Adverse effects of nsaids

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You might call them pain relievers. You might take them for back pain, headache, or arthritis. Your doctor calls them “NSAIDs,” which stands for nonsteroidal anti-inflammatory drugs. Whatever you call them and for whatever reason you take them, NSAIDs are among the most popular medications worldwide. In fact, estimates suggest that about 15% of the US population takes an NSAID regularly (including those that are over the counter and prescription strength). Along with sporadic users, more than 30 billion doses are taken each year.

Some of the most common NSAIDs include ibuprofen (as in Motrin), naproxen (as in Aleve) and celecoxib (as in Celebrex).

Contents

Why are NSAIDs so popular?

There are several reasons:

  • For many conditions, they work quite well — in addition to working as pain relievers, they can reduce fever and inflammation.
  • They are relatively inexpensive, with generic versions available for most of them.
  • They’re available over the counter or, in higher doses, by prescription.
  • They have a good safety profile.

The downside of NSAIDs

No medication is completely safe, and that’s certainly true of NSAIDs. At the top of the list are digestive problems including stomach upset, heartburn, and ulcers. Kidney injury, easy bruising or bleeding, and mild allergic reactions (such as rash) are common as well. Less common side effects, including severe allergic reactions and liver injury, can be serious. NSAIDs can also raise the risk of heart problems, though this risk varies depending on the particular NSAID and the person taking it. Still, the vast majority of people taking NSAIDs in the recommended doses who have appropriate monitoring (such as the occasional blood test) have no major problems with them.

It’s easy for things to go wrong

The widespread availability and good safety record of NSAIDs makes it easy to misuse them. For one thing, there are more than 20 different NSAIDs, so you could be taking more than one of them without realizing it. In addition, several of them are available over the counter and are included in combination with other medications. Examples include prescription drugs like Arthrotec (a combination of the NSAID diclofenac and misoprostol, a medication that helps protect the stomach) and products available on the drugstore shelf, like Advil PM (ibuprofen plus the antihistamine diphenhydramine). So whether intentionally or by accident, it’s easy to take more than recommended doses.

A new study finds that this may be a bigger problem than anyone realized. Among more than 1,300 people taking ibuprofen:

  • More than one-third also took a second NSAID. Less than half of these “double NSAID” users realized that more than one of their medications was an NSAID.
  • Up to 15% took more than the recommended dosage.
  • Exceeding the recommended maximum dose was especially common among men, those with chronic pain, those with poor knowledge of dosing recommendations, and those who believed in “choosing my own dose.”

The bottom line

NSAIDs can be remarkably helpful medications, but they can cause trouble. The risk of serious side effects goes up when taken in higher than recommended doses.

Except for low-dose aspirin (commonly taken to prevent heart attack or stroke), NSAIDs are taken primarily to relieve symptoms of pain or fever. If you don’t think your NSAID is helping you (or if you aren’t sure), talk to your doctor about stopping it — even minor risks aren’t worth taking if there’s no benefit. Or there may be a better option, such as acetaminophen (as in Tylenol).

Keep an updated list of all of the medications you take, including over-the-counter drugs. Read the labels and instructions and take them only as prescribed. When in doubt, ask your doctor or pharmacist.

Non-steroidal anti-inflammatory drugs and their skin side effects

What are non-steroidal anti-inflammatory drugs?

Non-steroidal anti-inflammatory drugs (NSAIDs) are medications used regularly in the treatment of arthritis and intermittently for fever, pain and headache.

They are most commonly used systemically, usually as an oral formulation but can also be used as a suppository or administered by intramuscular injection. Topical gels and creams containing NSAIDs may be applied to sports injuries, painful joints and, most recently, for the treatment of solar (actinic) keratoses (sun spots). NSAIDs are taken by children and adults.

Classification of NSAIDs

Non-steroidal anti-inflammatory drugs can be classified by action (effect on the COX enzymes) and chemical structure as traditional, non-selective COX inhibitors or as selective COX2 inhibitors.

Non-selective COX inhibitors

  • Acetates: diclofenac, indomethacin, sulindac
  • Fenamates: mefenamic acid
  • Oxicams: piroxicam
  • Propionates: ibuprofen, ketoprofen, naproxen
  • Pyrazolones: phenylbutazone
  • Salicylates: aspirin, diflunisal

Selective COX2 inhibitors

  • More COX2 selective: meloxicam, nimesulid
  • Coxibs:
    • First generation, highly selective: celecoxib
    • Second generation, highly selective: etorcoxib, valdecoxib

Another way to classify them is by half-life.

Skin side effects of NSAIDs: general information

Many skin side effects are seen with many different medications and are not specific or diagnostic for any particular medication or chemical structure. Most are mild but they can rarely be life-threatening.

NSAIDs are one of the commonest drug groups to cause skin side effects. The gastrointestinal tract and the skin are the two body systems most likely suffer a side effect with NSAIDs.

It is difficult to estimate the frequency of skin side effects with NSAIDs as they are commonly purchased without prescription, and only those reactions worrying enough to present to a hospital are usually recorded. Most studies assess presentations to hospital A &E (Emergency or Casualty) departments, serious reactions that require admission to hospital or study adverse drug reactions occurring in an inpatient population. In one prospective study of nearly 20,000 inpatients, 0.3% of those prescribed a NSAID developed a generalized skin reaction including morbilliform rash, urticaria, angioedema, serum sickness-like reaction and erythema nodosum. In a meta-analysis of randomized clinical trials, skin side effects were reported in 1–2% of patients using NSAIDs.

As with most drug-induced skin reactions, withdrawal of the trigger medication results in resolution of the rash, although this may take some months and is not universal.

Skin side effects of topical NSAIDs: gels and creams

Topical diclofenac gel is available for the treatment of sundamaged skin, including actinic keratoses. Skin side effects reported in clinical trials that were seen more commonly with the active gel compared to the vehicle placebo, included allergic contact dermatitis, dryness (irritant dermatitis) and scaling.

The use of topical NSAIDs gels or creams to treat pain has been reported to cause a photocontact dermatitis. Most commonly this has occurred with ketoprofen gel with an incidence of 0.013-0.028/1000. Often the reaction appears after stopping the application when the skin is next exposed to sunlight. Therefore it is usually reported in summer. The reaction commonly extends beyond the area where the gel had been applied. The reaction can be severe, requiring hospital admission in some cases. Testing has shown this to be a photoallergic contact dermatitis, crossreacting with other NSAIDs including tiaprofenic acid, fenofibrate, oxybenzone and benzophenone. Bufexamac has also been reported to cause contact dermatitis.

Common skin side effects of systemic NSAIDs

Common non-specific skin reactions to NSAIDs are:

  • Exanthem
  • Fixed drug eruption – especially phenazone derivatives
  • Itch
  • Morbilliform rash (maculopapular)
  • Photosensitivity – both phototoxic (propionate derivatives) and photoallergic
  • Urticaria (hives) and angioedema
Skin side effects from non-steroidal anti-inflammatory drugs

Less common, rare or serious cutaneous side effects of systemic NSAIDs

These skin side effects include:

  • Alopecia – ibuprofen, indomethacin, naproxen, piroxicam,
  • Autoimmune blistering diseases including linear IgA disease
  • Drug-induced chronic cutaneous lupus erythematosus
  • Erythema multiforme
  • Erythema nodosum
  • Exfoliative dermatitis
  • Lichenoid drug eruptions
  • Psoriasis
  • Serum sickness-like reaction
  • Stevens-Johnson syndrome and toxic epidermal necrolysis – mainly oxicam derivatives
  • Sweet disease
  • Vasculitis including cutaneous small vessel vasculitis

Skin reactions seen uniquely or most commonly with systemic NSAIDs

A number of skin reactions have been reported either to occur only with systemic NSAIDs or NSAIDs appear to be a common trigger. These include:

  1. Hypersensitivity/intolerance to nonselective NSAIDs
  2. Pseudoporphyria, particularly with naproxen
  3. Exacerbation of chronic ordinary urticaria
  4. True allergic reaction
  5. Effect on urticaria pigmentosa

1. Hypersensitivity/Intolerance to NSAIDs

NSAIDs can cause a pseudo-allergy due to their pharmacological effects with a prevalence rate of 0.1-0.3%. It is believed to be due to inhibition of the enzyme COX1. Typically in this condition, the reaction develops with multiple different drugs in this family, unlike a true allergy where it is a reaction to a specific drug.

Predisposing factors are:

  1. Atopic tendency (eczema, asthma, hay fever)
  2. Female sex
  3. Young adult life
  4. History of chronic urticaria
  5. Use of NSAIDs for acute pain
  6. Use of traditional non-selective NSAIDs

The most common presentation of NSAID hypersensitivity is facial swelling, particularly around the eyes (angioedema). One third of patients present with a mixed pattern of skin (angioedema and/or urticaria) and respiratory symptoms including cough, breathlessness, rhinorrhoea (runny nose), tearing or upper respiratory tract swelling.

There are four presentations recognised:

  1. patients with an atopic tendency – urticaria is the usual presentation, rarely involving the airways. 80% of intolerant-to-NSAID patients are atopic.
  2. in non-atopics, urticaria and anaphylactic reactions,
  3. or urticaria and angioedema with no respiratory symptoms can occur.
  4. patients with asthma, nasal polyps, eosinophilia and chronic rhinoconjunctivitis (Widal syndrome) – NSAIDs can cause swelling of the upper airways, bronchospam and, less commonly, urticaria.

In general, selective COX2 inhibitors are well tolerated by most patients who have experienced this reaction with non-selective NSAIDs, but skin reactions have been reported rarely even with these. Total avoidance of aspirin and NSAIDs is only essential where there has been a serious reaction such as upper airway swelling.

2. Pseudoporphyria

Pseudoporphyria resembles true cutaneous porphyria tarda. It was first reported with naproxen, but has subsequently been seen with other propionate type NSAIDs. It presents with skin blistering and fragility, sun sensitivity and scarring, so clinically looks like porphyria cutanea tarda, but on specific biochemical testing, there is no abnormality detected.

In children, early onset pauci-articular arthritis (a type of arthritis affecting only one or two joints) is a major risk factor for developing this skin reaction. In one study, 11% of children treated with naproxen developed pseudoporphyria cutanea tarda after an average of 18 months. Ceasing the naproxen did not always clear the skin problems.

3. Exacerbation of chronic urticaria

Patients suffering from chronic idiopathic or ordinary urticaria or dermographism may notice a worsening or relapse of their condition when taking aspirin or other NSAIDs. The rash may appear within minutes to hours after taking any one of this group of medications. It is rarely serious but often involves the mucous membranes.

4. Allergic reaction

True allergic reactions involving specific IgE can occur but are fortunately rare as they can be potentially fatal. They can be distinguished from the hypersensitivity/intolerance syndrome as there is usually no crossreactivity with other NSAIDs groups.

5. Salicylates in urticaria pigmentosa

Salicylates including aspirin can cause mast cell degranulation and aggravation of symptoms in patients suffering from urticaria pigmentosa.

Chemoprevention of the development of nonmelanoma skin cancers

There was some suggestion that taking a NSAID longterm might prevent the development of nonmelanoma skin cancer. However, the most recent analyses of skin cancer prevention trials suggest that longterm use of NSAID probably does not significantly prevent skin cancer development, but perhaps short term use may.

Health Information

Topic Overview

Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce fever and inflammation and relieve pain. Examples of NSAIDs include aspirin, ibuprofen, and naproxen.

Be sure to follow the nonprescription medicine precautions.

Ibuprofen (such as Motrin or Advil)

  • Adults: The initial dose is 400 mg. Follow-up doses are 200 mg to 400 mg every 4 hours as needed, up to a maximum of 4 doses in a 24-hour period.
  • Children: Your child’s over-the-counter medicine will have a “Drug Facts” label. On the label, you’ll find directions for your child’s age or weight, the dose to give, and how often to give the dose. For children younger than 6 months of age, follow what your doctor has told you about the amount to give.
    • Be extra careful with liquid medicines. Infants usually need a different dose than older children do. And some liquid forms are stronger (more concentrated) than others. Always read the label so that you give the right dose.
    • When you give medicine, use the tool that comes with the medicine, such as a dropper or a dosing cup. Don’t use a spoon instead of the tool. Spoons can be different sizes. If the medicine doesn’t come with a tool to give doses, ask your pharmacist for one.

Naproxen (such as Aleve)

  • Adults: Initial dose is 440 mg. Follow-up doses are 220 mg every 8 to 12 hours as needed. Drink a full glass of water with each dose. Do not take more than 440 mg in any 8-hour to 12-hour period or 660 mg in a 24-hour period.
  • Adults older than 65: Do not take more than 220 mg every 12 hours unless your doctor tells you to.
  • Children: Do not give naproxen to children younger than 12 unless your doctor tells you to. Your doctor may prescribe naproxen for your child.

Side effects

The most common side effects of NSAIDs are stomach upset, heartburn, and nausea. If the medicine upsets your stomach, you can try taking it with food. But if that doesn’t help, talk with your doctor to make sure it’s not a more serious problem.

  • NSAIDs can cause a severe allergic reaction. Symptoms may include hives, swelling of the face, wheezing, and shock. If you have any of these symptoms, call 911 or other emergency services immediately.
  • For safety, read the label carefully and do not take more than prescribed. Taking a larger dose or taking the medicine longer than recommended can increase your risk of dangerous side effects.
  • Do not use a nonprescription NSAID for longer than 10 days without talking to your doctor.

Reasons to stop taking NSAIDs

NSAIDs may delay healing. If you develop any of the following signs of infection, stop taking the medication:

  • An increase in pain
  • Skin that is hot to the touch around the injury or wound
  • Redness or red streaks extending from the injury or wound
  • Pus that continues to form in the wound
  • Fever with no other cause
  • Swollen glands above the injury or wound

NSAID risks

  • NSAIDs have the potential to increase your risk of heart attack, stroke, skin reactions, and serious stomach and intestinal bleeding. These risks are greater if you take NSAIDs at higher doses or for longer periods than recommended.
  • Aspirin, unlike other NSAIDs, can help certain people lower their risk of a heart attack or stroke. But taking aspirin isn’t right for everyone, because it can cause serious bleeding. Talk to your doctor before you start taking aspirin every day.

Talk to your doctor about whether NSAIDs are right for you. People who are older than 65 or who have existing heart, stomach, kidney, liver, or intestinal disease are at higher risk for problems. For other people, the benefits may outweigh the risks.

Do not take NSAIDS if you have ever had an allergic reaction to any type of pain medicine.

If you are pregnant, trying to become pregnant, or breastfeeding, talk to your doctor before you use NSAIDs. It is especially important to avoid using NSAIDs during the last 3 months of pregnancy unless your doctor tells you to. They can cause problems with the baby or the delivery.

Talk to your doctor before taking NSAIDs if you have:

  • Ulcers or a history of stomach or intestinal bleeding.
  • Stomach pain, upset stomach, or heartburn that lasts or comes back.
  • Anemia.
  • Bleeding problems.
  • A habit of drinking more than 3 alcoholic drinks a day. This increases your risk of stomach bleeding.
  • High blood pressure.
  • Kidney, liver, or heart disease.
  • Any serious health condition.

Talk to your doctor before using NSAIDs if you take:

  • Blood thinners (anticoagulants).
  • Lithium.
  • Diuretics (water pills).
  • Medicine for arthritis or diabetes.
  • Aspirin to protect your heart.
  • Any other drugs.

Do not give aspirin to anyone younger than 20 because of the risk of Reye syndrome, a rare but serious disease.

Solutions

Treatment and prevention of NSAID related gastrointestinal problems are shown in box 4.

Box 4: Treatment and prevention of NSAID related gastrointestinal problems

Healing of NSAID related ulcers
  • Reduce NSAID dose if possible, or use alternative NSAIDs

  • Use of acid suppressive drugs while continuing NSAIDs: high dose H2-receptor antagonists, or more effectively, proton pump inhibitors

Prevention of NSAID related gastrointestinal problems
  • Avoidance or reduction of risk factors if possible

  • Drugs which may improve mucosal protection: prostaglandin analogues (misoprostol)

  • Acid suppressive drugs: H2-receptor antagonists (high doses), proton pump inhibitors

  • COX-2 specific inhibitors

  • Eradication of Helicobacter pylori (in selected cases)

HEALING OF NSAID RELATED ULCERS

There is evidence from both animal and human studies that NSAIDs retard the healing of gastric ulcers. Although it is frequently stated that a first step if gastrointestinal problems occur with NSAIDs is to withdraw NSAIDs or reduce the dose, in practical terms this is generally unrealistic, especially when there is a major inflammatory condition such as rheumatoid arthritis.

It may be possible to reduce the dose of NSAIDs in some individuals. It is also appropriate to try alternative conventional NSAIDs as there is a wide variability in responses to individual drugs. Some NSAIDs are more likely than others to cause gastrointestinal problems; those associated with greatest risk include azapropazone, ketoprofen, and piroxicam.

H2-receptor antagonists, especially in high doses, do heal NSAID related ulcers while NSAIDs are continued,13 but proton pump inhibitors may be expected to be more effective, and have now been shown to be so. Omeprazole has been shown to heal gastric ulcers faster than ranitidine.14 In two large studies comparing omeprazole (20 mg or 40 mg daily) with misoprostol (200 μg four times a day), the proton pump inhibitors healed significantly more gastric and duodenal ulcers than ranitidine or misoprostol.

No extra benefit was gained from using omeprazole at the higher dose.15 16

PREVENTION OF NSAID RELATED GASTROINTESTINAL PROBLEMS

The lowest dose of the safest NSAID which is effective in individual patients should be used if possible.

Avoidance or reduction of risk factors may be possible in some patients, such as smoking, use in patients with a past history of dyspeptic problems or peptic ulcer, perioperative use, or cotherapy with other drugs such as corticosteroids, anticoagulants, or aspirin. Advice should be given about “over-the-counter” preparations.

There will inevitably be patients in whom additional requirements will be necessary, such as those who continue to require high dose NSAIDs or in those with risk factors which cannot be modified.

In such patients there has been much interest in recent years in attempting to reduce risk by the coprescription with NSAIDs of drugs which may improve mucosal protection (the prostaglandin analogue misoprostol) or reduce gastric acid (H2-receptor antagonists or proton pump inhibitors). More recently, newer NSAIDs—selective COX-2 inhibitors—offer the prospect of greater gastrointestinal safety.

PROSTAGLANDINS

The prostaglandin analogue misoprostol has shown a reduction in ulceration compared with placebo ranging from 50% to 90% over 3–12 months; the dose used initially was 200 μg four times a day and subsequently 400–600 μg per day. Protection has been generally similar for both gastric and duodenal ulcers.17 18 A large blinded study of misoprostol compared with placebo (the “MUCOSA” study) reported a significant reduction of gastrointestinal bleeding and perforation with misoprostol at 800 μg daily.19 In this study, 27% of patients withdrew because of side effects, principally diarrhoea. Diarrhoea remains a problem for many patients with this preparation. Misoprostol has also been combined with a standard NSAID, diclofenac (arthrotec), and this has proved popular with a number of patients.

Theoretically, prostaglandin analogues have an advantage over acid suppressants in that they should provide mucosal protection throughout the gastrointestinal tract.

ACID SUPPRESSION

As gastric acid is a factor in causing gastroduodenal damage associated with NSAID use, reduction of gastric acid by the coprescription of acid suppressant drugs has been studied.

The use of H2-receptor antagonists in standard doses for the prevention of NSAID associated ulcers has shown some protection against duodenal ulcers.20 and the use of high dose famotidine (40 mg twice a day) has been shown to significantly reduce the cumulative incidence of both gastric and duodenal ulcers in patients with rheumatoid arthritis on long term NSAID therapy.21

Proton pump inhibitors cause more effective acid suppression than H2-receptor antagonists, and several randomised controlled trials lasting 3–6 months using omeprazole 20 mg daily have shown efficacy in preventing both gastric and duodenal ulcers while continuing long term NSAIDs, with about a 75%–80% reduction in ulcers compared with placebo.15 16 22

The proton pump inhibitors were shown in two of these studies to provide more effective protection than ranitidine (150 mg twice a day) or misoprostol (200 μg twice a day).

Omeprazole 20 mg daily has also been shown to protect against bleeding from ulcers in long term NSAID users.23

NEWER NSAIDS: COX-2 SPECIFIC INHIBITORS

The search for safer NSAIDs has recently focused on the development of preferential or selective COX-2 inhibitors. These compounds aim to exploit the belief that COX-1 is associated predominantly with the production of protective prostaglandins and has a “housekeeping” role, whereas COX-2 is induced in inflammation and associated with inflammatory processes. The development of these concepts has been recently reviewed.24

The definition of, and screening for, COX-2 selectivity has given rise to much debate, involving a variety of suggested systems that includes purified recombinant enzyme, transfected cells, and whole blood assays. The latter method may be the most appropriate at present, but all drugs suggested as COX-2 specific inhibitors require to be shown to have no significant inhibition of gastric mucosal prostaglandins, in addition to a good clinical safety profile and effectiveness.

Conventional longstanding NSAIDs have been found to vary with respect to their relative COX-1 to COX-2 inhibition capacity, but all have a significant effect on COX-1, thus interfering with gastric mucosal protection.

One NSAID, etodolac, which has been used widely for some years, has been shown in several studies to be clinically effective and have reduced gastrointestinal toxicity, demonstrated endoscopically and clinically; these studies also found no significant reduction of gastric mucosal prostaglandins compared with naproxen.25 26 Etodolac has since been found to have some degree of COX-2 selectivity.27

Other drugs with probable relative COX-2 selectivity include nabumetone, nimesulide, and meloxicam.24

Newer more specific COX-2 inhibitors currently under study include celecoxib and rofecoxib (the latter now being available in this country). Preliminary results of studies with these drugs indicate effectiveness and a good gastrointestinal safety profile. Celecoxib (25–400 mg twice a day) was associated with a significantly reduced incidence of adverse upper gastrointestinal problems including ulcers, gastrointestinal bleeding, and perforation in patients with osteoarthritis and rheumatoid arthritis compared with standard NSAIDs.28 Rofecoxib (12.5–25 mg a day) demonstrated a lower incidence of endoscopic ulcers compared with ibuprofen in patients with osteoarthritis in a multicentre study over 24 weeks.29 Rofecoxib has also shown reduced occurrence of ulcers, perforations, and gastrointestinal bleeding.

COX-2 specific inhibitors have little, if any, effect on platelet function, and may therefore be associated with a marked reduction of gastrointestinal bleeding associated with NSAID use.

These studies are promising and more data are awaited. The long term safety of these drugs remains to be established, particularly with respect to the kidney and in the possible, although less likely, impairment of healing of pre-existing peptic ulcers. It is also theoretically possible that COX-2 inhibitors may have a benefit in preventing colon cancer and possibly also in Alzheimer’s disease. COX-2 inhibitors will not be effective in cardiovascular protection unlike aspirin, as the protective effects provided by aspirin are mediated through COX-1.

LOW DOSE ASPIRIN

Aspirin is widely used in low doses in patients with suspected or definite vascular disease. Aspirin is a major cause of upper gastrointestinal problems, and is a frequent cause of upper gastrointestinal bleeding. Even in low doses (75 mg daily), aspirin has effects on platelet levels of COX, which it acetylates and to which it binds irreversibly, thus impairing platelet function. This causes changes in the bleeding time, platelet aggregation, and the synthesis of thromboxane, which remain for the life of the platelet. The damage is worse with longer acting NSAIDs with long half lives and an extensive enterohepatic circulation, such as piroxicam.

With increasing use, aspirin is now a major cause of upper gastrointestinal problems, and in particular, upper gastrointestinal bleeding. One recent study reported an overall odds ratio of 3.2 (95% confidence interval (CI) 2.3 to 4.4) in gastrointestinal bleeding for daily aspirin use of at least one month, compared with 3.8 (95% CI 3.1 to 4.5) for non-aspirin NSAID use.9 This can be expected to increase with increasing use of low dose aspirin, especially common in older age groups.

Platelets contain only COX-1; thus only drugs such as aspirin and those NSAIDs which inhibit COX-1 will inhibit platelet function. COX-1 sparing NSAIDs such as etodolac, nabumetone, nimesulide, meloxicam, are likely to have little effect on platelet dysfunction. The highly specific COX-2 inhibitors (celecoxib, rofecoxib), have almost no effect on platelet function, and are likely, as mentioned previously, to lead to marked reductions in upper gastrointestinal bleeding. However, if used with low dose aspirin, there is likely to be a loss of benefit.

COX-2 specific inhibitors will not be helpful in vascular disease, and cannot be considered as a replacement in this respect for low dose aspirin.

A new antiplatelet agent, clopidrogel may be safer than aspirin, although more costly. Clopidrogel requires to be further assessed, but may be helpful in patients with peripheral artery disease, and in stroke or myocardial infarction in whom aspirin is contraindicated, or in whom aspirin fails to achieve the required therapeutic effect.

WHAT TO DO ABOUT H PYLORI?

H pylori and NSAIDs are the two most common causes of peptic ulceration.

The possible interactions of H pylori and NSAIDs have led to much discussion recently and no clear picture emerges that can apply to all situations. In many ways, NSAIDs andH pylori have similar adverse effects on mucosal protective mechanisms, and despite H pylori itself producing small amounts of prostaglandins, there remains the possibility of an additive damaging effect when both are present.30 Studies on mucosal adaptation and on neutrophils raise the possibility of some inter-relationship that may allow damage to occur more readily when NSAIDs are taken in the presence of H pylori.31

The development of an ulcer when NSAIDs are given to patients who are H pylori positive may depend on the interaction of a number of factors, including previous exposure to NSAIDs, past history, gastric acid output, and the use of acid suppression drugs such as proton pump inhibitors.

Aspirin may have different interactions with H pylori, particularly with respect to the risk of gastrointestinal haemorrhage.

Gastrointestinal haemorrhage from ulcers may be in a different category from non-bleeding ulcers, and really requires to be studied separately; other factors may be involved, such as the possible antiplatelet effects of many NSAIDs, which may be a further factor in bleeding.

Clinical studies in this area have given conflicting results, although one study in patients not previously given NSAIDs clearly demonstrated an advantage in eradicating H pylori before starting NSAIDs; significantly fewer lesions developed over two months in patients in whom H pylori had been eradicated before starting NSAIDs.32 In such patients, especially if risk factors are present (older age group, previous ulcer history), eradication of H pylori before starting NSAIDs may be indicated.

A large multicentre study has found that eradication ofH pylori did not reduce the rate of ulcer relapse in existing long term NSAID users.33 In this study, it was also reported in a subgroup of 41 patients with gastric ulcers found at baseline endoscopy that eradication ofH pylori was associated with delayed ulcer healing. However, in another prospective, randomised study of 195 patients with H pylori infection and NSAID associated bleeding ulcers, eradication of H pylori did not impair healing of gastric or duodenal ulcers.34 A prospective, randomised clinical outcome study compared H pylorieradication alone with long term omeprazole for the prevention of recurrent ulcer haemorrhage in high risk users of aspirin or non-aspirin NSAIDs.35 The results to date indicate that eradication of H pylori alone did not prevent recurrent ulcer bleeding associated with non-aspirin NSAIDs, but H pylorieradication alone was as effective as maintenance omeprazole in preventing recurrent haemorrhage associated with low dose aspirin. Perhaps the antiplatelet effects of NSAIDs are relevant there.

H pylori testing would probably not be indicated in patients who have already been on NSAIDs or aspirin for some time without any adverse effects. In patients with a past history of peptic ulcer or dyspepsia on NSAIDs, long term acid suppressive agents such as proton pump inhibitors are indicated even after eradication of H pylori.

More scientific and clinical data are required on these complex inter-relationships.

Guidelines to Help Reduce the Side Effects of NSAIDs (Nonsteroidal Anti-inflammatory Drugs)

What are NSAIDs?

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a group of drugs that are prescribed to reduce the pain and inflammation of arthritis. Some of these drugs require a prescription, while others are available without one (over-the-counter or OTC). They include such drugs such as (generic names first, brand names in parentheses):

NSAIDs do not include drugs that are purely pain relievers, such as acetaminophen (Tylenol) or codeine.

NSAIDs are generally tolerated very well by many patients, which is fortunate because these drugs are often very helpful for people with pain and inflammation. Most side effects are minor and easily reversible by discontinuing the drug or by adding a drug to counter such effects. The risk of serious side effects is small. Being aware of the possible side effects of these drugs can make them even safer to use. Although most side effects are minor, there is still a genuine concern regarding gastrointestinal problems (such as ulcer development) and cardiovascular side effects, as discussed.

If any of these guidelines are not clear, or if you think it does not apply to you, discuss the issue with your physician.

What are Possible Side Effects of NSAIDs?

Gastrointestinal Symptoms

  • Gastrointestinal symptoms are the most common side effects of NSAIDs. They are most likely to be stomach irritation and the sensations known as “heart burn” (which has nothing to do with your heart). In severe cases, NSAIDs can irritate the lining of your stomach so that an ulcer (a small erosion) forms. In the worst cases, such an erosion can lead to internal bleeding, which may be life-threatening.
  • Stop the drug and call your physician immediately if you have any severe abdominal pain or a black, tarry stool (bowel movement) or any blood in your stool.
  • To help reduce irritation of the stomach and prevent an ulcer,
    • Take NSAIDs at the end of a full meal or with an antacid
    • Limit alcohol intake (since alcohol can also irritate your stomach)
  • If you develop gastrointestinal problems, your physician may switch you to another drug (such as a COX-2 selective inhibitor – see section on this type of agent) or may add a drug to help reduce stomach irritation.
  • Drugs that reduce stomach irritation include misoprostol (Cytotec), or a proton pump inhibitor such as omeprazole (Prilosec), esomeprazole (Nexium), pantoprazole (Protonix), lansoprazole (Prevacid), or rabeprazole (Aciphex). Only lansoprazole, at this time, has received an official FDA indication for protection of ulcer in patients on nonsteroidal anti-inflammatory agents. These drugs can considerably reduce your risk of an ulcer and internal bleeding.

The black box warning for NSAIDs related to gastrointestinal risk reads as follows, in an example from the labeling for the NSAID naproxen (Naprosyn®):

Gastrointestinal Risk: NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events.

Heart Problems

The FDA has required a block box warning about cardiovascular thrombotic events be placed in the package description of all NSAIDs other than aspirin, including COX-2 specific and selective agent, and patients at high risk for cardiovascular disease need to weigh the risks and benefits with their physician before taking any NSAID or (COX-2 specific or selective agent). The black box warning for NSAID’s related to cardiovascular risk reads as follows, in an example from the labeling for the NSAID naproxen (Naprosyn®):

“Cardiovascular Risk: NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk.”

What is the Dosing?

When you are trying an NSAID for the first time, take the full dose prescribed every day, unless instructed otherwise. It may take as long as two weeks to build up to a “blood level” of the drug, and the drug may not help very much until then. If you take the drug irregularly, you may never know whether it actually can help you. This could lead to your being switched to a second drug when the first one actually could have helped. Each new drug you take carries a risk of allergic reaction (such as skin rash). Therefore, it’s important to find out if a drug can help you before switching to another.

Do not exceed the dose of the drug prescribed. The extra benefit is usually small and the increased risk is significant.

If you are taking the medicine regularly and miss a dose, take it as soon as possible. However, if it is almost time for your next dose, skip the one you missed and go back to your regular schedule. Do not take a double dose. If your arthritis improves, discuss with your physician the possibility of decreasing your dose of the NSAID.

Can I combine NSAIDs with Other Drugs?

  • Do not mix one NSAID with another. For example, don’t take aspirin or ibuprofen with any other nonsteroidal anti-inflammatory drugs. However, your physician may wish you to combine low-dose aspirin with an NSAID for heart attack or stroke prevention. This is an individual decision for each patient, and you should discuss this with your physician, since combining an NSAID with aspirin can increase the risk of ulcer.
  • Acetaminophen, especially in low dose, appears less likely to irritate the stomach than NSAIDs, so in many cases it is reasonable to take acetaminophen along with NSAIDs.
  • Always read the ingredients listed on the label of over-the-counter products. If acetylsalicylic acid or salicylate is listed, it may be better not to take this with NSAIDs, unless advised by your physician. Keep in mind that Alka-Seltzer, Anacin, some types of Excedrin, and even Pepto-Bismol contain aspirin.
  • If you are taking medications for high blood pressure, have your pressure checked regularly while on the nonsteroidal anti-inflammatory drug. This is especially important within the first several weeks of starting the drug. In some patients, NSAIDs can elevate the blood pressure.

When Should I Stop the Drug and Get Immediate Medical Attention?

  • If signs of allergy occur, such as rapid breathing, gasping, wheezing, hives, skin rashes, puffy eyelids, and/or rapid heart beat occur.
  • If you develop vision abnormalities.
  • If you develop dizziness, depression, or confusion.
  • If you develop yellowing of the eyes that could indicate liver injury (although liver injury is rare and your liver function is checked when you have standard chemistry blood tests, which should be done periodically, when you are taking an NSAID).
  • If your urine becomes cloudy or bloody, the amount of urine you pass should suddenly decrease, or you develop new ankle swelling, all of which could indicate kidney problems. This is especially important to watch for if your kidney function has been noted, on lab testing, to have been abnormal in the past.

When Should I Call My Doctor About Changing Dosage or Medications?

  • If you develop swelling of the ankles or sudden weight gain after starting one of these drugs due to fluid retention.
  • If you develop decreased hearing or ringing in your ears.
  • If you are planning to get pregnant, or become pregnant.

Updated: 9/6/2009

Authors

Theodore R. Fields, MD, FACP
Attending Physician, Hospital for Special Surgery
Professor of Clinical Medicine, Weill Cornell Medical College
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