World Health Organizations estimate suggests that the worlds population over 60 years will double from 11 in 2000 to 22 in 2050. Like most of the developed countries, population of Australia is ageing. According to Australian Bureau of Statistics, the proportion of people aged 65 years and over is estimated to increase from 13.6% in 2010 to 16.4% in 2015 (2). However, with the increase in the life expectancy there is significant increase in the chronic medical conditions leading to increased morbidity and disability (3).
Musculoskeletal disorder (such as arthritis and osteoporosis) identified by WHO as a major disabling condition is also a main cause of pain and disability in Australia, affecting almost one-third of the population (3,4). According to recent estimates, a high proportion of Australians have arthritis (14.8%, approximately 3.3 million people) and the most common form of arthritis is osteoarthritis, affecting more than half (55.9%) of the population having arthritis (5).
What are NSAIDs?
Nonsteroidal anti-inflammatory drugs or NSAIDs are non-opioid analgesic most widely prescribed to relieve chronic musculoskeletal pain conditions such as osteoarthritis 1, rheumatoid arthritis, and lower back pain 2. They are also prescribed for the management of mild to moderate pain associated with cancer 3,4.
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A UK based epidemiological study suggests that almost one in five people aged between 65-74 years were taking NSAIDs (8).
Several guidelines 5-6 suggest NSAIDs as one of the major pharmacotherapy for the management of pain who respond inadequately to paracetamol. They are also considered to be more effective than paracetamol for the relief of osteoarthritic pain (7).
On the basis of COX selectivity, NSAIDs can be broadly categorized into two different class namely nonselective NSAIDs inhibitor (ns-NSAIDs) and COX-2 selective inhibitors.
Table 1 lists different NSAIDs that are included in our study.
4 - 15
Selective COX-2 inhibitor
1 - 2
Oral, rectal, topical
Selective COX-2 inhibitor
2 - 2.5
4.5 - 6
1.5 - 2
Oral, rectal, topical
3 - 4
Selective COX-2 inhibitor (at low dosage)
12 - 15
3.5 - 4
(6.5 - 7)2
Selective COX-2 inhibitor
30 - 50
2 - 3
How Does NSAIDs act?
NSAIDs are capable of yielding brisk relief from pain and inflammation by impeding the activity of cyclo-oxygenase isoenzymes (COX-1 and COX -2). The inhibition of these isoenzymes is responsible for both beneficial and adverse effects of NSAIDs These are the key enzymes for converting Arachidonic acid into prostaglandins D2, E2, F2, prostacyclin (PGI2) and thromboxane A2 (TXA2) adhering to a series of distinct steps as shown in figure 1. Nonselective NSAIDs (ns-NSAIDs) inhibits both isoenzymes (COX-1 and COX-2) whereas the selective inhibitors (Coxibs) primarily block the activity of COX-2.
What are the adverse effects associated with use of NSAIDs?
Despite NSAIDs exhibits a remarkable efficiency in treating various musculoskeletal disorders, they are also known to have a number of side effects associated with its use mainly - gastrointestinal, cardiovascular and renal.
Gastrointestinal side effects:
Gastrointestinal effect is the most troublesome side effect associated with non-selective NSAIDs that can lead to conditions such as dyspepsia (affecting 10 to 20% of patients taking NSAIDs) including peptic ulcers (affecting 1 to 4% of NSAIDs taking patients), which might lead to complications such as bleeding and perforation. Study has revealed that patients using NSAIDs have three to five times increased risk of developing upper GI bleeding and hospitalization compared to patients not using NSAIDs (3).
The functions of prostaglandin produced by COX-1 in the stomach are to stimulate the secretion of mucus and bicarbonate, increase the mucosal blood flow and promote the proliferation of epithelium. On the other hand the prostaglandin produced by COX-2 aids in healing of the ulcer by triggering cell proliferation, improving angiogenesis and restoring integrity as shown in figure 1.
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The pharmacological effects of non-selective COX inhibitors are due to the inhibition of COX-2 and COX-1 inhibition produces adverse effects to the gastric mucosa causing it to be more vulnerable to attacks by various internal and external factors. This GI adverse effect of ns-NSAIDs led to the development of COX-2 selective inhibitors which mainly inhibit COX 2 function and exempts COX 1 and while doing so mitigates the GI toxicity related to NSAIDs and are known be as efficient as the ns-NSAIDs for pain relief.
Although selective COX-2 inhibitors reduce the risk of gastrointestinal complications in comparison to nonselective NSAIDs, studies have shown that selective COX-2 inhibitors are known to increase GI symptoms in comparison to placebo.
However, the risk of GI complications is not same for all the patients taking NSAIDs. Elderly patients (aged 60 years and over) are found to be more vulnerable to GI complications. This is primarily due to the increase in occurrence of peptic ulcer with age, thus rendering the older patients more at risk of bleeding and mortality due to peptic ulcer.
Beside age, there are several other risk factors causing gastrointestinal complications in patients taking NSAIDs. The following risk factors have been included in our study (Guideline: NICE, GESA).
History of complicated ulcer or bleeding,
Concurrent use of two or more than two NSAIDs,
High dose of NSAID,
Concurrent use of medications that are known to increase the likelihood of bleeding such as low dose aspirin 1, antiplatelet 2, oral/SC anticoagulant 3, oral corticosteroids 4, bisphosphonates 5, selective serotonin reuptake inhibitors (SSRIs)/SNRIs6,
The presence of H. Pylori infection,
Use of Alcohol,
National guidelines (Gastroenterology society of Australia, GESA) and international guidelines (American college of Gastroenterology, European league against Rheumatism) recommend the use of various strategies to reduce gastrointestinal complications such as use of gastro protectant co-therapy (PPI/H2) with non-selective NSAIDs (ns-NSAIDs), use of selective COX-2 inhibitors, use of COX-2 inhibitors with gastro protectant and eradication of Helicobacter Pylori (H. Pylori). Institute for health and clinical excellence (NICE) recommends that PPI be prescribed with all NSAIDs including COX-2 inhibitors (2).
Cardiovascular Side effects:
Both selective and nonselective NSAIDs are known to present significant cardiovascular risks. They are known not only to cause risk in patients with pre-existing cardiovascular disease but also in healthy individual.
Not surprisingly, the risk of cardiovascular effects due to NSAIDs is significantly higher on elderly patients. This is due to the fact that elderly patients have greater chances of cardiovascular disease, and patients with high prevalence of cardiovascular risk factors have an increased risk of NSAID-related adverse effect.
Hypertension, Ischemic heart disease, Myocardial infraction and Stroke are well-documented cardiovascular risks associated with the use of NSAIDs. Hypertension is a major cause of risk of stroke, heart failure, myocardial infraction and renal failure. Clinical trials have shown that the lowering of the blood pressure can reduce the occurrence of stroke and myocardial infraction.
High blood pressure and cardiovascular disease
High blood pressure is a major risk factor for stroke, coronary heart disease, heart failure, peripheral vascular disease and kidney failure. It has also been considered a CVD in its own right.
Studies have shown there is a relationship between blood pressure and risk of cardiovascular disease, chronic kidney disease and death (NHFA 2009).
The cardiovascular side effects of NSAIDs are due to an imbalance between the effects of thromboxane and prostacyclin on the endothelium.
In order to maintain healthy vascular system there need to be balance between thromboxane A2 produced by COX-1 isoform (stimulator of platelet aggregation and vasoconstrictor) and prostaglandin I2 (PGI2) (inhibitor of platelet function, and potent vasodilator) produced mainly by COX-2 isoform. It has been proposed that NSAIDs, in varying degrees, tip the TXA2/PGI2 balance, thereby increasing cardiovascular risk.
Studies have shown selective COX-2 inhibitors to be a cause of increase in cardiovascular risks. However, nonselective NSAIDs with high COX-2 inhibition such as Diclofenac have a higher cardiovascular risk compared to selective COX-2 inhibitors. Furthermore, nonselective NSAIDs with high COX-1 inhibition such as Naproxen, Aspirin, and Ibuprofen etc. are associated with higher gastrointestinal risks.
Renal adverse events
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In addition to gastrointestinal and cardiovascular risks, NSAIDs (both nonselective and COX-2 selective) have similar risks with regards to adverse renal effects. As the elimination of drugs through the kidneys is normally impaired in the elderly patients due to the reduced renal blood flow and decrease in glomerular filtration rate (GFR), the occurrence of renal toxicity is more in older patients. Furthermore, reduced renal function in elder patients is also due to their comorbid conditions such as diabetes, hypertension, atherosclerotic disease etc.
The isoforms of cyclooxygenase (COX-1 and COX-2) are both present in the kidney and the blocking of either of both of them may result in adverse effects on a patient's renal function.
The renal side effects of nonselective NSAIDs (ns-NSAIDs) and selective COX-2 inhibitors include edema, hypertension, hyperkalemia, acute renal failure and congestive heart failure which is due to inhibition of PGE2 and PGI2 as shown in figure 2.
However, the risk of renal adverse effect is not same for all the patients taking NSAIDs. Several risk factors causing renal complications in patients taking NSAIDs are patient with concomitant disease such as congestive heart failure, cirrhosis or Nephrosis and patient taking loop diuretics.
Drug -Drug interaction:
Drug interactions occur when the potency or toxicity of one drug is altered by the concomitant administration of another drug. The mechanism by which drugs can interact with each other can be branched into two specific categories - pharmacokinetic and pharmacodynamic (2).
Pharmacokinetic drug interactions occurs when one drug influences the absorption, distribution, metabolism or excretion of another drug causing changes in serum drug concentration, half life or area under the curve. On the other hand, pharmacodynamic drug interactions occur when the presence of one drug affects another drug without changing its pharmacokinetics (3).
Drug interactions have been associated with increased incidence of adverse events, hospitalizations and death. Co-prescription of NSAIDs and interacting drugs in the elderly is a major health problem leading to increased rate of morbidity and mortality.
For example, many elderly patients are treated with low dose aspirin for the prevention of cardiovascular events. A high percentage of individuals requiring cardioprotection dose of aspirin have chronic pain and receive a NSAID. The use of NSAIDs in combination with low dose aspirin increases the risk of gastrointestinal bleeding (22). Similarly other potentially interacting drugs with NSAIDs that can alter the risk of gastric ulceration and bleeding are listed in table 1.
NSAIDs can interfere with the effects of frequently prescribed cardiovascular agents, including cardioprotective aspirin, [60-64] warfarin,  diuretics and ACE inhibitors.
Drugs used for hypertension and congestive heart failure can, in combination with NSAIDs, increase the risk of fluid retention and the subsequent risk of hypertension and heart failure.[
Lithium and methotrexate are potentially toxic drugs that are dependent on intact renal function for safe use.
All of which are commonly prescribed to older adults, all have the
potential for an adverse drug interaction with co-prescribed NSAIDs.
Possible adverse effect
NSAIDs and low dose aspirin
NSAIDs and clopidogrel
NSAIDs and oral anticoagulants
Bleeding and gastrointestinal lesions
NSAIDs and oral corticosteroids
Increased peptic ulcer risk
NSAIDs and selective serotonin reuptake inhibitors (SSRIs)
Increased risk of GI bleeding
NSAIDs and Alendronate
Increases the risk of gastroduodenal ulcer
NSAIDs and loop or thiazide Diuretics, Potassium sparing diuretics
May increase the risk of fluid retention and may increase the risk of heart failure
NSAIDs with ACE Inhibitors / angiotensin II receptor antagonists
Risk of acute renal failure
NSAIDs and β-blockers
Elevate blood pressure and antagonize the blood pressure-lowering effect
NSAIDs and high dose methotrexate
Increased methotrexate toxicity
NSAIDs and lithium
NSAIDs decrease the renal clearance of lithium and increase lithium concentration
NSAIDs and cyclosporine
NSAIDs and Azole antifungal
Table: List of Drug-Drug interaction with NSAIDs.
High Concomitant Use of Interacting Drugs and Low Use of Gastroprotective Drugs among NSAID Users in an Unselected Elderly Population
The drug-drug interactions of interest to this study are listed in table 1
Pharmacy student's ability to identify potential drug interactions:
Include something similar
Drug -Disease interaction:
Drug-disease interactions can be defined as the aggravation of the prior disease or conditions due to the use of medicine.
NSAIDs are also known to exacerbate various pre-existing medical conditions such as peptic ulcer disease, heart failure, chronic renal failure and hypertension.
Elderly people often have multiple problems. Individuals on drug treatment for hypertension may have arthritis that requires medication for pain relief. NSAIDs provide the mechanism for pain relief but also have effects on renal functions in people with underlying disease such as age related decline in GFR (23).
We will investigate the prescription patterns of NSAIDs for elderly patients with the pre-existing disease conditions listed in table 2.
Include abt beers criteria, other explicit criteria and also many study abt drug-drug interactions but less about drug-disease.
Possible adverse effect
NSAIDs with a history of ulcers or bleeding.
May exacerbate existing or produce new ulcers, bleeding risk
NSAIDs/aspirin and asthma
Prescription of NSAIDs with heart failure
Promote fluid retention and exacerbation of heart failure.
NSAIDs with acute or chronic renal failure
May reduce renal blood flow and worsen heart failure.
NSAID with hypertension
May produce elevation of blood pressure secondary to salt and water retention.
NSAIDs and cerebrovascular accident (stroke) and transient Ischaemic stroke
Increased CV risk
NSAIDs and myocardial infarction
Increased CV risk
NSAIDs with dyspepsia
Elderly patient at high risk of Drug -Drug or Drug disease interactions, why?
The use of all medications increases with age and the elderly are at increased risk of adverse drug reactions.
Elderly patients are at higher risk of drug-drug interactions or drug-disease interactions. One reason for this is Polypharmacy and another factor is comorbidity.
Many drugs are prescribed to elderly patients at the same time. A study in Australia showed that almost two-third of Australians aged 60 years and over were taking more than four drugs.
• Comorbidity: Elderly patients generally have two or more disease at the same time. A greater severity of the patient disease correlates with an increase number of drugs prescribed, and an increased chance of adverse drug interactions (3).
Also, elderly patients may also have problems maintaining adequate nutritional status
Drug-Disease interactions may have a more deleterious clinical impact on older adults because these individuals have less physiological reserve than younger individuals.
Elderly individuals often have many chronic diseases and are consequently taking multiple medications. They also have increases risk for adverse drug reactions due to age related changes in the pharmacodynamics and pharmacokinetics of drugs, comorbidities and Polypharmacy.