Palliative Medicine Handbook
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Edition/Revision: 1.0
Validated 1 Aug 2001
NOTES ON PRESCRIBING » Pain

NSAIDs

Non-steroidal anti-inflammatory drugs (NSAIDs) are helpful in treating cancer pain[1,2] especially associated with inflammation e.g. bone metastases or soft tissue infiltration by cancer. They may also help in neuropathic pain associated with cancer.[3,4]

Prescribing an NSAID
  • Always consider whether an alternative method of analgesia is suitable, especially when risk factors are present.
  • Use NSAID with lower risk of GI toxicity e.g. diclofenac 50mg t.d.s.
  • Prescribe a gastro-protective drug prophylactically e.g. lansoprazole 15mg o.d. if at least one other risk factor present:
    • past history of peptic ulcer disease
    • co-administration of corticosteroids, anticoagulants or aspirin
    • advanced age - over 70 years (optional - use judgement)

 

Gastrointestinal toxicity
Lower Ibuprofen
Diclofenac
Naproxen
Higher Piroxicam
Indometacin
Ketorolac
Specific issues with prescribing NSAIDs
Problem Solution
Symptoms of dyspepsia, or has recently been treated for ulcer/dyspepsia Add PPI
If symptoms persist with PPI → increase PPI to treatment dose
If symptoms still persist change NSAID to a COX2 inhibitor
Symptomatic thrombocytopenia, or platelet count < 20 Use a COX2 inhibitor
Co-administering warfarin Ibuprofen, diclofenac and naproxen do not normally have a clinically significant interaction with warfarin.[5] INR should nevertheless be monitored carefully, for if GI bleeding does occur it may be severe.
Other NSAIDs, including the COX2 inhibitors, may potentiate the effect of warfarin.
Renal failure or poorly controlled cardiac failure There is no evidence that any NSAIDs such as sulindac,[6] or the COX2 inhibitors are safer in impaired renal function.[7-9] All should be avoided if possible, balancing the risks with benefit for the individual.
History of asthma or bronchospasm CSM data suggests COX2 inhibitor cross-reactivity to aspirin may be low,[10] but more studies are needed to estimate the safety in asthma/bronchospasm. All NSAIDs should be avoided if possible.
Taking low-dose aspirin as prophylaxis for MI or TIAs Most NSAIDs give a comparable effect on platelets to aspirin.[11] Unlike aspirin, NSAIDs' effect on platelet function is reversible, and waxes and wanes with blood levels of the drug. Therefore they may be less effective at prevention than aspirin (no trials have compared).
Aspirin should be continued in patients when starting an NSAID, unless prognosis is short and there are other risk factors for GI bleeding, or the burden of medication is too great for the patient.
Unable to swallow medication Ketorolac may be used by CSCI - see notes below. Naproxen and diclofenac have both been used by CSCI,[12-14] but do not mix well with other drugs, and probably carry a higher chance of site inflammation.
Suppositories may be used.

 

In all cases: consider whether use of an NSAID can be avoided.

Ketorolac

Ketorolac is a potent analgesic NSAID with relatively little anti-inflammatory action. It is licensed for post-operative short-term use only. In high doses of 60-90mg/24h there is a high risk of GI toxicity and licensed use is restricted to 48h. In one study with 60-120mg/day, 11% patients had a gastrointestinal bleed, despite being on misoprostol.[15] It has been used by CSCI for cancer pain of various kinds for longer periods when the benefit is seen to outweigh the risk. Lower doses of 30-40mg/day probably have a similar tolerability to other NSAIDs.[3,16-34]

Indications
  • severe cancer pain unresponsive to opioids and standard NSAID, especially bone pain:
    • ketorolac 60mg/24h CSCI
    • review after 48h and document clearly if ketorolac is to be continued; add PPI for prophylaxis e.g. lansoprazole 15mg o.d.
    • increase to maximum dose 90mg/24h if partially effective
    • reduce if possible to 30mg/24h
  • starting or continuing an NSAID in a patient who cannot take PO medication:
    • ketorolac 30mg/24h CSCI
    • convert to usual NSAID by oral route as soon as possible
Topical NSAIDs

Topical NSAIDs are more effective than placebo for musculo-skeletal pain.[35] They may be useful in selective cases of superficial inflammatory pain in patients who cannot take oral NSAIDs, e.g. chest wall tumour infiltration.

References

  1. Mercadante S, Casuccio A, Agnello A, et al. Analgesic effects of nonsteroidal anti-inflammatory drugs in cancer pain due to somatic or visceral mechanisms. (clinical trial) J Pain Symptom Manage 1999;17(5):351-6  [abstract]  [full text subs]  *
  2. Eisenberg E, Berkey CS, Carr DB, et al. Efficacy and safety of nonsteroidal antiinflammatory drugs for cancer pain: a meta-analysis. J Clin Oncol 1994;12(12):2756-65  [abstract]  [full text subs]  *
  3. Ripamonti C, Ticozzi C, Zecca E, et al. Continuous subcutaneous infusion of ketorolac in cancer neuropathic pain unresponsive to opioid and adjuvant drugs. A case report. Tumori 1996;82(4):413-5  [abstract]  *
  4. Dellemijn PL, Verbiest HB, van Vliet JJ, et al. Medical therapy of malignant nerve pain. A randomised double-blind explanatory trial with naproxen versus slow-release morphine. (clinical trial) Eur J Cancer 1994;30A(9):1244-50  [abstract]  *
  5. Stockley IH. Drug Interactions. 4th ed. London: Pharmaceutical Press, 1996
  6. Cook ME, Wallin JD, Thakur VD, et al. Comparative effects of nabumetone, sulindac, and ibuprofen on renal function. (clinical trial) J Rheumatol 1997;24(6):1137-44  [abstract]  *
  7. Swan SK, Rudy DW, Lasseter KC, et al. Effect of cyclooxygenase-2 inhibition on renal function in elderly persons receiving a low-salt diet. A randomized, controlled trial. (clinical trial) Ann Intern Med 2000;133(1):1-9  [abstract]  [full text subs]  *
  8. Rossat J, Maillard M, Nussberger J, et al. Renal effects of selective cyclooxygenase-2 inhibition in normotensive salt-depleted subjects. (clinical trial) Clin Pharmacol Ther 1999;66(1):76-84  [abstract]    *
  9. Whelton A, Schulman G, Wallemark C, et al. Effects of celecoxib and naproxen on renal function in the elderly. (clinical trial) Arch Intern Med 2000;160(10):1465-70  [abstract]  [FULL TEXT FREE]  *
  10. Palliative Care Formulary (on-line edition). 2005. Available from: www.palliativedrugs.com (accessed 3 Oct 2005)
  11. Cheng JC, Siegel LB, Katari B, et al. Nonsteroidal anti-inflammatory drugs and aspirin: a comparison of the antiplatelet effects. (clinical trial) Am J Ther 1997;4(2-3):62-5  [abstract]  [full text subs]  *
  12. Toscani F, et al. Sodium naproxen: continuous subcutaneous infusion in neoplastic pain control. Palliat Med 1989;3:207-11  *
  13. Toscani F. Sodium naproxen: continuous subcutaneous infusion in neoplastic pain control (letter). Palliat Med 1990;4:147  *
  14. Hall E. Subcutaneous diclofenac: an effective alternative? (comment) Palliat Med 1993;7(4):339-40  [more]  *
  15. Myers KG, Trotman IF. Use of ketorolac by continuous subcutaneous infusion for the control of cancer-related pain. (clinical trial) Postgrad Med J 1994;70(823):359-62  [abstract]  [FULL TEXT FREE]  *
  16. Blackwell N, Bangham L, Hughes M, et al. Subcutaneous ketorolac--a new development in pain control. (clinical trial) Palliat Med 1993;7(1):63-5  [abstract]  *
  17. Burns JW, Aitken HA, Bullingham RE, et al. Double-blind comparison of the morphine sparing effect of continuous and intermittent i.m. administration of ketorolac. (clinical trial) Br J Anaesth 1991;67(3):235-8  [abstract]  *
  18. Carretta A, Zannini P, Chiesa G, et al. Efficacy of ketorolac tromethamine and extrapleural intercostal nerve block on post-thoracotomy pain. A prospective, randomized study. (clinical trial) Int Surg 1996;81(3):224-8  [abstract]  *
  19. De Conno F, Zecca E, Martini C, et al. Tolerability of ketorolac administered via continuous subcutaneous infusion for cancer pain: a preliminary report. J Pain Symptom Manage 1994;9(2):119-21  [abstract]  *
  20. Duncan AR, Hardy JR, Davis CL. Subcutaneous ketorolac. (comment) Palliat Med 1995;9(1):77-8  [more]  *
  21. Gillis JC, Brogden RN. Ketorolac. A reappraisal of its pharmacodynamic and pharmacokinetic properties and therapeutic use in pain management. (review) Drugs 1997;53(1):139-88  [abstract]  [full text subs]  *
  22. Hughes A, Wilcock A, Corcoran R. Ketorolac: continuous subcutaneous infusion for cancer pain. (clinical trial) J Pain Symptom Manage 1997;13(6):315-6  [more]  [full text subs]  *
  23. Joishy SK, Walsh D. The opioid-sparing effects of intravenous ketorolac as an adjuvant analgesic in cancer pain: application in bone metastases and the opioid bowel syndrome. (clinical trial) J Pain Symptom Manage 1998;16(5):334-9  [abstract]  [full text subs]  *
  24. Kaynaroglu V, Agalar F. Efficacy of ketorolac tromethamine and extrapleural intercostal nerve block on post-thoracotomy pain. (comment) Int Surg 1997;82(3):322  [more]  *
  25. Lippmann M, Ginsburg R. Ketorolac for post-thoracotomy pain relief. (comment) Br J Anaesth 1994;73(2):281  [more]  *
  26. Middleton RK, Lyle JA, Berger DL. Ketorolac continuous infusion: a case report and review of the literature. (review) J Pain Symptom Manage 1996;12(3):190-4  [abstract]  [full text subs]  *
  27. Ribeiro S, Chandler S, Weinstein SM. Safety of chronic use of ketorolac tromethamine for cancer pain (Meeting abstract). Proc Annu Meet Am Soc Clin Oncol 1994;13  [abstract]  *
  28. Staquet MJ. A double-blind study with placebo control of intramuscular ketorolac tromethamine in the treatment of cancer pain. (clinical trial) J Clin Pharmacol 1989;29(11):1031-6  [abstract]  *
  29. Toscani F, Piva L, Corli O, et al. Ketorolac versus diclofenac sodium in cancer pain. (clinical trial) Arzneimittelforschung 1994;44(4):550-4  [abstract]  *
  30. Virdee H, et al. Is diamorphine/ketorolac stable? Pharm Pract 1997;February:82-83  *
  31. Yalçin S, Güllü I, Tekuzman G, et al. Ketorolac tromethamine in cancer pain. Acta Oncol 1997;36(2):231-2  [more]  *
  32. Reinhart DI. Minimising the adverse effects of ketorolac. (review) Drug Saf 2000;22(6):487-97  [abstract]  [full text subs]  *
  33. Resman-Targoff BH. Ketorolac: a parenteral nonsteroidal antiinflammatory drug. (review) DICP 1990;24(11):1098-104  [abstract]  *
  34. Litvak KM, McEvoy GK. Ketorolac, an injectable nonnarcotic analgesic. (review) Clin Pharm 1990;9(12):921-35  [abstract]  *
  35. Moore RA, Tramèr MR, Carroll D, et al. Quantitative systematic review of topically applied non-steroidal anti-inflammatory drugs. BMJ 1998;316(7128):333-8  [abstract]  [FULL TEXT FREE]  *
Edition/Revision: 1.0
Created 1 Aug 2001
Validated 1 Aug 2001 by Ian Back
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