Cyclooxygenase (COX) and prostaglandins. Tissue injury releases arachidonic acid, which COX enzymes convert into prostaglandins and thromboxane.

• COX-1 is always active: it protects the stomach lining, maintains kidney blood flow, and makes thromboxane A₂ in platelets (clotting).
• COX-2 is induced at sites of inflammation: it produces prostaglandins that cause pain, swelling, and fever; it also has protective roles in blood vessels and the kidney.

Why this matters for safety: loss of prostaglandins that protect the stomach and kidney explains GI ulcers and kidney injury; loss of platelet thromboxane explains bleeding; tipping the balance toward thromboxane in blood vessels explains the heart attack and stroke risk of non-aspirin NSAIDs.

Multimodal analgesia: scheduled acetaminophen plus an NSAID (when safe) lowers opioid needs and side effects after surgery and injury.

NSAIDs (including aspirin)

• GI: dyspepsia, peptic ulcer, GI bleeding and perforation — may occur without warning pain
• Kidney: reduced kidney blood flow → acute kidney injury, sodium and water retention, edema, hyperkalemia
• Cardiovascular (non-aspirin NSAIDs): myocardial infarction and stroke, higher blood pressure, worsening heart failure
• Bleeding: impaired platelet function (brief with reversible NSAIDs, 7–10 days with aspirin)
• Respiratory: bronchospasm in aspirin-exacerbated respiratory disease (asthma, nasal polyps, aspirin sensitivity)
• Hypersensitivity, rash, liver enzyme elevation, dizziness
• Pregnancy: from about 20 weeks, fetal kidney dysfunction and oligohydramnios; in the third trimester, premature closure of the ductus arteriosus

US boxed warnings (non-aspirin NSAIDs): increased risk of serious cardiovascular thrombotic events (can occur early in treatment; contraindicated for pain around coronary artery bypass graft surgery) and serious GI bleeding, ulceration, and perforation.

Aspirin-specific: tinnitus and hearing loss at high doses (an early sign of toxicity), Reye syndrome in children with viral infections (influenza, varicella).

Acetaminophen: well tolerated at recommended doses; overdose causes liver necrosis; rare serious skin reactions (SJS/TEN).

Suzetrigine: itching, muscle spasms, rash, raised creatine kinase.

NSAIDs

• Avoid or use with great caution: active GI bleeding or ulcer history, chronic kidney disease or AKI, dehydration, heart failure, recent myocardial infarction or stroke, uncontrolled hypertension, bleeding disorders or thrombocytopenia, liver cirrhosis, aspirin-exacerbated respiratory disease, perioperative CABG setting.
• Older adults: avoid chronic use unless other options fail, and then with a proton pump inhibitor (Beers Criteria); avoid indomethacin and ketorolac.
• Pregnancy: avoid NSAIDs from 20 weeks of pregnancy (FDA 2020) unless specifically prescribed; low-dose aspirin prescribed for preeclampsia prevention is an exception. Ibuprofen is compatible with breastfeeding.
• Children: ibuprofen not under 6 months; no aspirin with viral illness.
• Interactions:
  • Anticoagulants, antiplatelets, SSRIs/SNRIs, corticosteroids → GI bleeding
  • ACE inhibitors or ARBs + diuretics + NSAID ("triple whammy") → acute kidney injury; NSAIDs also blunt antihypertensive and diuretic effects
  • Lithium and methotrexate — NSAIDs raise levels (toxicity)
  • Potassium-sparing diuretics → hyperkalemia
  • Ibuprofen blocks aspirin's antiplatelet effect — take immediate-release aspirin at least 30 minutes before ibuprofen, or ibuprofen at least 8 hours before aspirin
  • Alcohol → GI bleeding
• Celecoxib: contraindicated with a history of allergic-type reactions to sulfonamides and in aspirin/NSAID-induced asthma or urticaria.
• Ketorolac (boxed warnings): contraindicated in labor and delivery, around CABG surgery, and with active bleeding or advanced kidney disease; reduced IV/IM dose (15 mg) for clients 65 years or older, under 50 kg, or with kidney impairment.

Acetaminophen

• Caution: liver disease, chronic heavy alcohol use, malnutrition, low body weight; duplicate products (cold medicines, prescription opioid combinations).
• Regular use of higher doses can raise the INR in clients taking warfarin — monitor.
• Pregnancy and breastfeeding: still the analgesic and antipyretic of choice (ACOG) — lowest effective dose for the shortest time. In September 2025 the FDA began a label change about a possible association with neurodevelopmental disorders; causality is not established, and the label had not been revised as of mid-2026.
• US boxed warnings: hepatotoxicity (prescription combination products and IV form) and IV dosing errors.

Suzetrigine: contraindicated with strong CYP3A inhibitors; avoid grapefruit; avoid in severe hepatic impairment (Child-Pugh C); with progestins other than levonorgestrel or norethindrone, use backup or alternative contraception during treatment and for 28 days after stopping.

Listed in priority order.

1. Bleeding and GI assessment — ask about black or tarry stools, coffee-ground vomitus, abdominal pain; check hemoglobin (about 12–16 g/dL (120–160 g/L) in adult women, 14–18 g/dL (140–180 g/L) in men) and platelets. Stop the NSAID and notify for signs of GI bleeding.
2. Kidney and fluid status — baseline and periodic creatinine (about 0.6–1.2 mg/dL (53–106 µmol/L)), BUN, potassium (3.5–5.0 mEq/L (3.5–5.0 mmol/L)), urine output, weight, edema. Hold and report a rising creatinine, falling urine output, or hyperkalemia; ensure hydration before ketorolac.
3. Cardiovascular — blood pressure; signs of worsening heart failure (weight gain, dyspnea, edema); chest pain or stroke symptoms.
4. Respiratory — wheeze after aspirin or NSAIDs in clients with asthma and nasal polyps.
5. Acetaminophen dose safety — total all sources over 24 hours; with IV acetaminophen, verify mg/kg dosing for clients under 50 kg and the mg versus mL volume (tenfold errors have occurred). Liver tests with long-term use or risk factors.
6. Administration — give oral NSAIDs with food, milk, or a full glass of water, and keep the client upright for about 30 minutes; a proton pump inhibitor may be prescribed for GI protection. Ketorolac: no more than 5 days (IV, IM, and oral combined).
7. Evaluate effect — pain and function 30–60 minutes after an oral dose; temperature for antipyretic effect.

• Acetaminophen: do not exceed the labeled maximum; read labels — many cold, flu, and prescription pain products contain it (it may be listed as APAP or paracetamol); limit alcohol.
• NSAIDs: take with food; use the lowest dose for the shortest time; do not combine two NSAIDs (e.g., ibuprofen plus naproxen).
• Report black stools, vomiting blood, stomach pain, reduced urine, swelling, sudden weight gain, chest pain, weakness on one side, or slurred speech.
• Stay well hydrated; avoid NSAIDs during vomiting, diarrhea, or dehydration.
• Pregnancy: avoid NSAIDs from 20 weeks unless your provider prescribes them; use acetaminophen for pain or fever.
• Aspirin: do not give to children or teenagers with flu-like illness or chickenpox; report ringing in the ears; tell surgeons and dentists — do not stop prescribed low-dose aspirin without asking the prescriber.
• Clients on blood pressure medicines, "water pills," lithium, or blood thinners should ask before using any NSAID.
• Tell every provider about aspirin or NSAID sensitivity, especially with asthma.

Acetaminophen overdose — the leading cause of acute liver failure in the US

• Risk rises with a single ingestion above about 150 mg/kg (or about 7.5–10 g in adults), and with repeated supratherapeutic doses.
• Stages: 0–24 hours nausea, vomiting, or no symptoms (deceptively well); 24–72 hours right-upper-quadrant pain and rising AST/ALT; 72–96 hours peak liver injury (jaundice, coagulopathy, hypoglycemia, encephalopathy); then recovery or liver failure.
• Plot a 4-hour (or later) level on the Rumack-Matthew nomogram; the treatment line starts at 150 mcg/mL (about 990 µmol/L) at 4 hours.
• Antidote: acetylcysteine (N-acetylcysteine) — replenishes glutathione; most effective within 8 hours, but still given later. IV regimens (e.g., 21-hour three-bag or two-bag protocols) or oral 72-hour regimen. IV: watch for anaphylactoid reactions (flushing, rash, wheeze) — pause and treat, then usually resume. Oral: foul odor causes vomiting — give chilled with juice and an antiemetic.
• Activated charcoal if within about 1–2 hours of ingestion and the airway is protected.

Salicylate (aspirin) poisoning

• Tinnitus, nausea, vomiting, hyperventilation, fever, diaphoresis, confusion, seizures.
• Acid-base pattern: early respiratory alkalosis, then mixed respiratory alkalosis and high anion gap metabolic acidosis.
• Levels above about 30 mg/dL (2.2 mmol/L) are toxic; clinical status matters more than a single value — repeat levels because absorption can be delayed.
• Treatment: activated charcoal, IV sodium bicarbonate (alkalinizes urine to increase excretion; keep potassium normal), glucose, and hemodialysis for severe toxicity (altered mental status, kidney failure, pulmonary edema, very high levels). Avoid intubation when possible — if needed, keep the ventilation rate high, because losing hyperventilation worsens acidosis.

NSAID overdose — usually GI upset, drowsiness, and kidney injury; large ingestions cause metabolic acidosis and seizures. Supportive care; no specific antidote.

• Acetaminophen: max 4 g/day (lower with liver disease or alcohol); not anti-inflammatory; count combination products
• Acetaminophen overdose → acetylcysteine, best within 8 hours; liver injury peaks at 72–96 hours
• NSAIDs: GI bleeding, kidney injury, cardiovascular events, fluid retention, hyperkalemia
• Avoid NSAIDs from 20 weeks of pregnancy; ductus arteriosus closure in the third trimester
• Ketorolac: 5 days maximum
• Aspirin: irreversible platelet effect (7–10 days); Reye syndrome in children with viral illness
• Salicylate toxicity: tinnitus, respiratory alkalosis then metabolic acidosis → sodium bicarbonate, dialysis
• Triple whammy: ACE inhibitor/ARB + diuretic + NSAID → AKI
• NSAIDs raise lithium levels and add bleeding risk with anticoagulants and SSRIs
• Ibuprofen not under 6 months
• Celecoxib: less GI injury, same cardiovascular risk; contraindicated with sulfonamide allergy