NSAIDs: uses, effects, risks and benefits

NSAIDs are among the most commonly used and prescribed painkillers but their popularity is perhaps surprising given the long-held — and continuing — concerns about their safety profile

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used and effective painkillers. They do exactly what their name implies; they are not steroids and they have anti-inflammatory effects. They are also non-narcotic. Some are also effective anti-pyretic agents and one of this class, aspirin, has additional and useful antithrombotic effects.

The NSAID group of drugs is extensive and many are available without prescription, over-the-counter (OTC). Worldwide it is estimated that around 30 million people benefit from their analgesic and anti-inflammatory effects and their use increases with age. In the UK approximately 10-20% of people 65 years and over have a current or recent prescription for an NSAID, with the highest use among those over 75 years.¹

NSAIDS have a long history. Salicin, derived from willow bark, was first used in 1874 to treat inflammation in rheumatic fever. A more effective and better tolerated synthetic version, aspirin, was developed by Felix Hoffman of the Bayer company in 1897. Paracetamol was synthesised in the United States at about the same time, but was discarded in favour of phenacetin, which was thought to be safer. This assumption was not challenged or disproved for a further half century and paracetamol was not finally launched until 1953. The first of the traditional NSAIDs (tNSAIDs), indomethacin, was introduced in 1963 and, in the 1990s, the more selective cyclo-oxygenase-2 (COX-2) inhibitors became available. This article will concentrate on the tNSAIDs and COX-2 inhibitors, examining how they work, the side effects they produce, and their risks and benefits.

PAIN AND INFLAMMATION

To understand how NSAIDS work, and why they produce the side effects they do, it is helpful to have a basic knowledge of the complex cellular mechanisms behind pain and inflammation.

Tissue damage sets in motion a sequence of events that results in the production of the signalling molecules, called eicosanoids. These are derived from phospholipids in cell membranes. (Figure 1) Eicosanoids exert control, in varied and extremely complex ways, over many body functions, particularly inflammation and immunity, and act as chemical messengers in the central nervous system. They fall into four main families:

• Prostaglandins
• Prostacyclins
• Thromboxanes
• Leukotrienes.

The eicosanoids are key in initiating and perpetuating the 'Four Pillars of Inflammation' recognised since classical times; namely:

1. Heat (calor)

2. Pain (dolor)

3. Swelling (tumor)

4. Redness (rubor).

Thromboxanes mediate the release of the vasodilators prostaglandin E2 (PGE2) and leukotriene B4 (LTB4), contributing to redness. LTB4 also promotes blood vessel permeability, increasing swelling. PGE2, as well as being a vasodilator, adds to pain by sensitising pain neurons and amplifying pain signals passing to the brain. PGE2 is also a potent pyretic agent, resulting in heat. (Figure 2)

NSAIDs block the cyclo-oxygenase pathway thereby reducing the production of these important eicosanoids, ameliorating inflammation and reducing pain.

USES

NSAIDs are indicated for the treatment of both acute and chronic conditions where pain and inflammation are present. Pain that is a result of inflammation is much more likely to respond to NSAIDs than pain unrelated to inflammation, such as neuropathic pain.

NSAIDs are used in a variety of rheumatoid conditions, e.g. rheumatoid arthritis and ankylosing spondylitis, where inflammatory processes are prominent. Inflammation also plays a role in osteoarthritis (OA), at least intermittently, and OA can also respond to NSAIDs. There is, however, convincing evidence that NSAIDs are ineffective in fibromyalgia,² and their effectiveness in chronic spinal pain is unclear. Short tem studies from the 1980s appeared to demonstrate effectiveness,3—5 but a more recent systematic review questions these findings.⁶

Inflammation occurs as a result of injury to any body tissue, making NSAIDs a logical choice for acute pain management following injury, e.g. sprains and strains, and for the management of mild to moderate postoperative pain. Unlike chronic spinal pain, acute back pain will generally respond well to short term NSAID use.⁷

NSAIDs are also useful for the relief of dysmenorrhoea, headache and migraine, and for metastatic bone pain.

EFFECTIVENESS

Studies involving large numbers of patients have not demonstrated that any single NSAID is more effective than any other, or than other analgesics such as paracetamol, narcotics or muscle relaxants.⁸ Wide variability in individual therapeutic response, as well as susceptibility to side effects, is well recognised, but poorly understood.

ADVERSE EFFECTS

Since NSAIDs are so widely used, their adverse effects are also prevalent. The main side effects related to NSAIDs involve the gastrointestinal (GI), renal and cardiovascular systems.

Gastrointestinal

The tNSAIDs inhibit both cyclo-oxygenase-1 (COX-1) and COX-2. COX-1 is protective of gastric mucosa. The discovery that the GI side-effects of NSAIDs were largely due to inhibition of COX-1 led to the development of the selective COX-2 inhibitors. However, the hope that COX-2 inhibitors would resolve the problem of NSAID-associated GI adverse effects has not been realised. Although COX-2 inhibitors appear to carry less risk than the tNSAIDs they cannot be considered to be 'risk-free' and upper GI symptoms remain a common problem — with both tNSAIDS and COX-2 inhibitors.⁹ Indeed, 16.1% of patients using tNSAIDs and 14.4% of those using a COX-2 inhibitor experience dyspepsia.¹⁰

Dyspepsia may signal the presence of peptic ulcer, with subsequent risk of GI bleeding, ulcer perforation and death. However, it has been estimated that as many as 50—60% of patients who develop peptic ulcers or life-threatening ulcer complications will have had no warning signs or symptoms.¹¹

Factors that place individuals at high risk of serious NSAID-induced GI adverse events are summarised in Box 1.12 An alternative to NSAIDs should be considered for these patients, e.g. paracetamol with or without codeine. If an NSAID is deemed necessary, a proton pump inhibitor should be co-prescribed to protect the gastric mucosa.^12,13

Some NSAIDs are associated with a higher risk of GI adverse events than others. Of the tNSAIDs, ibuprofen carries the lowest risk — although serious and fatal events have been reported — while diclofenac, naproxen, ketoprofen, piroxicam and indometacin carry intermediate risk.

Renal

One of the many actions of prostaglandins is mediation of renal blood flow, causing vasodilation of the afferent arterioles to the glomeruli, thus helping maintain normal glomerular perfusion and filtration rate. In renal failure, the level of angiotensin II rises in an effort to maintain normal perfusion pressure in the glomerulus. Angiotensin II normally constricts the efferent arteriole to the glomerulus, but at elevated levels it also constricts the afferent arteriole. NSAIDs, by blocking prostaglandin-mediated vasodilation of afferent arterioles, can reduce renal perfusion pressure, particularly in patients with compromised renal function, and lead to renal failure. This is also a particular risk for patients taking ACE inhibitors and other potentially nephrotoxic drugs.

Common adverse events associated with NSAID-induced altered renal function include salt and fluid retention, and hypertension. Rarely, they may also cause:

• Interstitial nephritis
• Nephrotic syndrome
• Acute renal failure
• Acute tubular necrosis.

Individuals with known renal impairment should, ideally, avoid NSAIDs. If NSAIDs are used their renal function will require careful monitoring.¹²

Cardiovascular

COX-1 mediates the production of thromboxane A2 (TXA2) via prostaglandin H2. TXA2 is a vasoconstrictor. It also activates new platelets and stimulates platelet aggregation. These effects are normally counterbalanced by prostacyclins mediated by COX-2 enzymes. Suppression of prostacylin production with COX-2 inhibitors leaves the pro-thrombotic actions of TXA2 unopposed, thus increasing the risk of thrombotic and atherosclerotic events.

Increased risk of myocardial infarction and stroke was observed in clinical trials of COX-2 inhibitors and led to the withdrawal or non-registration of some COX-2 inhibitors. A meta-analysis of trials of COX-2 inhibitors suggested that they may be associated with about three additional thrombotic events per 1,000 patients per year in the general population.¹⁴ However, cardiovascular risk is not confined to COX-2 inhibitors. A recent meta-analysis suggests that the cardiovascular risk associated with high dose diclofenac, and possibly ibuprofen, is comparable to that of the COX-2 inhibitors. High dose naproxen, however, is associated with lower risk than other tNSAIDs.¹⁵

NSAIDs pose particular risk to individuals with comorbidities that increase their cardiovascular risk, such as diabetes and rheumatoid arthritis. The NICE Clinical Knowledge Summaries advice for this area of prescribing is summarised in Box 2.12

NSAIDs and asthma

Aspirin-exacerbated asthma has long been recognised and affects about 10% of patients. People with asthma who are sensitive to aspirin are also at risk from any NSAID that inhibits COX-1 and are best advised to avoid both aspirin and the tNSAIDs. There is, however, some evidence that COX-2 inhibitors are a safer alternative.¹⁶

SUMMARY

As NSAIDs have become ever more widely used their potential to cause significant adverse effects has become more apparent, particularly in elderly patients and in those with serious comorbidities. Prescribers need to be vigilant about assessing an individual's risk of adverse events and they need to give patients accurate information about both the risks of NSAID use and the benefits they are likely to gain.

The golden rule, when NSAIDs need to be used, is to ensure that the lowest effective dose is used for the shortest possible time.^12,13 Used with caution, and with an understanding of their actions and potential risks, the NSAIDS are a useful and effective therapy for combating pain and inflammation.

REFERENCES

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9. Hawkey C, Skelly M. Gastrointestinal safety of selective COX-2 inhibitors. Curr Pharm Des 2002; 8: 1077-89

10. Silverstein F, Faich C, Goldstein J et al. Gastrointestinal toxicity with celcoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis.

11. Singh G. Recent considerations in nonsteroidal anti-inflammatory drug gastropathy. Am J Med 1998; 105 Suppl 1B: 31s-8s

12. NICE Clinical Knowledge Summaries. NSAIDs prescribing issues. 2013 http://cks.nice.org.uk/NSAIDs-prescribing-issues#!scenarioclarification

13. National Collaborating Centre for Chronic Conditions (2008). Osteoarthritis: The care and management of osteoarthritis in adults. Royal College of Physicians. Available at http://guidance.nice.org.uk/CG59/Guidance/pdf/English

14. Kearney M, Baigent C, Godwin J et al. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ 2006; 332:1302
www.bmj.com/content/332/7553/1302.full

15. Coxib and traditional NSAID Trialists' (CNT) Collaboration. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. The Lancet

Published online May 30, 2013 http://dx.doi.org/10.1016/S0140-6736(13)%3Csup%3E60900-9http://dx.doi.org/10.1016/S0140-6736(13)60900-9

16. West PM, Fernandez C. Safety of COX-2 inhibitors in asthma patients with aspirin hypersensitivity. Ann Pharmacother 2003; 37(10): 1497-501