GUIDELINES FOR THE USE OF NON- STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS) IN PALLIATIVE CARE
2 9.1 GENERAL PRINCIPLES
Non-steroidal anti-inflammatory drugs (NSAIDs) consist of a heterogenous group 1 of compounds that can be subdivided by virtue of their pharmacology:
− Non-selective NSAIDs inhibit both COX-1 and COX-2 receptors e.g. ibuprofen, naproxen.
− COX-2 selective NSAIDs display some selectivity for COX-2 receptors but this diminishes as the dose increases e.g. etodolac, meloxicam.
− COX-2 inhibitors specifically inhibit COX-2 receptors at therapeutic doses whilst being COX-1 sparing e.g. celecoxib, etoricoxib. All NSAIDs have significant cardiovascular and gastrointestinal toxicity. 2
Consider whether alternative treatment would be appropriate (e.g. topical NSAIDs, paracetamol, tramadol). 1 3 Prescribe the lowest effective dose of NSAID for the shortest time necessary.
29.2 GUIDELINES
29.2.1 Cardiovascular risk and NSAID prescribing
COX-2 inhibitors are contraindicated for use in patients with established ischaemic heart disease and / or cerebrovascular disease, and also in patients with peripheral arterial disease. 4 [Level 1]
Despite conflicting evidence, non-selective NSAIDs and COX-2 selective NSAIDs are currently licensed for use in these groups of patients, although they should be used with caution. 1 [Level 4]
29.2.2 Renal dysfunction and NSAID prescribing
Renal function should be assessed prior to the introduction of a NSAID and within 7 days of starting treatment or increasing the dose. 5, 6 [Level 4]
Care is required when prescribing NSAIDs for patients with heart failure, ascites or impaired renal function, particularly those who are dehydrated or have a low effective circulating volume. 5, 6 [Level 4] Long term administration of NSAIDs has been linked to papillary necrosis and other renal injuries. Patients with impaired renal function, heart failure, liver dysfunction, the elderly and those taking diuretics and / or angiotensin-converting enzyme inhibitors are at greatest risk from this rea ctio n . Discontinuation of NSAID therapy is usually followed by recovery to the pre-treatment state. 7 [Level 4] Use of NSAIDs in patients with advanced renal disease is not recommended due to a lack of safety data from controlled clinical studies. If NSAIDs are prescribed it is essential that renal function is monitored closely. 5, 6 [Level 4]
29.2.3 Gastrointestinal toxicity
8, Patients at high risk of gastrointestinal side effects from NSAIDs include the following: 9 [Level 4]
− Elderly (age >65 years). The risk increases with age.
− Previous upper gastroduodenal perforation, ulcers and bleeds.
− Concurrent use of aspirin, warfarin, corticosteroids or selective serotonin reuptake inhibitors (SSRIs).
− Patients receiving maximum doses of NSAIDs.
Undesirable gastric side effects from celecoxib are significantly less than from non- selective NSAIDs although it is not clear whether this lower risk continues with long term use. 10 [Level 4]
In patients taking clopidogrel, it is advisable to use an H2 antagonist at a higher dose than usual e.g. ranitidine 300mg bd. 19 [Level 4]
29.2.4 Proton Pump Inhibitors
A proton pump inhibitor (PPI) should be co-prescribed with a NSAID, regardless of which actual drug is chosen. 1 [Level 4] This is cost effective in the treatment of osteoarthritis, but the benefit of a PPI with a COX-2 inhibitor in other situations is unclear. 11 [Level 4]
The relationship between H. pylori infection and NSAIDs in gastroduodenal pathology is complex. Eradication of H. pylori infection may prevent peptic ulcer disease in patients who are naïve users of NSAIDs. Patients receiving long term PPI treatment for prevention of NSAID ulcers should be tested for H. pylori. Eradication of H. pylori will reduce the risk of accelerated loss of specialised glands and atrophic gastritis. 12 [Level 4] Appropriate proton pump inhibitors and oral doses include: 15 [Level 4]
− Esomeprazole 20mg od.
− Lansoprazole 30mg od.
− Omeprazole 20mg od.
− Pantoprazole 40mg od.
Misoprostol is a synthetic prostaglandin analogue with gastric anti-secretory and protective properties which can be used to protect against NSAID-induced gastrointestinal damage. It is more effective than PPIs but can be poorly tolerated. Side effects include colic and diarrhoea. A suggested starting dose is 200micrograms od, increasing by 200 micrograms every 1-2 days to a normal dose of 200micrgrams qds. 17, 18 [Level 1]
29.2.5 Choice of NSAID
Before deciding which NSAID t o u s e , the p r e s c r i b e r must first assess patient risk factors for cardiovascular and gastrointestinal toxicity (see Figure 29.1). 1, 2, 3 [Level 4]
Table 29.1 lists NSAIDs currently recommended for use; Table 29.2 lists additional NSAIDs that may be considered second line options. 1 [Level 4]
29.2.6 Monitoring Effectiveness
NSAIDs should be prescribed for at least 7 days before reviewing their clinical effectiveness. The analgesic effect of the drug becomes apparent within the first few days of treatment. The anti-inflammatory response may take at least 2 weeks to become evident. 8 [Level 4]
It may be appropriate to use an alternative NSAID before concluding that NSAIDs are ineffective. 8 [Level 4]
Due to the increased risk of renal and gastroduodenal toxicity, ketorolac should only be used for refractory pain (see Table 29.2). A PPI should always be co-prescribed with ketorolac unless the patient is in the dying phase. 8 [Level 4]
29.3 STANDARDS
1. COX-2 inhibitors are contra-indicated for use in patients with existing ischaemic heart disease, peripheral vascular disease or cerebrovascular disease. 4, 13 [Grade B]
2. In patients with existing cardiovascular disease, alternative analgesia should be considered before introducing a non-selective NSAID or a COX-2 selective NSAID (e.g. paracetamol, tramadol, topical NSAID). If NSAIDs are to be used, the lowest dose possible should be prescribed and the patient should be reviewed within 7 days.3 [Grade D]
3. It may be appropriate to use an alternative NSAID before concluding that NSAIDs are ineffective. 8 [Grade D]
4. Patients with risk factors for gastrointestinal toxicity should be prescribed proton pump inhibitors or misoprostol for gastric protection. 1 4 , 1 7 , 18 [Grade B ]
5. A PPI should be prescribed for all patients receiving subcutaneous NSAIDs, unless they are in the dying phase. 8 [Grade D]
6. Renal function should be assessed prior to the introduction of a NSAID and within 7 days of starting treatment or increasing the dose. 5, 6 [Grade D]
Table 29.1 NSAIDs currently recommended for use 1, [Level 4]
Class of Name of drug Oral dose CSCI over Additional notes NSAID 24 hours Non selective Naproxen 500mg bd n/a Suitable 1st line choice, together with PPI for patients with CV risk.
Ibuprofen 400mg-800mg n/a Low dose ibuprofen (≤1200mg) suitable 1st tds line choice, together with PPI, for patients with CV risk. If low dose aspirin is co- prescribed, ibuprofen should be given at least 8 hours before or 30 minutes afterwards. Alternatively, change aspirin to clopidogrel.1 COX-2 inhibitor Celecoxib 100mg-200mg n/a Suitable 1st line choice in patients at high bd risk of GI toxicity and low CV risk. PPI should be co-prescribed in high GI risk patients.
Table 29.2 Additional NSAIDs available for use 1, 8 [Level 4]
Class of Name of drug Oral dose CSCI over Additional notes NSAID 24 hours
Diclofenac 50mg tds Painful. Dose 150mg daily via rectal route. Diclofenac sodium 75mg m/r bd 150mg daily is associated with similar thrombotic risk to COX-2 inhibitors.
Nabumetone 500mg od-1g bd n/a Lowest GI risk of all non-selective NSAIDs. Some units may use first line.
Non Ketorolac n/a 30mg-90mg Can give 10mg stat subcutaneous dose. selective Carries greater risk of renal and gastrointestinal toxicity compared to other NSAIDs. Due to the propensity for toxicity, the continued need for a CSCI of ketorolac should be reviewed on a weekly basis.
Piroxicam melt 20mg od Increased risk of GI toxicity and serious (sublingual) skin reactions. Not to be used for first line treatment. COX- 2 Etodolac 600mg m/r od selective
COX-2 Etoricoxib 60mg-120mg od NICE do not recommend etoricoxib for inhibitor first line use in osteoarthritis. For this reason, consider as 2nd line choice.
Figure 29.1 – Flow Diagram of NSAID Choice 15 [Level 1]
Consider whether alternative treatment would be appropriate
Assessment of cardiovascular (CV) history
No CV History CV History
Assessment of Assessment of gastrointestinal (GI) gastrointestinal (GI) risk factors risk factors
Low GI risk ≥1 GI risk Low GI risk ≥1 GI risk
See LIST A See LIST B See LIST C See LIST D
Table 29.3 Choice of NSAID available, according to cardiovascular history and gastrointestinal risk factors. 15 [Level 4]
Step LIST A LIST B LIST C LIST D
No CV history No CV history CV history CV history
No GI risk GI risk No GI risk GI risk
1 Alternative analgesia Alternative analgesia Alternative analgesia Alternative analgesia
e.g. topical NSAID, e.g. topical NSAID, e.g. topical NSAID, e.g. topical NSAID, paracetamol, tramadol. paracetamol, tramadol. paracetamol, tramadol. paracetamol, tramadol.
2 Low dose ibuprofen COX-2 Inhibitor Low dose ibuprofen Low dose ibuprofen (≤1200mg/day) + PPI (≤1200mg/day) + PPI (≤1200mg/day) + PPI e.g. celecoxib + PPI. or nabumetone plus or naproxen or naproxen PPI +PPI +PPI
3 Non-selective COX-2 Inhibitor Non selective Non selective
NSAID e.g. etoricoxib + PPI. NSAID NSAID
e.g. diclofenac + PPI or e.g. nabumetone + PPI e.g. nabumetone +PPI naproxen +PPI
4 COX-2 selective Low dose ibuprofen (<1200mg/day) + PPI NSAID or nabumetone plus e.g. etodolac + PPI PPI
5 COX-2 inhibitor COX-2 selective NSAID
e.g. celecoxib e.g. etodolac + PPI
Note: Misoprostol can be considered as an alternative to a PPI
29.4 REFERENCES
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10. Juni P, Sterchi R, Dieppe P. Systematic review of celecoxib for osteoarthritis and rheumatoid arthritis. Problems compromise review's validity. Br Med J 2003; 326(7384): 334.
11. Chan FK, Wong VW, Suen BY, Wu JC, Ching JY, Hung LC et al. Combination of a cyclo- oxygenase-2 inhibitor and a proton-pump inhibitor for prevention of recurrent ulcer bleeding in patients at very high risk: a double-blind, randomised trial. Lancet 2007; 369(9573): 1621- 1626.
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13. Medicines and Healthcare products Regulatory Agency (MHRA). NSAIDs and coxibs: balancing of cardiovascular and gastrointestinal risks. Drug Safety Update 2007; 1(5): 13. Available from: http://www.mhra.gov.uk/Publications/Safetyguidance/DrugSafetyUpdate/CON2033216. [Last accessed 30 June 2009]
14. National Institute for Health and Clinical Excellence. Osteoarthritis: the care and management of osteoarthritis in adults. NICE clinical guideline 59. February 2008. Available from: www.nice.org.uk/guidance/index.jsp?action=byID&o=11926. [Last accessed 1 May 2009]
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16. Merseyside and Cheshire Palliative Care Network Audit Group. Use of NSAIDs in Palliative Care. Expert Consensus. December 2007.
17. Silverstien FE, Graham DY, Senior JR, Davies HW, Struthers BJ, Bittman RM et al. Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving non-steroidal anti-inflammatory drugs. A randomised double-blind, placebo-controlled trial. Ann Intern Med 1995; 123(4): 241-249.
18. Graham DY, Agrawal NM, Campbell DR, Haber MM, Collis C, Lukasik NL et al. Ulcer prevention in long-term users of non-steroidal anti-inflammatory drugs: results of a double- blind, randomised, multi-centre, active and placebo-controlled study of misoprostol vs lansoprazole. Arch Intern Med 2002; 162(2): 169-175.
19. Ho PM, Maddox TM, Wang L, Fihn SD, Jesse RL, Peterson ED et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA 2009; 301(9): 937-944
29.5 CONTRIBUTORS
Lead Contributors External Reviewer
Mr A Dickman Dr V Pace Specialist Principal Pharmacist Consultant in Palliative Medicine Marie Curie Palliative Care Institute St Christopher’s Hospice Liverpool London
Dr J Bellieu Specialist Registrar in Palliative Medicine Marie Curie Hospice Liverpool
Dr M Makin Chief of Staff ( Cancer Services) Consultant and Visiting Professor in Palliative Medicine Betsi Cadwaladr University Health Board and Glyndwr University Wales