Contents
Introduction
Non-steroidal anti-inflammatory drugs (NSAIDs) are some of the most widely used and prescribed medications. They are commonly used for analgesia, particularly in inflammatory and musculoskeletal conditions (e.g. gout).
They are usually used as an adjunct to paracetamol, and should be used on as as-required basis. Their analgesic effect is typically similar to that of a dose of paracetamol. They may be used more regularly in chronic inflammatory conditions such as rheumatoid arthritis.
NSAIDs have been known of from plant extracts (particularly the willow tree) since ancient times.
They act by inhibiting COX enzymes – which in turn reduces the production of pro-inflammatory prostaglandins.
However, they typically should be used with caution due to a wide-range of adverse effects. As such, their use should typically be for the shorter duration and lowest dose possible. Notable risks include; gastritis / reflux and GI bleeding, kidney injury (particularly if overdose or long-term use) and an increased risk of cardiovascular events in those aged >55.
- Rofecoxic (aka Vioxx) is an NSAID that was withdrawn from the market after a study which was assessing its effectiveness in bowel polyp prevention noted a doubling of the risk of cardiovascular events.
Also be very cautious of the Triple Whammy – a combination of NSAID, ACE-inhibitor (or ARB) and thiazide diuretic that a high risk of inducing acute kidney injury.
Recent evidence has also shown that the use of NSAIDs after fracture increases the risk of nonunion or malunion. This effect is time and dose dependent – and as such many specialist now recommend avoiding the use of NSAIDs for the first three days after a fracture or after surgery for ORIF. It does not seem to apply to children.
As a result, the use of NSAIDs is probably less widespread than it once was, although they are still an important step in analgesia management and can be highly effective for this purpose.
In my own practice, I am cautious to recommend NSAIDs to the over 55s, despite their obvious efficacy in pain management – particularly seemingly for those with osteoarthritis. If there are limited other suitable options for patients I warn about the cardiovascular and renal risks and advise patients to use NSAIDs infrequently and at lower doses.
Taking NSAIDs with food may help to reduce GI side effects. Unless for chronic inflammatory conditions such as rheumatoid arthritis, regular use for >10 days should be discouraged. Ensuring adequate hydration may help to reduce the risk of renal impairment. Enteric coated formulations are NOT associated with a decrease in GI risk.
Topical formulations enter the systemic circulation, but highest concentrations are achieved at the site of administration.
Mechanism of action
- Inhibition of COX enzymes (Cyclooxygenase)
- This results in inhibition of synthesis of prostaglandins from arachidonic acid
- There are two main COX enzymes – COX-1 and COX-2
- COX-1 stimulates productions of certain prostaglandins that are important in preserving the integrity of the gastric mucosa, as well as ensuring adequate renal perfusion by dilating the renal arteries and inhibiting thrombus formation
- COX-2 stimulate production of prostaglandins in response to inflammatory stimuli
Generally, the desired effects of NSAIDs are due to inhibition of COX-2, and negative effects mostly attributable to inhibition of COX-1, although there is some overlap.
Selective COX-2 inhibitors were developed to try to address some of these issues, and do typically result in fewer adverse effects.
Indications
- Acute injury
- Osteoarthritis
- Rheumatoid arthritis
- Ankylosing spondylitis
- Pericarditis
- Gout
- Dysmenorrhoea
- Renal colic
- Headache
- Post-operative pain
- Fever
Adverse effects
- Gastrointestinal symptoms – mainly gastritis and reflux type symptoms, also increased risk of GI bleeding
- Renal impairment
- Increased risk of cardiovascular events
The risk of adverse events varies between NSAIDs. Non-selective agents generally have higher risk of GI effects, but lower risk of cardiovascular events. Renal adverse effects are similar between both groups.
Other important adverse effects include:
- Bronchospasm – avoid if there is a history of this, but this is not an absolute contra-indication for asthmatics
- Hypersensitivity reactions
- Angioedema
- Fluid retention – typically avoid use in heart failure for this reason
Consider PPI ‘cover’
- Concurrent use of gastro-protective PPIs should be consider for patients at high risk of GI bleed
- For example – 20mg omeprazole daily for the duration of NSAID treatment
- High risk patients might include:
- Those aged >65
- Previous peptic ulcer disease
- Known cardiovascular disease
- Known diabetes
- Concurrent steroid use
- Be wary of using COX-2 drugs in these patients due to the increased risk of cardiovascular events
Interactions
- Increased risk of GI bleed – aspirin, anticoagulants, steroids
- Increased risk of renal impairment – ACE inhibitors, ARB, thiazide diuretics
Examples
Most NSAIDs are given orally, but various routes are available. Some can be given topically (e.g. gel to rub on sore joints or muscles, or eye drops), indomethacin can be given PR, and ketorolac can be given IM or IV.
Non-selective
Generally have higher rates of gastrointestinal adverse effects, but lower risk of cardiovascular events.
- Aspirin
- Analgesic dose can be as much as 900mg QID
- Ibuprofen
- Available over the counter
- Lowest incidence of GI effects of non-selective agents
- Low risk of cardiovascular events
- Typical dose – 400mg TDS
- Diclofenac
- Available over the counter in lower doses
- Typical dose – 50mg BD / TDS
- Naproxen
- Low risk of cardiovascular events
- Typically used for dysmenorrhoea
- 250-750mg daily
- Ketorolac
- Used IV or IM – traditionally typically for lower back pain in the acute setting
- 15mg IM or IV
- Comes in 30mg vials – several studies have suggested that a 30mg dose greatly increases the risk of adverse events without much therapeutic benefit
- Indomethacin
- Often used for renal colic
- Can be given PO or PR
- Typical cose 50mg BD / TDS
- Ketoprofen
- Often used in NSAID eye drops
- Mefanamic acid
- Traditionally used for dysmenorrhoea
Selective
- Celecoxib
- Meloxicam
Typically have low risk of GI effects, but higher risk of cardiovascular events
Cautions
- Avoid in pregnancy. Are associated with increased risk of miscarriage (in first trimester), and a whole host of cardiovascular adverse events in the foetus in the third trimester
- Safe in breastfeeding
- Be careful in asthma, dehydration and coagulation disorders
- It is NOT recommended to stop low-dose aspirin in those whom take it when starting an NSAID – the NSAID anti-platelet effect is very variable and unpredictable.
- Consider use of topical agents first in those with localised conditions as this is likely to reduce adverse effects
References
- The Top 100 Drugs. 1st Ed. (2015). Hitchings, A, Lonsdale D, Burrage D, Baker, E.
- Murtagh’s General Practice. 6th Ed. (2015) John Murtagh, Jill Rosenblatt
- Oxford Handbook of General Practice. 3rd Ed. (2010) Simon, C., Everitt, H., van Drop, F.
- Beers, MH., Porter RS., Jones, TV., Kaplan JL., Berkwits, M. The Merck Manual of Diagnosis and Therapy