NSAIDs (inflammation)

NSAIDs have historically been classified according to their chemical composition, but as mechanism of action has come to the fore, this is also used to classify these drugs.

NSAIDs within classes have similar characteristics and tolerability, with little difference in clinical efficacy at equivalent doses. The prescribers’ choice will be determined by other factors such as dosing regimens, route of administration and tolerability. For example, ibuprofen and diclofenac have half-lives of just 2–3 hours, whereas the oxicams have half-lives 10 times longer.

The majority of NSAIDs are non-selective, inhibiting both cyclooxygenase-1 (COX-1) and COX-2. ‘Coxibs’ which are COX-2 selective NSAIDs were developed to limit the gastrointestinal side-effects attributed to COX-1 inhibition. Unfortunately, these have been plagued by reports of increased risk of myocardial infarction and stroke, which led to some being withdrawn from the market. However, current advice notes that non-selective NSAIDs and coxibs are viable and effective options to treat chronic pain and have manageable cardiovascular safety profiles. Prescribers are advised to be cautious when treating patients at high risk of both cardiovascular and gastrointestinal toxicity, taking in to consideration the risk of thrombotic cardiovascular events and gastrointestinal complications as well as renovascular effects and congestive cardiac failure. Aspirin is not affected by the warnings of increased cardiovascular adverse effects attributed to the other NSAIDs.

A consensus document containing prescribing guidance developed by a multidisciplinary group of experts has been published in BioMed Central (BMC) Medicine (PMID: 25857826). The published guidelines are:

• Prescribe the lowest effective dose for the shortest period of time
• Chronic pain: consider as required dosing only and review regularly
• Advise patient regarding potential toxicities
• Arrange appropriate monitoring: renal function, BP, liver function
• Patients on aspirin: avoid traditional NSAIDs and coxibs where possible
• Renal insufficiency: avoid where possible and in those with GFR <30 ml/min
• Hepatic insufficiency: avoid where possible and diclofenac in particular
• Anti-coagulation: avoid traditional NSAIDs in patients on warfarin or heparin

In the UK, NICE advises co-prescription of a proton pump inhibitor (PPI) with traditional NSAIDs and coxibs.

Many NSAIDs are available OTC, with aspirin, ibuprofen and naproxen being amongst the most commonly prescribed/used.

Salicylates

• Aspirin is used to manage mild to moderate pain and pyrexia, in addition to widespread use for its anticoagulant effects in ischaemic stroke and for secondary prevention in cardiovascular disease.
• Diflunisal (approved in the US but not in the EU or UK) is used to treat mild to moderate pain, osteoarthritis, or rheumatoid arthritis.

Acetic acid derivatives (generic names ending in –ac)

• Aceclofenac (PubChem  CID 71771) is administered orally for pain and inflammation in rheumatoid arthritis, osteoarthritis and ankylosing spondylitis.
• Bromfenac is applied topically to the eye to control postoperative inflammation following cataract surgery.
• Diclofenac is the most potent NSAID over a broad range of measures. It can be administered as the potassium salt for pain and inflammation of rheumatic disease and other musculoskeletal disorders, acute gout, postoperative pain, migraine. The sodium salt is additionally used to manage juvenile idiopathic arthritis, and can be applied topically for actinic keratosis and in a gel for relief of pain in musculoskeletal conditions and as adjunctive treatment in knee or hand osteoarthritis. Diclofenac sodium is also used for deep intramuscular injections used to manage postoperative pain, ureteric colic or by intravenous infusion for acute postoperative pain and prevention of postoperative pain in hospital settings. Diclofenac diethylamine is contained in some topically applied formulations.
• Etodolac for pain and inflammation in rheumatoid arthritis and osteoarthritis.
• Felbinac (the active metabolite of fenbufen) is used to manage pain and inflammation in musculoskeletal conditions including osteoarthritis of the hand or knee.
• Indomethacin is prescribed to treat pain and inflammation associated with rheumatic disease, other musculoskeletal disorders, acute gout and dysmenorrhoea.
• Ketorolac trometamol is delivered orally as short-term management of moderate to severe acute postoperative pain, and topically to the eye for prophylaxis and reduction of inflammation and related symptoms following ocular surgery.
• Nepafenac is prescribed for prevention and treatment of ocular inflammation following cataract surgery.
• Sulindac is administered orally to manage pain and inflammation in rheumatic disease, other musculoskeletal disorders and acute gout.

‘Profen’ class (arylpropionic acid or propionic acid derivatives)

• Dexibuprofen is administered orally to manage pain and inflammation e.g. for osteoarthritis, other musculoskeletal disorders, dental pain and pain and inflammation in dysmenorrhoea.
• Dexketoprofen is administered orally for short-term treatment of mild to moderate pain including dysmenorrhoea.
• Fenoprofen is administered orally for mild to moderate pain and pain and inflammation in rheumatic disease and other musculoskeletal conditions.           
• Flurbiprofen is administered orally to manage pain and inflammation in rheumatic disease and other musculoskeletal disorders, migraine, postoperative analgesia, mild to moderate pain including that of dysmenorrhoea. Flurbiprofen lozenges can be used to provide sore throat relief.
• Ibuprofen is administered orally to manage pain and inflammation of various aetiologies, including pain and moderate/severe rheumatic/musculoskeletal inflammation.
• Ketoprofen is administered orally to provide relief of pain in musculoskeletal disorders, rheumatic inflammation, dysmenorrhoea, acute gout etc.
• Naproxen is administered orally to manage pain and inflammation in rheumatic disease, other musculoskeletal disorders, dysmenorrhoea and gout.
• Tiaprofenic acid is prescribed to manage pain and inflammation in rheumatic disease and other musculoskeletal disorders. It may cause severe cystitis, so is contra-indicated in patients with urinary-tract disorders. Advise patients to cease medication if urinary-tract symptoms develop.

Coxibs (COX-2 selective)

• Celecoxib is administered orally to manage pain and inflammation associated with osteoarthritis, and rheumatoid arthritis (RA), and for ankylosing spondylitis.
• Etoricoxib is used to manage pain and inflammation in rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and acute gout
• Parecoxib is a water soluble prodrug of valdecoxib. It is used for short-term management of acute postoperative pain.

Note: Parecoxib and etoricoxib are both licenced in the EU but have been withdrawn from the US market.

Enolic acid (oxicam) derivatives

• Meloxicam is prescribed to relieve pain and inflammation in rheumatic disease, osteoarthritis and ankylosing spondylitis. It can be prescribed for juvenile idiopathic arthritis and other musculoskeletal disorders in children (aged 12-17) who are intolerant to other NSAIDs.
• Piroxicam is administered orally to manage pain and inflammation in rheumatoid arthritis, osteoarthritis and ankylosing spondylitis. For these indications prescribing is usually initiated by a specialist clinician. It can also be applied topically to the skin to provide pain relief in musculoskeletal conditions and adjunctively for inflammation relief in knee or hand osteoarthritis.
• Tenoxicam is prescribed to manage pain and inflammation in rheumatic disease and acute musculoskeletal disorders.

Anthranilic acid derivatives (fenamates)             

• Mefenamic acid is prescribed for relief of pain and inflammation of rheumatoid and osteoarthritis, postoperative pain, dysmenorrhoea, etc.
• Tolfenamic acid is prescribed to manage acute migraine.

Others

• Nabumetone is the only 1-naphthaleneacetic acid derivative NSAID. It is sometimes included in the acetic acid derivative class. It is prescribed to treat severe and persistent pain and inflammation in osteoarthritis and rheumatoid arthritis.
• Acemetacin is a glycolic acid ester of indomethacin, administered orally for pain and inflammation in rheumatoid arthritis and other musculoskeletal disorders, and postoperative analgesia.
• Benzydamine hydrochloride is administered orally (as mouthwash or oromucosal spray) to treat painful conditions of the oropharynx.