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A number of Bandolier's readers have asked for information on the safety of the various NSAIDs available orally. This probably stems from uncertainty about when to prescribe, or perhaps when not to prescribe, oral NSAIDs alone or together with mucosoprotective agents.

Use of analgesics

One of the problems with analgesics is that people use them all the time because they are available without prescription. An insight into the use of both prescription and nonprescription analgesics in Sweden is provided by a recently published paper looking at data collected in 1988/9 [1].
The survey was based on a random sample of the Swedish population aged 16 years and older, who were asked specific questions relating to analgesic use. The participation rate was 79%, and information was available from just under 12,000 people.

Results of the survey

In a report full of detail, the following picture emerges. Overall, 7% of men and 12% of women use prescription analgesics, while 20% and 30% use non-prescription analgesics. Use of prescription analgesics increases with age in men and women (Figure 1), but use of non-prescription analgesics is similar in all age groups.
Deeper analysis showed some fairly obvious relationships. For instance, headache and musculoskeletal pain were associated with increased use of analgesics, as were high levels of physical work stress, poor physical fitness and perceived poor health. In the previous 12 months, 13% of men and 20% of women had visited alternative therapists.

Prescribers' knowledge of NSAIDs

Medicine is a complex business. Audit can inform us on many of the activities in medicine, but occasionally more direct methods may be tried in order to assess the appropriateness of decision-making processes. To evaluate the extent to which NSAIDs are prescribed unnecessarily and how well NSAID-related adverse effects are diagnosed, a rather ingenious study was undertaken in Montreal [2].


Two clinical scenarios were devised. One was of a 67 year old person with a history of stiffness and pain in the right hip that radiated to the groin, taking 2.6 grams of paracetamol/day, plus some paracetamol/codeine combination, and with peptic ulcer disease and intolerance to aspirin. The other was a 67 year old with three week history of intermittent mid-epigastric pain, history of peptic ulcer, history of right hip osteoarthritis, and taking naproxen 1 g daily, plus ibuprofen in the past week.
Two men and two women were trained for each case to present the essential features (much more detail available than that given above), as well as to record details of visits to a physician using a structured questionnaire. The idea was to present standardised patients for clinicians to make diagnosis and management decisions.
Invites to participate were sent to 34 GPs in a hospital-based family medicine residency programme, 32 family medicine residents in a program at McGill University, 29 internal medicine residents in a hospital-based teaching programme and a random sample of 82 GPs. Each physician was to see one to four patients over eight months. They were invited to send reply-paid cards if they thought they had identified the standardised patients.
Eight physicians, representing different disciplines, and taking into account published guidelines for prescribing, came to a consensus about what would constitute optimal, acceptable, suboptimal and unsafe management decisions for each case (Table 1).
Table 1: Consensus on precribing decisions for standardised patients
Quality of management Case 1: Episodic hip pain Case 2: NSAID-related gastropathy
Optimal Increase paracetamol to 4 g/day, or nonpharmacological therapy Stop therapy with both NSAIDs
Acceptable Prescribe paracetamol and codeine (≤15 mg) or codeine (≤15 mg 3-4 times a day) Stop therapy with both NSAIDs and prescribe antiulcer therapy or reduce NSAID dose by at least half and prescribe antiulcer therapy
Suboptimal Prescribe NSAID with a gastroprotective agent or codeine (>15 mg 3-4 times a day) Reduce current NSAID dose by at least half with or without gastroprotective agent
Unsafe Prescribe NSAID without protection Continue with current dose of NSAIDs


Most (63%) of the physicians approached agreed to participate, ranging from 40% of community-based GPs to 100% of academic affiliated GPs. There were 312 visits to 112 physicians, and in 36 cases (12%) the physician unblinded the study by guessing that s/he was seeing a standardised patient (real patients were suspected only twice).

Case 1

In 139 blinded visits, osteoarthritis of the hip was the diagnosis made 90% of the time, with optimal/acceptable management decisions being taken in 58% of visits. Management decisions judged to be unsafe were made in 22% of cases (Figure 2).

Case 2

In 137 blinded visits, NSAID-related gastropathy was diagnosed 93% of the time, with optimal/acceptable management decisions being taken in 78% of visits. Management decisions judged to be unsafe were made in 10% of cases (Figure 2).
In both cases, longer visit times contributed significantly to the likelihood that a relevant history would be obtained, which, in turn, contributed to the likelihood that treatment would be appropriate.

How big is the problem?

NSAIDs cause ulcers in some people. Some of those who have ulcers also have symptoms, which include bleeding. In some of those who have bleeding ulcers, the bleeding is sufficiently severe to result in hospital admission, and may cause death. This is a fairly simplified version of events, and many of the papers in this field have as many as 10 different classifications of upper gastrointestinal complaints from which to classify an event.
Clearly, the important issue is the overall incidence of severe adverse events, including hospital admission and death, however much we might like information about the risk of any particular event happening to any particular patient. The variables are drug and dose, duration of exposure, and patient characteristics.
Most of the publications referenced in this focus have reams about the scale of the problem of NSAID-related GI problems. They make good reading, and would repay the effort if someone were to pull the information together. But for those with little time, a flavour is given in Table 2.
Table 2: NSAID-related deaths and admissions to hospital
  UK USA Canada
Annual NSAID prescriptions 20 million 70 million 10 million
NSAID-related deaths   7,600 365
NSAID-related admissions 3500-12,000 76,000 3,900
Other widely quoted factlets are that 1-3% of NSAID users develop GI bleeding, and 26% will be prescribed anti-ulcer therapy, that in Alberta, NSAID use was the reason for half the antiulcer prescribing for elderly persons, and that surveys show many prescribers lack awareness of the adverse events associated with NSAIDs.

Who needs protection?

We know that NSAIDs cause ulcers. The average risks for gastric ulcers were 3.6% and 6.8% with <2 weeks and >4 weeks use of NSAIDs, and for duodenal ulcers the average risks were 3.0% and 4.0% with <2 weeks and >4 weeks use respectively [3] ( Bandolier 39 ). The risk of developing serious GI injury was higher in a large clinical trial [4] which used a multiple linear regression model with 18 potential risk factors. It showed that risk factors for serious complications with oral NSAIDs were age 75 years or more, history of peptic ulcer, history of gastrointestinal bleeding and history of heart disease ( Bandolier 25 ).
The model predicted that for patients with none of the four major risk factors, the one-year risk of a complication was 0.8%, for patients with any single risk factor it was 2%, and for patients with all four factors it was 18%. With combinations of three of the factors, the one year risk was 8 - 10%.
Age and sex were also highlighted as important determinants of risk of serious GI complications with NSAID use in a large case-control study [5]. Figure 3 shows the increasing odds ratios with age for all patients (60% men), and the increased risk for women over men.

Are some NSAIDs safer?

Two reports indicate that some NSAIDs are associated with more harm than others [6,7]. One [6] is a meta-analysis of case-control studies, while the other is a cohort study of about 130,000 people over 50 years in Scotland. They give somewhat different magnitudes of difference, but the direction is similar in both (Table 3).

Table 3: Relative risk of gastrointestinal complications with NSAIDs, relative to ibuprofen
Drug Case-control studies [6] Cohort study [7]
Ibuprofen 1.0 1.0
Fenoprofen 1.6 (1.0 to 2.5) 3.1 (0.7 to 13)
Aspirin 1.6 (1.3 to 2.0)  
Diclofenac 1.8 (1.4 to 2.3) 1.4 (0.7 to 2.6)
Sulindac 2.1 (1.6 to 2.7)  
Diflusinal 2.2 (1.2 to 4.1)  
Naproxen 2.2 (1.7 to 2.9) 1.4 (0.9 to 2.5)
Indomethacin 2.4 (1.9 to 3.1) 1.3 (0.7 to 2.3)
Tolmetin 3.0 (1.8 to 4.9)  
Piroxicam 3.8 (2.7 to 5.2) 2.8 (1.8 to 4.4)
Ketoprofen 4.2 (2.7 to 6.4) 1.3 (0.7 to 2.6)
Azopropazone 9.2 (2.0 to 21) 4.1 (2.5 to 6.7)
There are differences, but the reasons are complicated, not least by the fact that few studies are able to take account of non-prescription aspirin or NSAIDs, which, as we have seen, may be taken by 20-30% of the population [1].

Do the risks change over time?

The cohort study from Scotland suggest not [7]. The relative risk of hospital admission was similar at all times after first day of NSAID exposure.

NSAID problems - the burden

The cohort study from Scotland [7] looked at all people over 50 years during a two year period, many of whom were also taking anti-ulcer medicines. In this time, 1034 of 52,293 people (1.98%) who had at least one prescription for an NSAID (not including aspirin) had a hospital admission, compared to 1005 of 73,792 people (1.36%) who did not. These numbers suggest a number needed to harm (NNH) of 163 (95% CI 131 to 213), with a relative risk of 1.5 (1.3 to 1.6).
So over two years an extra 0.62% of over 50s using NSAIDs had a hospital admission. Given that in the Scottish population 41% of over 50s had a prescription for an NSAID, this works out at 0.41 x 0.62/2 = 0.13% of all over 50s might be admitted in any one year. This is 130 people per 100,000 population over 50 years, despite indications that antiulcer medicines were being used appropriately.

How effective are anti-ulcer treatments with NSAIDs?

In Bandolier 25 , we gave the NNT for misoprostol to prevent one bleeding event compared with placebo in one year, the number-needed-to-treat as 83 (95%CI 55 - 160) in one large randomised trial. In Bandolier 39 we discussed how the NNTs would be lower for patients at higher risk.
Two further large RCTs have compared omeprazole with misoprostol, and with ranitidine and placebo.

Misoprostol, omeprazole and ranitidine

The first study [8] randomly assigned 935 patients who needed continuous NSAID therapy and who had ulcers or erosions to 20 or 40 mg omeprazole once daily, or 200 µg misoprostol four times a day. Healing over 4 to 8 weeks was assessed, and then patients with healed ulcers or erosions were randomly re-assigned to maintenance therapy of 20 mg omeprazole or misoprostol, or placebo, for six months. The second study [9] had a similar design, but with 20 and 40 mg omeprazole daily and 150 mg ranitidine twice a day in the healing phase, and randomisation of 432 patients to 20 mg omeprazole or 300 mg ranitidine a day in the maintenance phase, over six months.
Omeprazole 20 mg was more effective than misoprostol 800 µg a day. Compared with placebo the NNT for omeprazole 20 mg over six months was 3.0 (2.3 to 4.1), while for misoprostol 800 µg compared with placebo the NNT was 5.8 (3.8 to 12).
For omeprazole 20 mg compared with misoprostol 800 µg the NNT was 6.0 (4.0 to 12). For omeprazole 20 mg compared with ranitidine 300 mg the NNT was 6.2 (4.0 to 15).
These NNTs are impressive compared with those obtained for misoprostol previously [4]. But these are different studies, and the two recent omeprazole studies [8,9] use patients with established ulcers or erosions, in which the baseline risk of an ulcer with NSAID is much higher than in the complete population. Though the population studied was not particularly old (mean late 50s), all had previous symptoms or established gastroduodenal problems (see Bandolier 39 ).

What about H pylori?

Both Helicobacter pylori and NSAIDs cause ulcers, so there may be some interactions. The evidence up to now has been unclear, perhaps because there are so many different things going on in epidemiological studies. A randomised trial [10] indicates that perhaps eradicating the bug in people on NSAIDs may be a good thing.
Briefly, some 200 patients who needed NSAID treatment for musculoskeletal pain were tested for H pylori. Just over half were positive, and of these H pylori positive patients 47 were randomised to naproxen without eradication therapy. Another 45 were randomised to eradication therapy (which was effective in 40) before starting on naproxen (750 mg daily in all cases. Endoscopy was performed before treatment and after eight weeks.
None of the patients had an ulcer before starting naproxen. After eight weeks, 12 of 52 patients (27%) who had not had H pylori eradication, or in which it had failed had an endoscopically evident ulcer. Of 40 patients with successful eradication, only 1 (2.5%) had an ulcer. This gives an NNT of 4.1 (2.7 to 8.8) for preventing an endoscopic ulcer at eight weeks.
Now this is but one, small, RCT. The outcomes were endoscopic ulcer, not symptomatic ulcer, and the time-scale was short, but this is a significant straw in the wind. It suggests that H pylori eradication might be considered for those at highest risk and who are being started on long-term NSAID therapy.

What's the bottom line?

This focus has been on some of the bad things that can happen with oral NSAIDs. It is worth remembering that NSAIDs are excellent analgesics and anti-inflammatories, and bring huge benefits to many people who need them. But the gastrointestinal consequences of long-term NSAID use are not negligible. So what can be done to minimise them?
The evidence we have is that using paracetamol as a first-line agent is sensible. It is an effective and safe analgesic. It is worth remembering that NSAIDs given by topical routes are not associated with any of the gastrointestinal adverse effects seen with the oral route [11]. Meta-analysis has also shown them to be effective, with NNTs of about 3 in chronic conditions [12]. Thereafter the rule would seem to be to use ibuprofen for preference, at the lowest effective dose, and with mucosoprotective agents for those at highest risk of developing severe adverse gastrointestinal effects.


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