Nonopioid Analgesics

Nonopioid analgesics relieve pain without acting mainly on opioid receptors. The group covers paracetamol, nonsteroidal anti-inflammatory drugs (nonselective and COX-2 selective) and, in some regions, metamizole, with topical agents. They are first-line for mild to moderate nociceptive pain and the opioid-sparing base of multimodal analgesia in severe pain.

Classification. Paracetamol (central analgesic and antipyretic, negligible anti-inflammatory action); nonselective NSAIDs; selective COX-2 inhibitors; metamizole (a pyrazolone, withdrawn or unlicensed in several countries); topical NSAIDs, lidocaine and capsaicin. Gabapentinoids and tricyclic antidepressants used for neuropathic pain are separate classes.

Mechanism. NSAIDs inhibit cyclo-oxygenase, lowering prostaglandin and thromboxane synthesis, which reduces nociceptor sensitisation, inflammation and fever. Paracetamol acts mainly within the central nervous system through weak COX inhibition and enhancement of descending serotonergic and cannabinoid signalling; the exact mechanism is incompletely defined.

Pharmacokinetics. Oral onset is 30 to 60 minutes; intravenous paracetamol peaks within 15 minutes. Most NSAIDs are over 95% protein bound, metabolised in the liver and cleared as metabolites by the kidney. Half-life ranges from 2 hours (ibuprofen) to 12 to 17 hours (naproxen) and about 50 hours (piroxicam).

Dose ceiling. NSAIDs have an analgesic ceiling: doses over the labelled maximum add toxicity without more analgesia. Anti-inflammatory effect needs higher doses than analgesia alone (ibuprofen 1.2 to 2.4 g daily).

Topical agents. Topical diclofenac or ibuprofen gel gives low systemic exposure and suits localised knee or hand osteoarthritis. Lidocaine 5% plaster (up to 3 plasters, worn up to 12 hours in 24) suits localised neuropathic pain such as post-herpetic neuralgia.

• First-line. Paracetamol for mild pain and fever. Add an NSAID for moderate pain with an inflammatory or musculoskeletal component, dysmenorrhoea, renal colic, dental pain, acute gout and postoperative pain.
• Alternative. A COX-2 inhibitor where gastric risk is high but cardiovascular and renal risk are low, or where platelet function must be preserved around surgery. Naproxen when cardiovascular risk is the main concern. Topical NSAID for localised osteoarthritis.
• Specialist. Short parenteral ketorolac; metamizole where licensed when other agents fail or are not tolerated.
• Emergency. Intravenous paracetamol 1 g (adults over 50 kg) and parenteral ketorolac or diclofenac 75 mg intramuscularly for renal colic or severe pain when the oral route is unavailable.

Selection rules.

• Use the lowest effective dose for the shortest time; schedule doses regularly for the first 24 to 72 hours after surgery or injury rather than as needed.
• Combine paracetamol with an NSAID for additive effect; never combine two NSAIDs.
• Add a proton pump inhibitor (omeprazole 20 mg daily) when an NSAID is used in patients over 65 years or those with prior ulcer, or taking a corticosteroid, anticoagulant, antiplatelet or SSRI.
• Paracetamol is the safer first choice in renal impairment, heart failure, peptic ulcer disease, anticoagulation and pregnancy.

Paracetamol weight-based dosing. Adults 50 kg or under: 15 mg/kg every 6 hours, maximum 60 mg/kg in 24 hours. Children: 15 mg/kg orally every 4 to 6 hours, maximum 4 doses and 60 mg/kg in 24 hours.

Contraindications.

• NSAIDs: active or recent gastrointestinal bleeding or ulceration; severe heart failure; hypersensitivity to aspirin or any NSAID (asthma, urticaria or angioedema after exposure); eGFR under 30 mL/min; third trimester of pregnancy; the perioperative period of coronary artery bypass surgery.
• Diclofenac and COX-2 inhibitors: also ischaemic heart disease, cerebrovascular disease and peripheral arterial disease.
• Ketorolac: also bleeding diathesis, suspected cerebral haemorrhage, labour and concurrent NSAID or probenecid use.
• Metamizole: previous agranulocytosis, bone marrow disorder, acute intermittent porphyria, G6PD deficiency.

Serious adverse effects.

• NSAIDs: gastrointestinal bleeding and perforation (highest with ketorolac and piroxicam); acute kidney injury; hyperkalaemia; sodium and water retention; hypertension; heart failure; myocardial infarction and stroke (boxed-warning-level risk); bronchospasm in aspirin-exacerbated respiratory disease; severe skin reactions.
• Paracetamol: hepatic necrosis in overdose; rarely severe skin reactions and thrombocytopenia.
• Metamizole: agranulocytosis at any time, presenting with fever and sore throat.

Major interactions.

• Warfarin, direct oral anticoagulants, antiplatelets, SSRIs and corticosteroids with NSAIDs: bleeding.
• ACE inhibitors or ARBs plus diuretics plus NSAID: acute kidney injury and hyperkalaemia.
• Lithium, methotrexate (higher doses), ciclosporin and tacrolimus: reduced clearance or added nephrotoxicity.
• Ibuprofen blunts the antiplatelet effect of low-dose aspirin unless taken at least 30 minutes after immediate-release aspirin or more than 8 hours before it.
• Paracetamol: regular use raises INR on warfarin; enzyme inducers and chronic alcohol excess increase toxic metabolite formation; flucloxacillin raises the risk of high anion gap metabolic acidosis.

Common prescribing errors.

• Duplicate paracetamol from combination products.
• Intravenous paracetamol prescribed in mL rather than mg (tenfold error; the solution is 10 mg/mL).
• Fixed 1 g doses in patients under 50 kg.
• NSAIDs continued during dehydration, sepsis, vomiting or diarrhoea.
• Missing gastroprotection; ketorolac continued past 5 days.

Special groups.

• Pregnancy: paracetamol at the lowest effective dose is preferred. Avoid NSAIDs from 20 weeks (foetal renal impairment, oligohydramnios, ductus arteriosus constriction); contraindicated in the third trimester.
• Breastfeeding: paracetamol and ibuprofen are compatible.
• Children: ibuprofen 5 to 10 mg/kg every 6 to 8 hours, maximum 30 mg/kg daily; avoid under 3 months of age.
• Older adults: avoid prolonged NSAIDs; lower ketorolac dose; use gastroprotection.
• Kidney: avoid NSAIDs at eGFR under 30 mL/min; extend paracetamol interval to at least 6 hours.
• Liver: paracetamol 2 to 3 g daily at most in chronic liver disease, alcohol excess or malnutrition; avoid NSAIDs in cirrhosis with ascites.
• East Africa: avoid NSAIDs in suspected dengue and in children who are dehydrated; test for malaria before attributing fever to another cause and avoid masking it with antipyretics alone.

Monitoring. Blood pressure and oedema; creatinine and potassium after 1 to 2 weeks in those at renal risk, then every 3 to 6 months with prolonged use; haemoglobin if dyspepsia or melaena; liver enzymes with prolonged high-dose paracetamol or diclofenac; full blood count if metamizole is used.

Referral and escalation. Haematemesis or melaena; creatinine rise of 26 micromol/L or more, or 1.5 times baseline; bronchospasm or angioedema; paracetamol ingestion of 150 mg/kg or 12 g or more, or any uncertain or staggered overdose; unexplained jaundice; fever with sore throat on metamizole.

Comparison with alternative classes. Nonopioids cause no respiratory depression, dependence or sedation, but carry organ-specific toxicity and a ceiling effect. Opioids are added when severe pain persists despite maximum scheduled nonopioid therapy; nonopioids still lower opioid requirement and are continued alongside.