NSAIDs are the most widely used class of drugs in the United States. Some of them are available both in the States and UK without a prescription, over the counter(OTC) at a pharmacy.

These drugs are used to treat conditions which involve pain, inflammation and fever, both acute problems such as injuries or post-operatively, or for ‘flu and chronic disorders such as Rheumatoid Arthritis and osteoarthritis. The term “non-steroidal” indicates that these drugs do not contain steroids such as cortisone which are also used to treat inflammation.

HOW DO THEY WORK?

NSAIDs inhibit prostaglandin(PG) synthesis through their action on the enzyme cyclo-oxygenase(COX). PGs are synthesised in various tissues and have several physiological actions which include their role in inflammation. It is this role that is targeted when using NSAIDs.

There are 2 iso-forms of COX : COX-1 and COX-2. The traditional NSAIDs such as ibuprofen are non-specific and affect both subtypes, whereas the newer drugs such as celebrex are specific COX-2 inhibitors. COX-1 is particularly involved in the gut but is also expressed in most tissues; it is involved in the synthesis of PGs in response to physiological stimuli. It helps to protect the stomach and kidneys and it is thought that this is the reason why non-selective NSAIDs have serious adverse effects on these organs.(see Adverse Effects below) COX-2 inhibitors were developed with this in mind and have been successful in reducing the risks somewhat but not entirely.

ADMINISTRATION:

Predominantly, these drugs are given by mouth, but they can also be administered rectally as suppositories(e.g.diclofenac, indomethacin, ketoprofen, meloxicam, naproxen) ; topically as cream/gel (e.g. diclofenac: Emulgel;); intravenous(diclofenac); intramuscular (e.g.diclofenac/piroxicam/ketoprofen)

In general, the maximum dose for NSAIDs should be set at 1.5-2 times the standard recommended starting dose. Failure with one drug does not preclude trial of a different one (provided the failure relates to efficacy rather than adverse effects). However, trials must be sequential.

If taking NSAIDs orally, it is best to take them with or after food, to help minimise any adverse effects on the stomach.

COX-2 INHIBITORS:

Studies on these drugs indicate that their efficacy is similar to that of the more traditional NSAIDs. However, they are associated with a decreased risk of gastrointestinal effects. Thus far, COX-2 inhibitors have largely been used as second-line drugs for management of pain in patients who cannot tolerate other NSAIDs, but they will probably become first-line treatment in the future.

CAUTIONS:

1. ASTHMA: asthma may be worsened by NSAIDs

2. IMPAIRED LIVER FUNCTION

3. IMPAIRED RENAL(kidney) FUNCTION

4. HISTORY OF GASTRO-INTESTINAL PROBLEMS such as bleeding ulcer, Ulcerative Colitis.

5. HISTORY OF HYPERSENSITIVITY (such as rashes due to NSAIDs)

6. BLEEDING DISORDERS

7. CARDIAC IMPAIRMENT

CONTRA-INDICATION: active peptic ulcer

GASTROINTESTINAL (GI) EFFECTS:

The most common side-effects of NSAIDs are constipation and indigestion, because they are acidic in nature and also promote acid production in the stomach. Nausea and heartburn are common problems, which may be relieved by ensuring that you take the medication during or after a meal. It may also be helpful to reduce other irritating factors such as coffee, spicy food, alcohol and smoking. Antacid preparations such as Maalox or Gaviscon may help to relieve the symptoms, but if they persist, you should seek advice from your doctor. Antacids may actually reduce the effectiveness of the NSAID medication as they will reduce its absorption.

See below for other methods of reducing this problem.

NB. The motility stimulant drug Cisapride (Prepulsid) which may have been used to treat symptoms of indigestion, has been withdrawn from use due to serious adverse effects such as cardiac arrythmias.

THE DANGER SIGNS:

IMPORTANT: in view of the potentially serious nature of the adverse effects on the stomach, patients are advised to seek medical attention if they experience any symptoms such as indigestion, heartburn, waterbrash, etc.

If vomiting occurs, it is important to check for signs that there may have been bleeding in the stomach: the vomitus may have frank blood in it or may appear like coffee grounds. Also, faeces(stools) may be black and tarry. If this occurs, you must seek urgent medical attention.

Accompanying symptoms may include feeling faint/dizzy/nausea/abdominal pain/back pain (often between the shoulder blades).

To put the incidence of gastrointestinal adverse effects into clinical context, note that NSAID-related deaths have a higher incidence than those from cervical cancer. In the UK, there are over 2,000 such deaths each year.

Generally the rate of gastric/duodenal ulceration runs at about 1-2%, but as the number of people using NSAIDs is enormous, we are dealing with a large number of cases.

The following are recognised risk factors for upper GI ulceration:

a. Age over 65
b. A history of previous gastrointestinal symptoms associated with NSAIDs.
c. Concomitant use of oral corticosteroids
d. High NSAID doses
e. A high disability index.

REDUCING NSAID-RELATED ULCERS:

Some NSAID preparations contain misoprostol(Cytotec), which may also be given as a separate preparation in cases of NSAID-induced gastric ulceration. It is a synthetic prostaglandin analogue which protective properties for the gastric mucosa (stomach lining) and also reduces stomach acid production. Omeprazole (Losec) is a proton pump inhibitor which inhibits acid production and promotes healing of ulcers. Other similar drugs include Lansoprazole (Zoton) and Pantoprazole (Protium).

Some patients are prescribed drugs such as ranitidine (Zantac; Pylorid) or cimetidine (Tagamet, Dyspamet, Algitec) which are H2-receptor antagonists. (H2 receptors are involved with acid production in the stomach).

THE ROLE OF H.PYLORI

It has been found that an organism called Helicobacter pylori is responsible for the majority of gastric and duodenal ulcers not associated with NSAID use : it may therefore be appropriate for the patient to be tested to exclude this to reduce the risk of GI complications. There are several different treatment regimes that can be used to eradicate this organism. There is no evidence to date that H. Pylori and NSAIDs together carry an increased risk : H. Pylori does not appear to have either a potentiating or attenuating effect on NSAID-related ulcer formation. However, presence of H. pylori might be a useful clinical indicator of a patient who is at increased risk of developing ulcers. Eradication might be worth considering if the patient has other risk factors for ulcers.

RENAL(kidney) ADVERSE EFFECTS:

Prostaglandins are involved in the regulation of renal blood flow, glomerular filtratin rate (GMR) the release of the hormone renin, reabsorption of water and excretion of sodium and potassium.

Therefore in blocking prostaglandin function, NSAIDs are inevitably going to affect kidney function. High risk patients include the elderly and those who have pre-existing kidney problems, and also patients with heart disease, liver disease or diabetes.

Renal problems can occur with short-term use of NSAIDs but are more of a concern with long-term use. A range of problems can occur, including end-stage renal failure with chronic high dose NSAID use.

The most common renal problem is sodium retention which also causes water retention and thus oedema. This results in weight gain, swelling of the limbs and abdominal bloating and the patient may notice reduced urine output and shortness of breath. This problem is of particular concern in patients who have pre-existing heart failure as it will exacerbate the condition.

NSAIDs may also cause hyperkalaemia (high potassium in the blood) due to inhibition of the hormone aldosterone. This effect will be greater in patients who suffer from diabetes, heart failure or multiple myeloma. In addition, if the patient is taking potassium sparing diuretics ( a type of water tablets) to treat fluid retention or heart failure, or is taking drugs like captopril (an ACE inhibitor)or enalapril (Innovace) then the hyperkalaemia may be particularly marked.

If you develop swelling of the ankles, feet or lower legs or an unexplained weight gain and a decreased urine output, you should seek medical attention immediately.

Nephrotic syndrome with interstitial fibrosis is another condition caused by NSAIDs. Nephrotic syndrome involves loss of protein into the urine. Fenoprofen is associated with this problem.

Papillary necrosis may occur with aspirin/acetaminophen(paracetamol) combination, with phenacetin or in massive NSAID overdose. It is irreversible.

Acute renal failure may be asymptomatic (no symptoms) or present as:

• decreased urine output (There may be none.)
• excessive urination at night
• ankle/feet/leg swelling
• decrease in sensation in hands and feet
• changes in mental status/mood: agitation, difficulty concentrating, hallucinations
• drowsiness>>coma
• seizures
• hand tremor
• excessive diffuse itching
• nausea/vomiting
• flank pain

High blood pressure due to renal failure may be detected at routine medical checks or may present as persistent headaches.

If you experience any of these symptoms, you must seek urgent medical attention.

Acute renal failure is usually reversible within a week of discontinuing the drug but if it is not recognised at an early stage, dialysis may be necessary.

HEPATIC (liver) EFFECTS:

Virtually all analgesic drugs are metabolised by the liver, therefore damage to this organ is associated with the majority of analgesics. NSAIDs actually carry a relatively low risk of liver toxicity. Serious toxicity is uncommon with proper therapeutic use.There have been isolated reports of chronic active hepatitis associated with use of salicylates. Reye’s syndrome is a rare liver condition which can be fatal. Salicylate has been linked with this condition and use of aspirin in the under-12s is not recommended as the condition resembles subacute salicylate toxicity in children.

HAEMATOLOGICAL (BLOOD) ADVERSE EFFECTS:

Most NSAIDs affect platelet aggregation and hence the clotting of the blood. Aspirin has an irreversible effect on platelets, which is why it is used prophylactically to prevent strokes and heart attacks in those at risk. One dose may increase the bleeding time for up to 7 days. Other NSAIDs exert a reversible effect which only lasts until the drug has been eliminated from the body. This is of particular relevance clinically in patients requiring surgery. Aspirin must be discontinued at least a week prior to the planned procedure and other NSAIDs must be stopped for a period approximating to 4-5 half-lives of the relevant drug.

Anaemia is rarely of a severity to necessitate discontinuation of the drug. Of course, if there is evidence of anaemia or a drop in haemoglobin, then this should raise suspicion of an occult GI bleed.

Patients should be instructed to be vigilant for signs such as easy bruising, bleeding gums, black tarry stools and severe headaches.

CENTRAL NERVOUS SYSTEM ADVERSE EFFECTS:

These include headaches, dizziness or drowsiness and possibly cognitive dysfunction(difficulty in thinking clearly, loss of short-term memory) but usually these are mild symptoms and not attributed by the patient to his/her medication. They tend to be easily and rapidly reversible on discontinuing the drug.

High doses of salicylates and other NSAIDs may cause tinnitus: it is a warning sign of high blood levels of the drug. It is generally reversible.

You should consult your doctor if you have any of the following: persistent headaches, ringing in the ears, extreme fatigue, disorientation or confusion.

DRUG INTERACTIONS:

Note: these do not generally apply to topical preparations.

· ACE inhibitors, other analgesics(NB: avoid use of other NSAIDs including aspirin.), anticoagulants; antidiabetics ;antiepileptics; diuretics(water tablets);steriods: increased risk of gastrointestinal ulceration/bleeding; muscle relaxants; vasodilators.

This is not an exhaustive list: further information should be checked using the relevant information sources for any proposed medication to be taken in conjunction with the NSAID.

Dr. S. A. Andreae-Jones MB BS
Patron of the Arachnoiditis Trust
July 2000.

NOTE: THIS IS AN EXCERPT FROM THE FULL ARTICLE ON NSAIDs : which is available from the Arachnoiditis Trust (contact e-mail arachnoiditis@cableinet.co.uk )

This is part of a series of articles about treatment of chronic non-malignant pain.

Others available include:

TREATING CHRONIC PAIN WITH OPIOID MEDICATION(EXCERPT: OPIOID MEDICATION)

TREATING NEUROPATHIC PAIN WITH ANTIDEPRESSANTS (EXCERPT: ANTIDEPRESSANTS)

ANTICONVULSANTS: THEIR USE TO TREAT NEUROPATHIC PAIN (EXCERPT: ANTICONVULSANTS)

BENZODIAZEPINES AS ADJUVANT MEDICATION AND OTHER SKELETAL MUSCLE RELAXANTS (EXCERPT: BENZODIAZEPINES; BACLOFEN AND OTHER SKELETAL MUSLCE RELAXANTS)

LOCAL ANAESTHETICS, KETAMINE AND OTHER NMDA RECEPTOR ANTAGONISTS (EXCERPT: LOCAL ANAESTHETICS)

MISCELLANEOUS ADJUVANT MEDICATION TO TREAT NEUROPATHIC PAIN(EXCERPTS: CLONIDINE AND OTHER ADJUVANTS; CAPSAICIN, CCK ANTAGONISTS ETC.)

NON-STEROIDAL ANTI-INFLAMMATORY DRUGS(EXCERPT: NSAIDs)