unlike tramadol). Useful in diabetic peripheral neuropathy as well as acute pain. |
| Nalbuphine / butorphanol / pentazocine | Variable, parenteral (nalbuphine/butorphanol) or PO (pentazocine) | 10 (nalbuphine) / 2 (butorphanol) | Second-line mixed agonist-antagonists; ceiling analgesic effect; can precipitate withdrawal in dependent patients. Low-dose nalbuphine is actually used to treatopioid-induced pruritus. |
Four steps, every time:
Methadone's conversion ratio isn't fixed, it gets more potent relative to other opioids as the prior opioid dose rises: roughly 4:1 (morphine:methadone) below 90 mg MME/day, 8:1 between 90-300, and 12:1 above 300. You cannot use a standard equianalgesic chart for methadone. "Start low, go slow," and never re-titrate more often than weekly given the long, unpredictable half-life.
Fentanyl patch conversionshave their own rule: per the product labeling, do notuse a standard equianalgesic table to convert froma fentanyl patch back to another opioid, that direction of conversion using generic tables has caused overdoses.
A programmable pump lets the patient self-deliver preset IV opioid doses (commonly morphine, hydromorphone, or fentanyl) on demand, and it beats traditional PRN nursing-administered dosing on both pain control and satisfaction with similar adverse effect rates. Four components to set: loading dose(bring pain under control first), basal rate(continuous background infusion, avoid in opioid-naïve patients), demand/bolus dose(what the patient triggers), and lockout interval(minimum time between triggered doses, a built-in overdose safeguard, e.g., 10 minutes for a typical morphine PCA).
Most opioid-related itching, flushing, and rash is not a true allergy, it's direct histamine release from cutaneous mast cells (a pseudoallergic reaction), especially common with morphine and codeine. True IgE-mediated allergy (hives, angioedema, severe hypotension, bronchospasm) is uncommon and occurs mainly with natural/semisynthetic opioids. If a genuine allergy is suspected, you can often switch to a different structural class(phenanthrenes, benzomorphans, phenylpiperidines, diphenylheptanes) without cross-reactivity, but the mixed agonist-antagonist class behaves pharmacologically most like the morphine-like phenanthrenes for this purpose, so don't assume it's automatically safe.
| Effect | Mechanism / presentation | Management |
|---|---|---|
| Respiratory depression | Decreased rate, periodic breathing, desaturation | Have naloxone available; avoid combining with alcohol or benzodiazepines |
| Sedation | Dose-related CNS depression | Avoid stacking other sedating drugs |
| Nausea/vomiting | Chemoreceptor trigger zone stimulation | Take with food; consider an antiemetic, especially early in therapy |
| Constipation | ↓ GI motility, ↑ sphincter tone; does notresolve with tolerance the way sedation does | Scheduled stimulant laxative + stool softener ("mush and push") from day one of chronic therapy; hydration and exercise; PAMORAs (methylnaltrexone, naldemedine, naloxegol) if refractory |
| Pruritus / urticaria | Histamine release, usually pseudoallergic not true allergy | Antihistamine; switch opioid if persistent |
| Confusion, delirium, hallucinations, myoclonus | More common with meperidine, high doses, or renal impairment | Reduce dose, rotate opioids, avoid meperidine, ensure adequate hydration |
| Tolerance / physical dependence | Expected physiologic adaptations, not the same as addiction | Anticipate with long-term use; taper rather than stop abruptly |
| Hypogonadism | Fatigue, depression, reduced libido, amenorrhea | Consider with unexplained fatigue/mood change on chronic opioids |
| Sleep disruption | Dose-dependent REM suppression | Counsel proactively; contributes to daytime fatigue |
Classic overdose picture: pinpoint pupils, blue/purple lips or nail beds, pale clammy skin, slow heart rate/blood pressure, slow or stopped breathing, unresponsiveness. Naloxoneis a pure competitive antagonist, it reverses respiratory depression but produces no analgesia itself, and its half-life (roughly 0.5-1.3 hours) is often shorter than the opioid it's reversing, so repeated or continuous dosing may be needed, especially after long-acting or high-dose opioids. Reversal doses are typically 0.4-2 mg IV/IM/IN. If the goal is reversing respiratory depression withoutreversing analgesia in a patient who still needs pain control, dilute and titrate in small increments (0.1-0.2 mg q2-3min) instead of pushing a full reversal dose. Call 911 after any administration. Many states have standing orders letting patients and family obtain naloxone without an individual prescription, and training household contacts on recognition and administration is genuinely standard of care, not optional.
| Term | Definition |
|---|---|
| Addiction | Behavioral: impaired control over use, compulsive use, continued use despite harm, craving |
| Physical dependence | A physiologic adaptation producing a drug-class-specific withdrawal syndrome on abrupt cessation, rapid dose reduction, or antagonist administration, expected with chronic opioid use even without addiction |
| Tolerance | Diminished effect from the same dose over time, requiring dose increases to maintain the same benefit |
Opioid use disorder is a formal DSM-5 diagnosis requiring ≥2 of 11 criteria within a year (loss of control, craving, continued use despite harm/role impairment, tolerance, withdrawal, and similar). Effective treatment is medication-based: buprenorphine (partial agonist, acts like an antagonist), methadone (full agonist, dispensed only through certified treatment clinics), or naltrexone (antagonist, monthly long-acting injection, requires 7-10 days opioid-free before the first doseto avoid precipitating withdrawal, reserved for highly motivated patients).
Anxiety, insomnia, abdominal pain, vomiting, diarrhea, diaphoresis, mydriasis, tremor, tachycardia, and piloerection ("goosebumps") are the withdrawal picture. Management is mostly symptomatic and about slowing the taper rather than pushing through:
Taper when pain has improved, the patient requests it, pain/function haven't meaningfully improved despite dose escalation, there's evidence of misuse, side effects are eroding quality of life, an overdose or serious event has occurred, or comorbidities (benzodiazepine use, lung/liver/kidney disease, fall risk, advanced age) raise the risk of continuing. It should almost never be abrupt, unless there are active signs of impending overdose (confusion, sedation, slurred speech).
| Duration of use | Suggested pace |
|---|---|
| Chronic (>1 year) | ~10% of the dose per month, or slower |
| Short-term (<1 year) | ~10% of the dose per week, or slower |
In practice, available tablet strengths mean the real step size often ends up closer to ~20%. Tapers can be paused at any point to let the patient adjust to a new non-pharmacologic plan or a new baseline pain level, and once the smallest available tablet strength is reached, extend the interval between doses rather than trying to cut pills smaller.
| Parameter | When | Watching for |
|---|---|---|
| Pain intensity (NRS or equivalent) | Postop/acute cancer exacerbation: hourly. Chronic nonmalignant pain: daily or less often. | Adequacy of current regimen |
| The 5 A's(Analgesia, Activities, Adverse effects, Aberrant use, Affect) | Every visit on chronic opioid therapy | Whether the regimen is still net-beneficial, not just whether pain score dropped |
| Respiratory status | Any dose increase, new opioid, or added CNS depressant; for at least 24h after a single dose of intrathecal/epidural morphine | Respiratory depression; have naloxone orders standing |
| Renal function | Baseline and periodically on morphine, hydromorphone, or codeine | Active metabolite accumulation, especially at CrCl ≤30-60 |
| QTc | Before and during methadone therapy | Do not initiate if >500 ms; reassess with dose changes |
| Bowel function | Every visit on any chronic opioid | Constipation, since it doesn't improve with tolerance the way sedation does |
| PDMP / urine drug screen | Before starting and at least annually during chronic therapy | Concurrent controlled substances, especially benzodiazepines, that raise overdose risk; framed as informing care, not punitive |
| CBC, LFTs, sodium | Periodically on carbamazepine | Blood dyscrasias, hepatic enzyme elevation, hyponatremia |
| Quality of life / mood | Regularly on any chronic pain regimen | Depression and anxiety amplify pain, and pain worsens them, this is bidirectional |