NSAIDS in Palliative Care

Palliative Care Au

NSAIDS in Palliative Care
Prof Peter Brooks

Aboriginal Health

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Common Problems with Morphine Use

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Morphine in Nursing Homes

NSAIDS in Palliative Care

Antidepressants in Palliative Care

Bowel Obstruction in Palliative Care

Secondary Malignancy

Strontium 89

Strontium in Prostate Cancer

Terminal Restlessness

The non-steroidal anti-inflammatory drugs (NSAIDs) constitute one of the largest single group of drugs prescribed in Australia. They act primarily as inhibitors of prostaglandin synthase but also have a number of other activities including inhibition of neutrophil migration, mild immunosuppression, and interference with cell membrane function. As well as being useful in a wide range of inflammatory arthropathies, they may also be beneficial in other types of pain such as renal colic, bone pain due to cancer and in hypercalcaemia. Recent studies have also shown that NSAIDs may inhibit tumour growth and the ability of tumours to metastasise in animal models, and a recent paper has demonstrated that suldinac will reduce the rate of growth of colonic polyps in humans.

Mean (SD) Plasma Half-Lives of Different NSAIDS

Drug Half-life (hr)

Short half-life

Aspirin 0.25 0.03
Diclofenac 1.1 0.2
Flufenamic acid 1.4;9.0
Ibuprofen 2.1 0.3
Indomethacin 4.6 0.7
Ketoprofen 1.8 0.4
Tiaprofenic acid 3.0 0.2

Long half-life

Diflunisal 13 2
Naproxen 14 2
Phenylbutazone 68 25
Piroxicam 57 22
Salicylate 2 - 15
Suldinac (sulfide) 14 8
Tenoxicam 60 11

The non-steroidal anti-inflammatory drugs available in Australia, together with their dose range and plasma half-life, are shown in Table 1⁽¹⁾. Although the plasma half-life is often used to differentiate NSAIDs, even short half-life NSAIDs stay in tissues for considerably longer periods of time and hence may be given less frequently than determined by their plasma half-life. NSAIDs are produced in a number of different forms including oral (standard, enteric-coated and slow release), suppositories, parenteral preparations and recently available transcutaneous preparations. Transcutaneous preparations may be useful for localised areas of pain such as bony metastases. Certainly, in joint diseases significant concentrations are found within a synovial joint over which the transcutaneous NSAID has been applied.

The major problem with NSAIDs is their adverse drug reactions which often determine their acceptability by patients. Variability in response to NSAIDs, both in terms of efficacy and adverse effects, is a reality but cannot be explained simply in pharmaco-dynamic terms.

The major side effects of NSAIDs are shown in Table 2 ⁽²⁾. Skin rashes and abnormal liver function tests are usually mild and transient but renal and gastric adverse events can be more severe.

Non-steroidal anti-inflammatory drugs should be given very carefully to any patients with underlying renal dysfunction, and this is particularly important if the patient becomes dehydrated such as during an operative procedure. Hypercalcaemian is another situation where a person might be at risk from NSAID induced renal dysfunction.

Adverse Reactions to Non-steroidal Anti-inflammatory Drugs

Gastrointestinal

Peptic Ulceration
Oesophagitis and strictures
Small and large bowel erosive disease

Renal

Reversible acute renal failure
Fluid and electrolyte disturbance
Chronic renal failure and interstitial fibrosis
Interstitial nephritis
Nephrotic syndrome

Cardiovascular

Exacerbation of hypertension
Exacerbation of angina

Hepatic

Transaminitis
Fulminant hepatic failure (rare)

Central nervous system

Headache
Drowsiness
Confusion and behaviour disturbance
Aseptic meningitis

Haematological

Thrombocytopaenia
Haemolytic anaemia
Agranulocytosis and aplastic anaemia

Other

Exacerbate asthma and nasal polyposis
Skin rash

The whole of the gut might be affected by NSAIDs, whether it be reflux oesophagitis, gastric or duodenal ulceration or ulceration in the small or large intestines. The relative risk of developing a peptic ulcer when taking an NSAID varies from approximately 2-5 but is significantly greater in elderly women, particularly if they have co-morbidity such as renal dysfunction, heart failure, or a pervious history of peptic ulceration. Over the last 12 months several papers have suggested a hierarchy of NSAIDs in terms of adverse drug reactions, as shown by Table 3 ⁽³⁾ from Langman, et al 1994.

Relative Risk of Peptic Ulceration from NSAIDs.

Drugs Ratio 95% Confidence Interval

Ibuprofen 2.0 1.4 - 2.8
Diclofenac 4.2 2.6 - 5.8
Naproxen 9.1 5.5 - 15.1
Indomethacin 11.3 6.3 - 20.3
Piroxicam 13.7 9.1 - 25.3
Ketoprofen 23.7 7.5 - 74.2

Care should be taken in interpreting some of these data with wide confidence intervals but ibuprofen, diclofenac and naproxen were also noted as the NSAIDs least likely to be associated with GI toxicity by Rodriguez et al 1994. ⁴

There is good evidence to show that the dose of NSAID is related to gastric adverse events and thus the dose should be kept to a minimum. In patients who have a previous history of gastric ulceration or who develop a GI side effect while taking an NSAID, the following steps should be carried out:

Ask, does the patient need the NSAID?
If yes, then change the NSAID or lower the dose or add an H2 blocker (for gastric ulceration).
If duodenal ulceration is found, then misoprostil may be used. This has the common dose related adverse event of diarrhoea (which may be useful in patients on opioids).
Reflux oesophagitis may be alleviated by a change of NSAID, co-prescribing metoclopramide (Maxolon) or using cisapride (Prepulsid) or a proton pump inhibitor such as omeprazole (Losec).

The variability in response to NSAIDs is a very real thing but it should only take about a week to see if a patient is going to respond or not. If they do not, then change the NSAID, starting with the maximum tolerated dose. The dose of NSAID can sometimes be reduced by co-prescribing paracetamol plus or minus codeine.

Indomethacin is particularly useful for hypercalcaemia (not usually in the acute situation but for keeping the calcium down once it has been lowered). Cerebral adverse events such as a feeling of unreality, giddiness, etc. can occur with NSAIDs and, in particular, with indomethacin.

Used carefully, NSAIDs can be extremely beneficial in the management of pain whether it comes from a joint or from bone pain associated with neoplasia. With careful attention to dose and type of NSAID used, adverse events should be kept to a minimum and reasonable pain relief provided to patients.

References:

Brooks PM and Day RO. New England J Med 1991;324:1716
Girgis L and Brooks PM. Drugs and Ageing 1994;4:101-102.
Langman MJ et al. Lancet 1994;343:1075-1078.
Garcia Rodriguez IA, Jick K. Risk of upper gastrointestinal bleeding and perforation associated with individual NSAIDS. Lancet 1994;343:769-772.

Professor Peter Brooks
St Vincent's Hospital
University of New South Wales
Presented at the Education Meeting of May 25, 1994

Discussion

NSAIDS in Palliative Care

bill mcgrady, mcgradyw@bigplanet.com
Posted 24/2/99 8:21 PM

I am trying to design an experiment in fibroblasts cells. How can I arrive at an accurate dose rate in culture cells using NSAID's? I am going to compare COX1 and COX2 levels using different NSAIDS. Thank you for your time and effort.

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