Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in cancer, yet they are also responsible for many, often serious, adverse effects. This review examines the various mechanisms through which NSAIDs work. It looks at the experience built up in using NSAIDs in cancer pain in general, but then particularly examines whether the evidence available supports the claim often made that these drugs have a specific role in relief of pain from bony metastases. Criteria for choosing one NSAID over another, including adverse effect profiles, efficacy and tolerability, are considered, as are methods for improving the safe use of these drugs.
Gabriel SE, Fehring RATrends in the utilisation of non-steroidal anti-inflammatory drugs in the United States, 1986-1990. J Clin Epidemiol1992; 45: 1041-44.
2.
Day ROVariability in response to NSAIDs: what progress?Agents Actions Suppl 1993; 44: 3-6.
3.
Bateman DN, Kennedy JGNon-steroidal antiinflammatory drugs and elderly patients [Editorial]. Br Med J1995; 310: 817-18.
4.
World Health Organization.Cancer pain relief . Geneva: WHO, 1986: 18-20.
5.
Ventafridda V., Fochi C., de Conno D., Sganzerla E.Use of non-steroidal anti-inflammatory drugs in the treatment of pain in cancer. Br J Clin Pharmacol1980; 10: 343S-46S.
6.
Nuki G.Pain control and the use of non-steroidal analgesic anti-inflammatory drugs . Br Med Bull1990; 46: 262-78.
7.
Misoprostol for co-prescription with NSAIDs. Drug Ther Bull1990; 28(7): 25-26.
8.
Vane JRInhibition of prostaglandin synthesis is a mechanism of action for aspirin-like drugs. Nature1971; 231: 232-35.
9.
Abramson S.Therapy with and mechanisms of nonsteroidal anti-inflammatory drugs. Curr Opin Rheumatol1991; 3: 336-40.
10.
De Witt DL, Mead EA, Smith WLPGH synthase isoenzyme selectivity: the potential for safer nonsteroidal antiinflammatory drugs. Am J Med1993; 95 suppl 2A: 40S-44S.
11.
McCormack K. , Brune K.Dissociation between the anti-nociceptive and anti-inflammatory effects of non-steroidal anti-inflammatory drugs: a survey of their analgesic efficacy. Drugs1991; 41: 533-47.
12.
Malmberg AB , Yaksh TLAntinociceptive actions of spinal non-steroidal anti-inflammatory agents on the formalin test in the rat. J Pharmacol Exp Ther1991;263:136-46.
13.
Backonja M. , Arndt G., Gombar KA, Check B., Zimmermann M.Response of chronic neuropathic pain syndromes to ketamine: a preliminary study. Pain1994 ; 56: 51-57.
14.
Catania A., Arnold J., Macaluso A., Hiltz ME, Lipton JMInhibition of acute inflammation in the periphery by central action of salicylates . Proc Natl Acad Sci USA1991; 88: 8544-47.
15.
Malmberg AB , Yaksh TLHyperalgesia mediated by spinal glutamate or substance P receptor blocked by spinal cyclooxygenase inhibition. Science1992; 257: 1276-79.
Ferrer-Brechner T., Ganz P.Combination therapy with ibuprofen and methadone for chronic cancer pain. Am J Med1984; 77: 78-83.
18.
Martino G., Emanueli A., Mandelli V., Ventafridda V.A controlled study of the analgetic effect of two non-steroidal anti-inflammatory drugs in cancer pain. Arzneim Forsche1978 ; 28(II): 1657-59.
19.
Sunshine A. , Olson NZAnalgesic efficacy of ketoprofen in postpartum, general surgery, and chronic cancer pain. J Clin Pharmacol1988; 28: S47-S54.
20.
Stambaugh J. , Drew J.A double-blind parallel evaluation of the efficacy and safety of a single dose of ketoprofen in cancer pain. J Clin Pharmacol1988; 28: S34-S39.
21.
Stambaugh JE, Tejada F., Trundowski RJDouble-blind comparisons of zomepirac and oxycodone with APC in cancer pain . J Clin Pharmacol1980; 20: 261-70.
22.
Stambaugh JE, Sarajian C.Analgesic efficacy of zomepirac sodium in patients with pain due to cancer . J Clin Pharmacol1981; 21: 501-507.
23.
Ventafridda V. , Martino G., Mandelli V., Emanueli A.Indoprofen, a new analgesic and antiinflammatory drug in cancer pain. Clin Pharmacol Ther1974 ; 17: 284-89.
24.
Ventafridda V.Diflunisal in the treatment of cancer pain. In: Huskisson EC, Caldwell ADS eds. Diflusinal: new perspectives in analgesia . London: Royal Society of Medicine , 1979: 137-39.
25.
Staquet MJA double blind study with placebo control of intramuscular ketorolac tromethamine in the treatment of cancer pain. J Clin Pharmacol1989; 29: 1031-36.
26.
Max MB, Laska EMSingle dose analgesic comparisons. In: Max MB, Portenoy RK, Laska EM eds. The design of analgesic clinical trials. (Advances in pain research and therapy vol 18.)New York: Raven Press, 1991: 55-95.
27.
Weingart WA , Sorkness CA, Earhart RHAnalgesia with oral narcotics and added ibuprofen in cancer patients. Clin Pharm1985; 4: 53-58.
28.
Ventafridda V., De Conno F., Panerai AE, Maresca V., Monza GC, Ripamonti C.Non-steroidal anti-inflammatory drugs as the first step in cancer pain therapy: double-blind, within-patient study comparing nine drugs. J Int Med Res1990; 18: 21-29.
29.
Ventafridda V., Toscani F., Tamburini M. et al. Sodium naproxen versus sodium diclofenac in cancer pain control. Arzneim Forsche1990 ; 40: 1132-34.
30.
Tonachella R., Gallo Curcio C, Grossi E.Diclofenac sodium in cancer pain: a double blind within patients comparison with pentazocine. Curr Ther Res1985; 37: 1130-33.
31.
Minotti V., Patoia L., Roila F. et al. Double-blind evaluation of analgesic efficacy of orally administered diclofenac, nefopam and acetylsalicylic acid (ASA) plus codeine in chronic cancer pain. Pain1989; 36: 177-83.
32.
Saxena A., Andley M., Gnanasekaran N.Comparison of piroxicam and acetylsalicylic acid for pain in head and neck cancers: a double-blind study. Palliat Med1994; 8: 223-29.
33.
Gallucci M. , Toscani F., Mapelli A., Cantarelli A., Veca G., Scaricabarozzi I.Nimesulide in the treatment of advanced cancer pain: double-blind comparison with naproxen. Arzneim Forsche1992; 42(II): 1028-30.
34.
Toscani F., Barosi K., Scazzina M., Camerini S., Gallucci M.Sodium naproxen: continuous subcutaneous infusion in neoplastic pain control . Palliat Med1989; 3: 207-11.
35.
Hall E.Subcutaneous diclofenac: an effective alternative? [Letter]. Palliat Med1993; 7: 339-40.
36.
Blackwell N. , Bangham L., Hughes M., Melzack D., Trotman I.Subcutaneous ketorolac: a new development in pain control. Palliat Med1993; 7: 63-65.
37.
Myers KG, Trotman IFUse of ketorolac by subcutaneous infusion for the control of cancer-related pain. Postgrad Med J1994; 70: 359-62.
38.
Duncan A., Hardy JR, Davis CLSubcutaneous ketorolac [Letter]. Palliat Med1995; 9: 77-78.
39.
Rawlins M.Non-opioid analgesics. In: Doyle D, Hanks GW, Macdonald N eds. Oxford textbook of palliative medicine. Oxford : Oxford Medical Publications, 1993 : 186.
40.
Campa JA, Payne R.The management of intractable bone pain: a clinician's perspective. Semin Nucl Med1992; 22: 3-10.
41.
Payne R.Pharmacological management of bone pain in the cancer patient. Clin J Pain1989; 5 (suppl 2): S43-S50.
42.
Kaye P.A-Z of hospice and palliative medicine. Northampton: EPL Publications, 1992: 34.
43.
Regnard Cfb.A guide to symptom relief in advanced cancer, third edition. Manchester: Haigh and Hochland, 1992: 17.
44.
Twycross RG, Lack SATherapeutics in terminal cancer, second edition. Edinburgh: Churchill Livingstone , 1990: 18.
45.
Baines MJCancer pain. Postgrad Med J1984; 60: 852-57.
46.
Twycross RG , Fairfield S.Pain in far advanced cancer. Pain1982; 14: 303-10.
47.
Banning A., Sjogren P., Henriksen H.Pain causes in 200 patients referred to a multidisciplinary cancer pain clinic . Pain1991; 45: 45-48.
48.
Hanks GWPharmacological treatment of bone pain. Cancer Surv1988; 7: 87-101.
49.
Klein DC, Raisz LGProstaglandins: stimulation of bone resorption in tissue culture. Endocrinology1970 ;86:1436-40.
50.
Tashjian AH , Voelkel EF, Levin L., Goldhaber P.Evidence that the bone-resorbtion stimulating factor produced by mouse fibrosarcoma cells is prostaglandin E2. J Exp Med1972; 136: 1329-43.
51.
Powles TJ, Clark SA, Easty DM, Easty GC, Munro-Neville A.The inhibition by aspirin and indomethacin of osteolytic tumour deposits and hypercalcaemia in rats with Walker tumour, and its possible application to human breast cancer. Br J Cancer1973; 28: 316-21.
52.
Bennett A., McDonald AM, Simpson JS, Stamford IFBreast cancer, prostaglandins, and bone metastases. Lancet1975; i: 1218-20.
53.
Galasko Csb.Mechanisms of bone destruction in the development of skeletal metastases. Nature1976; 263: 507-508.
54.
Galasko Csb, Bennett A.Relationship of bone destruction in skeletal metastases to osteoclast activation and prostaglandins. Nature1976; 263: 508-10.
55.
Powles TJ, Dowsett M., Easty DM, Easty GC, Neville AMBreast cancer osteolysis, bone metastases, and anti-osteolytic effect of aspirin . Lancet1976; i: 608-10.
56.
Jenkins MV, Polanska N., Wills MRBone resorption by breast cancer tissue [Letter]. Lancet1976;i:1186-87.
57.
Powles TJ, Dady PJ, Williams J., Easty GC, Coombes RCUse of inhibitors of prostaglandin synthesis in patients with breast cancer . Adv Prostaglandin Thromboxane Res1980; 6: 511-16.
58.
Coombes RC, Munro-Neville A., Gazet J-C. et al. Agents affecting osteolysis in patients with breast cancer. Cancer Chemother Pharmacol1979; 3: 41-44.
59.
Bennett A., Berstock DA, Carroll MA, Stamford IF, Wilson AJBreast cancer, its recurrence, and patient survival in relation to tumour prostaglandins. Adv Prostaglandin Thromboxane Leukotriene Res1983;12:299-302.
60.
Bennett A.The role of biochemical mediators in peripheral nociception and bone pain . Cancer Surv1988; 7: 55-67.
61.
Ueda K., Saito A., Nakano H. et al. Cortical hyperostosis following long term administration of prostaglandin E1 in infants with cyanotic congenital heart disease . J Pediatr1980; 97: 834-36.
62.
Chenu C., Valentin-Opran A., Chavassieux P. et al. Insulin-like growth factor hormonal regulation by growth hormone and 1,25(OH)2D3 and activity on human osteoblast-like cells in short term cultures. Bone1990; 11: 81-86.
63.
Mundy GR, Luben RA, Raisz LG, Oppenheim JJ, Buell DNBone-resorbing activity in supernatants from lymphoid cell lines. N Engl J Med1974; 290: 867-71.
64.
Yoneda T., Mundy GRProstaglandins are necessary for osteoclast-activating factor production by activated peripheral blood leucocytes. JExp Med1979;149:279-83.
65.
Mundy GRMechanisms of osteolytic bone destruction. Bone1991; 12 suppl 1: S1-S6.
66.
Ross Garrett I.Bone destruction in cancer. Semin Oncol1993; 20 suppl 2: 4-9.
Wagner G.Frequency of pain in patients with cancer. Rec ResultsCancer Res1984; 89: 64-71.
69.
Front D., Schenck SO, Frankel A., Robinson E.Bone metastases and bone pain in breast cancer: are they closely associated ? JAMA1979; 242: 1747-48.
70.
McLain RF, Weinstein JNOrthopaedic surgery. In: Wall PD, Melzack R eds. Textbook of Pain, third edition. Edinburgh: Churchill Livingstone, 1994: 1095-12.
71.
Stoll BAIndomethacin in breast cancer [Letter]. Lancet1973; ii: 384.
72.
Brodie GNIndomethacin and bone pain [Letter]. Lancet1974; i: 1160.
73.
Pollen JJ, Schmidt JDBone pain in metastatic cancer of the prostate. Urology1979 ; 13: 129-34.
74.
Lomen PL, Samal BA, Lamborn KR, Sattler LP, Crampton SLFlurbiprofen for the treatment of bone pain in patients with metastatic breast cancer. Am J Med1986; 80: suppl 3A: 83-87.
75.
Levick S., Jacobs C., Loukas DF, Gordon DH, Meyskens FL, Uhm K.Naproxen sodium in the treatment of bone pain due to metastatic cancer. Pain1988; 35: 253-58.
76.
Johnson JR, Miller AJThe efficacy of choline magnesium trisalicylate (CMT) in the management of metastatic bone pain: a pilot study. Palliat Med1994; 8: 129-35.
77.
Willkens RFThe selection of a nonsteroidal antiinflammatory drug: is there a difference? J Rheumatol1992 ; 19 suppl 36: 9-12.
78.
Heller CA, Ingelfinger JA, Goldman P.Nonsteroidal antiinflammatory drugs and aspirin: analysing the scores. Pharmacotherapy1985; 5: 30-38.
79.
Ellis GA, Blake DRWhy are non-steroidal anti-inflammatory drugs so variable in their efficacy? A description of ion trapping. Ann Rheum Dis1993; 52: 241-43.
80.
Henry D., Dobson A., Turner C.Variability in the risk of major gastrointestinal complications from non-aspirin non-steroidal antiinflammatory drugs. Gastroenterology1993 ; 195: 1078-88.
81.
Hetherington JW, Philip NHDiclofenac sodium versus pethidine in acute renal colic. Br Med J1986; 292:237-38.
82.
Luggen ME, Gartside PS, Hess EVNonsteroidal anti-inflammatory drugs in rheumatoid arthritis: duration of use as a measure of relative value. J Rheumatol1989; 16: 1565-69.
83.
Wijnands M. , van Riel P., van't Hof M., Gribnau F., van de Putte L.Long term treatment with nonsteroidal anti-inflammatory drugs in rheumatoid arthritis: a prospective drug survival study. J Rheumatol1991; 18: 184-87.
84.
Loeb DS, Ahlquist DA, Talley NJManagement of gastroduodenopathy associated with use of nonsteroidal anti-inflammatory drugs. Mayo Clin Proc1992; 67: 354-64.
85.
Roth SH, Bennett RENon-steroidal antiinflammatory drug gastropathy: recognition and response . Arch Intern Med1987; 147: 2093-100.
86.
Duggan JM, Dobson AJ, Johnson H., Fahey P.Peptic ulcer and non-steroidal anti-inflammatory agents. Gut1986; 27: 929-33.
87.
McIntosh JH , Byth K., Piper DWEnvironmental factors in aetiology of chronic gastric ulcer: a case control study of exposure variables before the first symptoms. Gut1985; 26: 789-98.
88.
Bollini P., Rodriguez Lag, Gutthann SP, Walker AMThe impact of research quality and study design on epidemiological estimates of the effect of non-steroidal anti-inflammatory drugs on upper gastrointestinal tract disease. Arch Intern Med1992; 152:1289-95.
89.
Labelling revisions for NSAIDs. FDA Drug Bull1989; 19: 3-4.
90.
Laine L.Helicobacter pylori, gastric ulcer, and agents noxious to the gastric mucosa . Gastroenterol Clin North Am1993; 22: 117-25.
91.
Langman Mjs.The risk of NSAID-associated ulcer and its complications. Hosp Update1992; 18: 41-47.
92.
Dahl SLNabumetone: a 'non-acidic' nonsteroidal antiiflammatory drug. Ann Pharmacother1993; 27: 456-63.
93.
Friedel HA, Langtry HD, Buckley MMNabumetone: a reappraisal of its pharmacology and therapeutic use in rheumatic diseases. Drugs1993; 45:131-56.
94.
Roth SHNon-steroidal anti-inflammatory drugs: gastropathy, deaths and medical practice . Ann Intern Med1988; 109: 353-54.
95.
Ballinger A.Prevention of peptic ulceration in patients receiving NSAIDs. Br J Hosp Med1993; 49: 767-72.
96.
Bjarnson I. , Hayylar J., Macpherson AJ, Russell ASSide effects of nonsteroidal anti-inflammatory drugs on the small and large intestines in humans. Gastroenterology1993; 104: 1832-47.
Rabinovitz M., Van Thiel DH.Hepatotoxicity of nonsteroidal anti-inflammatory drugs. Am J Gastroenterol1992; 87: 1696-704.
100.
Prescott LFEffects of non-narcotic analgesics on the liver . Drugs1986; 32: (suppl 4): 129-47.
101.
Simon LSNonsteroidal anti-inflammatory drug toxicity. Curr Opin Rheumatol1993; 5: 265-75.
102.
Pope JE, Anderson JJ, Felson DTA meta-analysis of the effects of nonsteroidal anti-inflammatory drugs on blood pressure. Arch Intern Med1993; 153: 477-84.
103.
Kincaid-Smith P.Effects of non-narcotic analgesics on the kidney. Drugs1986; 32 (suppl 4): 109-28.
104.
Miescher PABlood dyscracias secondary to nonsteroidal anti-inflammatory drugs. Med Toxicol1986;1:57-70.
105.
Szczeklik A.Analgesics, allergy and asthma. Drugs1986; 32 (suppl 4): 148-63.
