NSAIDs: risks and benefits.
At the same time, non-aspirin NSAIDs have a worsening reputation for cardiovascular risk. How do these drugs act to provide pain relief and reduce inflammation? And how does this relate to their other preventive or harmful effects? Do the benefits outweigh risks associated with their use?
Understanding the actions of these drugs allows nurses to identify risk of adverse reactions in their patients. It also enhances their ability to educate patients, especially those using over-the-counter aspirin or NSAIDs in combination with other medications, or who are self-medicating to try to reduce disease
Bitter-tasting extracts from willow leaves and bark have been used since ancient times to manage inflammation, pain and fever. (1) In the 19th century, the active ingredient of willow--salicin--was isolated and purified into salicylic acid. In 1897, Bayer, a German pharmaceutical company, manufactured acetylsalicylic acid (ASA) as a pure, stable and cheap formulation of the drug, and gave it the brand name Aspirin. (1) It was the first drug available in tablet form worldwide. Bayer lost the trademark to aspirin as part of reparations at the end of World War I, which is why aspirin is now a generic name for the drug. Worldwide, the equivalent of 100 billion standard aspirin tablets are manufactured each year and 30 million people take nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, every day. (2,3)
The discovery, in the 1970s, of the molecular target for aspirin--the cyclo-oxygenase enzymes--led to an explosion of similar-acting drugs. With more than 50 different types of NSAIDs on the market, these are the most commonly used drugs globally. (4) Aspirin is now less often used for its analgesic and anti-inflammatory effects. It regained popularity when, in 1980, a meta-analysis of clinical trials showed it reduced the risk of secondary heart attack by 21 per cent. By 1985, the evidence was sufficient to recommend that aspirin be used in the treatment and secondary prevention of myocardial infarction. In the 1990s, aspirin's efficacy in reducing risk of stroke was also recognised. (1)
Aspirin is seen by some (health professionals and the public) as a potential wonder drug. However, aspirin and other NSAIDs have significant adverse effects that are a natural extension of their actions in the body and can be life-threatening. Recent research has shown no overall benefit for aspirin on all-cause mortality, dementia or physical disability in adults aged over 70. (5)
Aspirin and the non-aspirin NSAIDs act by inhibiting cyclooxygenase enzymes (COX).
These enzymes are responsible for the production of prostaglandins and thromboxane from arachidonic acid (found in cell membranes) (see Figure 1, p23). Prostaglandins (PGs) are locally-acting signal molecules that alter activity in surrounding tissues. Thromboxane is found in platelets and triggers platelet activation and thus clot formation. There are two known forms of the COX enzyme, each with different roles in the body.
* COX-1 is found in most tissues and produces PGs that regulate normal function and homeostasis (see Table 1, p22). Key roles include gastro-protection, regulation of renal blood flow and control of platelet clumping. (4)
* COX-2 is triggered by inflammatory mediators released following cellular injury or stress. (4) It is responsible for the production of PGs that regulate fever, pain and inflammation. Fever occurs when endogenous pyrogens (signalling molecules) are released from immune cells during an infection. These pyrogens trigger COX-2 to synthesise PGs in the hypothalamus. In turn, this raises the "set point" for body temperature, triggering responses to increase internal body temperature. Heat generation continues until the new "set point" is reached. Fever resolves when COX-2 activity stops, either through resolution of the infection or following NSAID administration.
Pain is experienced when nociceptors (pain receptors) in the tissues are activated by chemical mediators released from damaged or stressed cells. These chemical mediators also trigger the manufacture of COX-2 enzymes.
PGs synthesized by COX-2 increase the sensitivity of nociceptors to the chemical mediators, thus increasing pain. In the central nervous system, PGs enhance transmission of pain signals and may have a role in processing incoming pain signals in the brain.
Inflammation is a complex event controlled by numerous hormones and locally released cytokines that trigger the synthesis of COX-2. PGs manufactured by COX-2 cause vasodilation (and therefore oedema) and enhance the action of other inflammatory mediators, leading to the cardinal signs of inflammation: pain, swelling, heat and redness.
COX-2 was, for a long time, thought to be only present during injury or pain. However, it is now known that COX-2 also plays a role in normal body function. In particular, COX-2 is present in arteries, where it induces vasodilation and inhibits platelet activation--countering the vasoconstricting effects of COX-1 and thromboxane-induced activation of platelets (see Table 1). COX-2 also regulates the release of renin in the kidneys, which affects blood pressure and renal handling of sodium and water. (6)
The degree to which the various classes of NSAIDs inhibit COX-1 over COX-2 depends on the specific drug. Aspirin is a nonspecific COX inhibitor, with more effect on COX-1 enzymes. Aspirin, unlike other NSAIDs, is an irreversible inhibitor of COX. This means the effects of a single dose of aspirin will continue until the COX enzymes that have been exposed are replaced through natural turnover. Because platelets do not have a nucleus, they cannot replace their COX enzymes once exposed to aspirin, so the effect of the drug lasts for the life-span of the platelet. Other non-selective NSAIDs include ibuprofen, diclofenac, naproxen and indomethacin.
Selective COX-2 inhibitors (coxibs, eg celecoxib, rofecoxib) are designed to target only COX-2 enzymes but, while they are selective, they also inhibit a proportion of COX-1 enzymes. Therefore, while their adverse effects in relation to COX-1 inhibition are reduced compared to the nonspecific NSAIDs, they still carry some risk. In addition, their selective targeting of COX-2 increases cardiovascular adverse effects due to the role COX-2 plays in vasodilation and inhibition of platelets. (7)
NSAIDS AS ANALGESICS
NSAIDs and paracetamol are the most commonly used analgesics worldwide. Their safety profiles differ, with paracetamol being largely safe unless the maximum dose is exceeded (4g per 24 hours) whereas NSAIDs can have troublesome adverse effects even at therapeutic doses. The superiority of one over the other has not been demonstrated in clinical trials for minor musculoskeletal trauma, (8) chronic lower back pain, (9) or soft tissue injury, (10) but NSAIDs do provide better analgesia in some conditions.
NSAIDs are well recognised for management of dysmenorrhoea. Their effectiveness is due to the involvement of PGs in the cramping and pain associated with menstruation. NSAIDs reduce symptoms of dysmenorrhoea by inhibiting PG production. (11)
They may be a useful adjunct to opioids for managing cancer pain, although high-quality evidence is lacking. (12,13) Moderate to severe pain was shown to reduce after one to two weeks' therapy. (14) Research also supports the use of NSAIDs for gout, renal colic and orthodontic pain.
ASPIRIN AND VASCULAR DISEASE
Low-dose aspirin reduces the risk of secondary events following myocardial infarction by 21 per cent (1) and for embolic stroke by about 13 per cent. (15) Aspirin at normal doses, commenced within 48 hours of an ischaemic stroke, reduces early recurrent stroke by 12 per cent and risk of death or permanent disability by five per cent. Long-term use of aspirin reduces risk of recurrent ischaemic stroke by about 17 per cent, while acute use of aspirin in mild stroke may reduce risk of recurrence by up to 80 per cent. (16)
This risk reduction is due to the antiplatelet effects of aspirin: inhibiting production of thromboxane decreases activation and clumping of platelets. Platelets are activated in response to injury in a blood vessel wall, such as occurs when atherosclerotic plaques--present in CVD--rupture. The resulting thrombosis (clot) or embolism then obstructs blood supply to downstream tissues in the myocardium or brain. Platelets exposed to low-dose aspirin do not synthesise thromboxane so cannot be activated, thus reducing formation or extension of clots. (17)
At the same time, but to lesser extent, aspirin inhibits COX-2-mediated production of prostacyclin (PGI2) in the endothelial cells in blood vessel walls. Prostacyclin normally induces vasodilation and inhibits platelet activation. Endothelial cells, because they contain a nucleus (unlike platelets), can replace their aspirin-inactivated COX enzymes. The outcome of longterm, low-dose aspirin therapy is that thromboxane is inhibited while prostacyclin remains active. Platelet function is inhibited, but endothelial cell function is maintained. (17)
Studies in the 1980s suggested aspirin led to a small benefit in primary prevention of CVD, but this was a time when risk management for CVD was less aggressive than now: smoking was prevalent while hypertension management and the use of statins were suboptimal. (18) Now, the benefits of aspirin in the primary prevention of CVD, vs the risks of long-term use, are finely balanced. While there is a significant reduction in cardiovascular mortality, myocardial infarction and stroke (57.1 per 10,000 participant years with aspirin, vs 61.4 without), there is also significantly increased risk of major bleeding (23.1 per 10,000 participant years with aspirin, 16.4 without). (19,20)
The most recent recommendations from the United States Preventive Task Force (USPTF) are that low-dose aspirin only be used for primary prevention of CVD in adults aged 50 to 59 with a 10-year CVD risk of [greater than or equal to] 10 per cent, with no increased risk of bleeding and a life expectancy of 10 years or more. For adults aged 60 to 69, decisions should be based on the value the person places on the potential benefits vs the potential harms of aspirin. USPTF makes no recommendations for adults younger than 50, or older than 70, due to a lack of robust evidence. (21)
In New Zealand, use of aspirin for primary prevention should be considered for adults under 70 where the five-year risk is > 15 per cent, (22) following careful consideration of risks and benefits--recognising that risk may lessen if the patient makes lifestyle improvements. (20) Primary risk factors for CVD include older age; male sex; Maori, Pacific or South Asian ethnicity; dyslipidaemia; hypertension; diabetes; and smoking. By contrast, the European and Australian guidelines do not recommend use of aspirin in primary prevention of CVD, due to the increased risk of bleeding. (23,24)
ASPIRIN AND CANCER
Low-dose aspirin, taken over a long period, reduces the development of a number of cancers. In one study, daily aspirin taken for five years reduced the incidence and mortality associated with colorectal cancer by 30-40 per cent at 20 years follow-up, with longer duration of aspirin therapy showing increased benefit. All-cause cancer mortality fell by 20 per cent. (25) The minimum duration of therapy to see an effect is three years of daily low-dose aspirin. Aspirin also potentially reduces progression of preexisting cancers. (25) COX-2 is known to play a significant role in the development of cancer and is found in elevated concentrations in some tumours. COX-2, or its products (especially PGE2), promote carcinogenesis. Aspirin, by blocking the actions of COX-2, may reduce cancer risk. Interestingly, omega-3 fatty acids can also interfere with this process by becoming a substrate for the COX-2 enzyme that results in the manufacture of substances other than PGs. (4) This may account for the reported benefits of omega-3 fatty acids in cancer prevention.
Another theory about the role of aspirin in cancer is related to its effects on platelets. Platelets are known to play a role in carcinogenesis with "crosstalk" between tumour cells and platelets that promote tumour development and growth, invasion and metastasis. (25)
While long-term, low-dose aspirin reduces the risk of developing some cancers, non-aspirin NSAIDs may increase risk. Ovarian cancer increases in women taking NSAIDs, increasing with duration of use and cumulative weekly dose, although these findings, from the Nurses' Health Study, require confirmation. (26) Previous observational studies have been inconclusive about whether NSAID use lowers or increases risk for ovarian and endometrial cancers. (27)
ASPIRIN AND DEMENTIA
Vascular dementia, thought to occur as a result of atherosclerotic changes in the blood supply to the brain, could, in theory, be reduced or prevented by the use of aspirin, in much the same way as for stroke and myocardial infarction. However, research evidence does not show any benefit for low-dose aspirin in preventing cognitive decline. (28)
Epidemiological evidence suggests aspirin helps prevent the onset of Alzheimer's disease. Although clinical trials demonstrate no benefit, and in some cases deterioration, for people who already have the disease, aspirin taken more than two years before onset of symptoms may have a protective effect. (29,30) Animal studies suggest aspirin clears amyloid plaques seen in Alzheimer's. (31)
Aspirin and venous leg ulcers
Daily aspirin (300mg) may increase healing and delay recurrence of venous leg ulcers, but the two studies suggesting this were small and of low quality. (32) A recent study comparing aspirin to placebo found no difference in the time for ulcers to heal. (33) Use of aspirin for venous leg ulcers carries the risk of bleeding and other adverse events, so the decision to include it must be made very carefully.
Adverse effects of NSAIDs relate to inhibition of COX enzymes (see Table 1) and, for aspirin, to the specific effects of salicylate drugs. Gastric side effects of NSAIDs are well recognised, but other effects are often overlooked. Each type of NSAID has a slightly different risk profile related to their potency on each of the COX enzymes and their duration of action in the body. (34)
GI adverse effects
COX-1 has gastro-protective functions: increased secretion of protective mucus lining the gut and decreased production of pepsin and hydrochloric acid. Inhibition of this protection by NSAIDs causes gastroduodenal ulcers with both short-term use, and up to 40 per cent of long-term users. (2) This damage extends to the small intestine, with up to 70 per cent of long-term users developing inflammation or erosions and ulcers. (2) The development of gastric distress and of serious or fatal gastric complications, such as perforated ulcer or gastric bleeding, is a significant barrier to NSAID therapy. (35)
Lower GI tract complications are less reported but remain significant. Forty to 70 per cent of users develop increased permeability of the intestinal lining.
This leads to inflammation and ulceration, causing malabsorption and mild, continuous protein and blood loss, leading to anaemia and hypoalbuminaemia. (35) Lesions can progress to ulceration, perforation and haemorrhage or obstruction. (35) The rate of lower GI complications is increasing and the rate of upper GI decreasing, due mainly to prophylactic use of proton pump inhibitors.
Risk for GI complications increases with: age over 65 years; use of two or more NSAIDs concurrently; use of other anticoagulant therapies; history of peptic ulcer; and severity of illness. (36) Different types of NSAIDs have varying severity of effects on the GI tract: (35)
low-dose aspirin (least severe) < ibuprofen, celecoxib < diclofenac < tenoxicam, naproxen, indomethacin < piroxicam (most severe)
While selective COX-2 inhibitors reduce the incidence of adverse GI effects, these are not entirely eliminated. This suggests mechanisms other than COX-1 inhibition may be involved in at least some aspects of GI damage. (2)
Adverse GI effects occur, whatever route the NSAID is administered by. Oral aspirin may cause local increases in drug effect on the gastric mucosa, but incidence of adverse effects is not reduced by administration through other routes or with the use of enteric coated tablets.
While the antiplatelet effect of aspirin is desirable for preventing thrombus formation in CVD, the risk associated with this is unwanted bleeding. The risk of major GI haemorrhage with the use of non-selective NSAIDs is increased fourfold (and three-fold for coxibs), while GI bleeds have a mortality rate of 21 per cent in those taking NSAIDs, compared to seven per cent in non-users. (37) There is also a very slight increased risk of intracranial haemorrhage and haemorrhagic stroke. (38)
Low-dose aspirin therapy causes easy bruising or prolonged bleeding. This can be distressing for older adults with fragile skin. It is important to monitor for this effect and educate about avoiding trauma and applying firm pressure to bleeding sites.
Contraindications for aspirin therapy (apart from allergy) include: active peptic ulcer, recent history of GI or intracranial haemorrhage, bleeding disorder or current use of anticoagulants, severe liver disease, thrombocytopaenia, renal failure and concurrent NSAID use. (39)
Cardiovascular adverse events
People using coxibs, ibuprofen at high doses and diclofenac have an extra risk of seven to nine non-fatal and two fatal cardiovascular events per 1000 patients per year. This is due to the effect on blood vessels and platelet function, but also because NSAIDs increase blood pressure. Five to eight per cent of people on long-term NSAIDs develop clinical hypertension, (34) caused by arterial vasoconstriction and the impact of NSAIDs on renal function. Renal effects also cause sodium and water retention, leading to a doubling of the risk of hospitalisation with heart failure for all NSAIDs. (37)
About 18 per cent of NSAIDs users experience adverse renal effects. Risk increases for those with renal impairment, diabetes, heart failure or older age. (6)
PGs regulate blood flow through the kidneys and are more important where blood supply may be compromised due to renal artery stenosis or heart failure. Inhibition of COX enzymes by NSAIDs disrupts renal blood flow, glomerular filtration and the release of renin. This can lead to renal failure.
Sodium retention (leading to higher blood pressure) is a common adverse effect of NSAIDs. This is due in part to the reduction in glomerular filtration rate (mediated by COX-1) and also to inhibition of sodium excretion in the renal tubules (mediated by COX-2). Hyperkalaemia is also a risk, related to impaired renin activity that reduces potassium excretion via the renin-angiotensin-aldosterone system. NSAIDs also interfere with the actions of diuretics, contributing to hypertension and heart failure.
Allergy and asthma
Originally called aspirin-induced asthma, NSAID-exacerbated respiratory disease has long been recognised as an adverse effect, affecting about one in 10 adults who have moderate to severe asthma or rhinosinusitis with nasal polyps. (40) Upper and lower respiratory tract symptoms develop within 30 to 180 minutes of taking NSAIDs.
Initially, nasal congestion and rhinorrhoea develop, followed by wheeze, coughing and dyspnoea. For people with unstable or brittle asthma, effects may appear much faster with severe bronchospasm and increased risk of death. (40)
Aspirin is not given to children under the age of 12 or to teenagers with viral infections because it increases the risk of developing Reye's syndrome 35-fold. Reye's syndrome involves liver failure and acute encephalopathy. (41) Salicylates (but not non-aspirin NSAIDs) damage mitochondria affecting metabolism of fatty acids. In genetically susceptible children, who are also infected with a virus, this causes severe damage in the liver and central nervous system. Risk of mortality is between 20 and 40 per cent (younger age means greater risk) and up to 40 per cent of survivors have long-term neurological effects. (41)
RISKS vs BENEFITS
Risks must be balanced against benefits with the use of any drug. Analyses of primary prevention (prevention of a first stroke, myocardial infarction) trials have repeatedly shown the benefits of using low-dose aspirin do not outweigh the increased risk of serious haemorrhage.
The availability of low-dose aspirin over the counter may encourage people who read news stories about the potential benefits in prevention of CVD, cancer, dementia and other conditions to self-medicate. Media coverage of new medical treatments tends to overemphasise benefits while failing to adequately report harms. (42,43)
Cardiovascular and bleeding risks of NSAIDs must be measured against the benefits for each individual. Patient and health professional must make the decision together, once the risks and benefits have been clearly described. People use complex processes to reach personal decisions about drug and other therapies. Age, gender, ethnicity, past experience, monetary and social costs, and familiarity may affect a decision, regardless of the risk/benefit data presented by a health professional. (44)
After completing this activity, you should be able to:
* Describe the actions of aspirin and non-aspirin NSAIDs.
* Discuss key adverse effects of aspirin and NSAIDs.
* Outline the role of aspirin in disease prevention.
* Discuss the risks and benefits of low-dose aspirin.
* References are at www.cpd4nurses.co.nz
Georgina Casey, RN, BSc, PGDipSci, MPhil (nursing), is the director of CPD4nurses.co.nz. She has an extensive background in nursing education and clinical experience in a wide variety of practice settings.
Caption: Figure 1. Role of COX enzymes in prostaglandin synthesis
Table 1. Regulatory functions of COX enzymes Location Effect Effects of Inhibition Renal system Maintenance of renal Reduced glomerular blood flow (COX-1). filtration rate. Control of sodium Sodium and fluid excretion. retention. Important in renal failure. Opposes actions of diuretics. Control of renin release Elevated blood pressure (COX-2). and hyperkalaemia. Gastrointestinal Decreases secretion of Increased acid-pepsin tract gastric acid and pepsin. secretion and loss of Increases mucus protective mucus lining secretion along whole leads to oesophagitis, tract. gastric and duodenal ulceration and haemorrhage. Cardiovascular Vasoconstriction and Increased risk of system platelet activation (via bleeding. COX-1 and thromboxane). Vasodilation and Increased platelet inhibition of platelet activation. activation (COX-1 and Vasoconstriction [right COX-2). arrow] hypertension and increased risk of heart failure. Pregnant uterus Contraction of the Relaxation/inhibition myometrium. of labour. Respiratory Bronchodilation. Bronchoconstriction. system
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|Title Annotation:||CPD + nurses; non-aspirin nonsteroidal antiinflammatory drugs|
|Publication:||Kai Tiaki: Nursing New Zealand|
|Date:||May 1, 2019|
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