Pharmacology Notes

The primary effect of NSAIDs in rheumatology is symptom relief. Despite their widespread use in rheumatoid arthritis and osteoarthritis, they have not been shown to modify the disease process in these conditions. They may improve radiological outcomes when used continuously in ankylosing spondylitis.

Due to their toxicity, NSAIDs should always be used in the lowest possible dose, and for the shortest possible time. NSAID use should not delay the appropriate commencement of disease-modifying antirheumatic drugs where indicated. Topical drugs should be used where appropriate. Other issues to consider when prescribing NSAIDs are shown in Choice of NSAID.

An anti-inflammatory dose of fish oil (see Fish oil (omega-3 long chain polyunsaturated fatty acids)) should be considered as part of long-term treatment, to minimise NSAID use. Onset of this effect requires weeks to a few months.

Some NSAIDs have a role in the treatment of rheumatological conditions in children, and appear to be safe at recommended doses. The usual NSAID adverse effect profile applies to children, and renal impairment can occur in children who are dehydrated. For more information on the use of NSAIDs in children, refer to Pauciarticular-onset arthritis in the 'Children and adolescents' chapter of the Rheumatology guidelines.

NSAIDs are indicated for mild to moderate pain and are particularly effective for bone pain, which makes them very useful for many dental conditions. Evidence exists to indicate that an NSAID should be the drug of first choice for acute dental pain. There are many different NSAIDs available. They have similar efficacy; hence, the choice of which drug to use is largely based on safety, availability, cost, and the route of administration required. The most commonly used NSAIDs for dental, oral and facial pain are ibuprofen and aspirin. Severe pain usually requires the additional use of another analgesic, such as paracetamol.

The dose of NSAID used affects its performance, particularly its anti-inflammatory action. Lower doses can provide pain relief, but higher doses are required for effective anti-inflammatory action (eg a single dose of 200 mg ibuprofen may relieve pain temporarily, but at least 400 mg is required to reduce the inflammatory response; it is even more effective with 600 mg or 800 mg). The time interval of the drug doses is important to maintain blood levels at a level that reduces the inflammatory response. These drugs should be used as a ‘course of treatment’ with regular doses at the correct time intervals rather than just when the patient feels pain or discomfort. It is important to educate the patient about how to use these drugs properly.

Ibuprofen produces greater analgesia than paracetamol+codeine combinations, and produces a dose-related analgesia over the range of 200 mg to 800 mg (ie increasing the dose from 400 mg to 600 mg will provide better pain relief, as will increasing it from 600 mg to 800 mg). However, adverse effects are also dose-related, and therefore the analgesic needs of the patient must be balanced with the risk of producing adverse effects. If ibuprofen is required following dental treatment, a dose range of 200 to 600 mg every 4 to 6 hours up to a daily maximum of 2400 mg can be used for a short time (up to 24 hours). A higher dose (600 to 800 mg) can be used as a loading dose for severe pain. The dose range of ibuprofen for children is 5 to 10 mg/kg every 6 to 8 hours (to a maximum daily dose of 2400 mg).

Aspirin has a dose range in adults of 300 to 900 mg, every 4 to 6 hours up to a daily maximum of 3600 mg. Aspirin should be avoided in children because it has been implicated as a cause of Reye’s syndrome (a disorder of hepatic and central nervous system function).

All NSAIDs have potential adverse effects; these should be discussed with the patient. In patients who require NSAIDs, particularly where risk factors are present, strategies may be needed to reduce the risk of gastrointestinal toxicity. 

NSAIDs are available both as over-the-counter medications and on prescription; they are packaged in different dosages for different markets. It is important that the prescriber prescribes the correct dosage and explains the potential problems to the patient. Some commercial formulations combine NSAIDs with other drugs; hence a careful history needs to be taken to determine a total daily dose of each component.

Topical and transdermal formulations are widely used, and are useful in the treatment of local musculoskeletal disorders. Some NSAIDs that are used systemically are available for topical use (see Table 1.2). They are gels that are usually used for muscular aches and pains. They are a safer alternative to oral NSAIDs, are usually absorbed only in small amounts, and may be somewhat less effective. However, they can still cause gastrointestinal haemorrhage. Methyl salicylate and benzydamine, NSAIDs that are not used systemically, are available as topical formulations.

No single NSAID has been shown to be generally more effective than any other, but some patients seem to respond better to one than to others. Generally, NSAIDs should be used for the shortest possible time. In chronic pain management, however, it is important to give individual NSAIDs an adequate therapeutic trial of 2 to 4 weeks, as its maximum effect may be delayed.

In general, the less gastrotoxic, shorter-acting drugs should be chosen for preference, and used at the lowest dose consistent with symptom control, and for the shortest possible time. Using a short-acting drug is especially important in the elderly, and in patients with impaired renal function. Issues to consider when prescribing NSAIDs are shown in Box 1.1 below.

Information regarding toxicity associated with NSAIDs is evolving, and remains somewhat unclear. None of the NSAIDs are risk-free, and this should be discussed with the patient. Generally, the toxicity profile for selective COX-2 inhibitors is similar to that of preferentially selective and nonselective NSAIDs. The main exception is gastrointestinal toxicity (see below); however, all NSAIDs can cause serious ulcers. The elderly are more at risk of NSAID-related adverse effects and the need for NSAID therapy should be assessed carefully.

In the stomach, prostaglandins generated by both COX-1 and COX-2 may play a role in protection against, and healing of, ulcers. Prostaglandin E2 and prostacyclin are particularly important in this regard. NSAIDs increase the incidence of gastric erosions and the risk of upper gastrointestinal complications (bleeds, perforation). The relative risk of a serious gastrointestinal adverse event varies between NSAIDs and is also dose-related. Highly selective COX-2 inhibitors reduce, but do not eliminate, gastrointestinal toxicity. There is less convincing evidence of benefit in terms of reduced serious upper gastrointestinal complications with the preferentially selective COX-2 inhibitors (eg celecoxib, meloxicam) over nonselective NSAIDs (eg ibuprofen). The concomitant use of low-dose aspirin eliminates the upper gastrointestinal safety advantage of selective COX-2 inhibitors.

NSAIDs with shorter plasma half-lives (eg ibuprofen) appear to be less gastrotoxic than those with long half-lives (eg piroxicam) (see Table 1.2).

Patient risk factors for increased gastrointestinal toxicity include age over 65 years, history of peptic ulcer, concomitant use of corticosteroids, antiplatelet drugs or anticoagulants, cigarette smoking, alcoholism and prolonged use of high-dose NSAIDs. Helicobacter pylori infection combined with NSAID use increases the risk of ulcer disease 60-fold. If treatment with an NSAID cannot be avoided, proton pump inhibitors may be necessary. Although misoprostol has been shown to reduce the risk of gastrointestinal complications in this setting, it causes diarrhoea, abdominal pain, and loose stools in 10% to 15% of patients at therapeutic doses, and so has limited clinical usefulness.

The selective COX-2 inhibitor rofecoxib was withdrawn worldwide in September 2004 because of an increase in myocardial infarction and stroke during its use. There is evidence that cardiovascular risk is a more general property of NSAIDs other than aspirin. It is therefore recommended to use the lowest possible dose of any NSAID for the shortest possible duration. Fish oil can be used as an NSAID-sparing drug, and has the added benefit of reducing cardiovascular risk 

Other cardiovascular risks should be closely monitored and managed actively in patients taking NSAIDs. in the Cardiovascular guidelines for further information.

Low-dose aspirin may reduce the increased cardiovascular risk associated with NSAIDs, but will increase gastrointestinal adverse effects. However, patients requiring low-dose aspirin for cardiovascular protection should continue to take it regardless of their need for NSAIDs.

Some NSAIDs, such as ibuprofen, can interfere with the effect of low-dose aspirin on platelets, and separation in time of dose is suggested. Diclofenac does not have this effect.

All NSAIDs can cause renal impairment. Maintenance of renal function is dependent on prostaglandins generated by COX-2; therefore, renal toxicity is not less with COX-2–selective inhibitors. Adverse effects on renal function are particularly problematic when NSAIDs are used perioperatively in older and sicker patients, and in patients with pre-existing renal impairment. Other risk factors include congestive heart failure, cirrhosis, a salt-reduced diet and co-administration of diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, cyclosporin or aspirin. Patients at risk should be closely monitored if treatment with NSAIDs is unavoidable.

NSAIDs can also cause oedema, hypertension and congestive heart failure. Some drugs have specific problems; for example, indomethacin can cause headache, confusion and drowsiness.

The pharmacokinetic properties and adult dosing schedules of NSAIDs are summarised in Table 1.2 below. See also Table 1.19 for recommended paediatric doses for oral NSAIDs.

Nonsteroidal anti-inflammatory drugs (NSAIDs) have their primary role in relief of nociceptive pain associated with tissue damage or inflammation. For a discussion of the physiological basis of nociceptive pain, . NSAIDs exert their main effect by inhibition of cyclo-oxygenase (COX), with consequent reduction in the synthesis of pro-inflammatory prostaglandins from arachidonic acid. This occurs at both peripheral sites in the body and in the central nervous system.

NSAIDs may differentially inhibit the COX-1 and COX-2 isoforms of COX. COX-1 plays a major role in normal functioning of the gastrointestinal tract, platelets and kidneys. Inhibition of COX-1 reduces thromboxane A2 synthesis, effectively inhibits platelet aggregation, and is associated with gastrointestinal toxicity. COX-2 is constitutively expressed in the kidney and probably contributes to the production of prostaglandins, which regulate renal blood flow. COX-2 is induced by inflammatory stimuli and cytokines. Inhibition of COX-2 reduces pain associated with inflammation, and is the basis for the use of NSAIDs in inflammatory states. Prostacyclin, a vascular patency factor, is produced in blood vessels via COX-2. All NSAIDs inhibit COX-2 and, as a class, their use has been associated with an increased risk of serious cardiovascular events. As COX-2 inhibition has no effect on production of thromboxane A2 by platelets, which occurs through COX-1, this risk may be especially problematic with COX-2–selective inhibitors.

The nonselective inhibitors of COX are NSAIDs that inhibit both COX-1 and COX-2 (eg ibuprofen). Some NSAIDs preferentially (eg celecoxib, diclofenac, meloxicam) or selectively (eg parecoxib) inhibit COX-2. They have analgesic effectiveness equivalent to that of nonselective COX inhibitors. COX specificity may depend on the concentration of the drug at the receptor sites. Since both COX-1 and COX-2 inhibition are associated with significant health risks, no NSAID should be considered ‘safe’.