Nonsteroidal anti-inflammatory drugs as adjuvant analgesics in cancer patients

Abstract

The role of nonsteroidal anti-inflammatory drugs (NSAIDs) is examined in the control of cancer pain with a particular focus on their use as adjuvants to opioids in advanced cancer pain. These agents have both a peripheral effect on inflammation and a role in attenuating central pain pathways. The possibility of obtaining the benefits of NSAIDs with fewer side-effects by using COX-2-specific agents is discussed. The gastrointestinal, renal, haemostatic, cognitive and hypersensitivity side-effects of NSAIDs are reviewed and their potential impact assessed. The evidence for the efficacy of NSAIDs as single agents for cancer pain is reviewed together with the nine papers which have reported the effects of NSAIDs as adjuvants to opioids in cancer pain. All of these papers reported positive results of NSAIDs, but, in the absence of any randomized, double-blind controlled trials, where NSAIDs were used as adjuvants on a long-term basis alongside optimal opioid use, definite conclusions cannot be reached. Guidelines for the safe use of NSAIDs are suggested. Finally, suggestions for future research are made.

Keywords

anti-inflammatory agents,nonsteroidal analgesics pain palliative care

Get full access to this article

View all access options for this article.

References

Pace V . Use of nonsteroidal anti-inflammatory drugs in cancer. Palliat Med 1995; 9: 273–286.

Ripamonti C , Bruera E . CNS adverse effects of opioids in cancer patients. Guidelines for treatment. CNS Drugs 1997; 8: 21–37.

Galer BS , Coyle N , Pasternak GW , Portenoy RK . Individual variability in the response to different opioids: report of five cases. Pain 1992; 49: 87–91.

Glare PA , Walsh TD , Pippenger CE . Normorphine, a neurotoxic metabolite? Lancet 1990; 335: 725–726.

Sjogren, P , Erikson J . Opioid toxicity. Current Opinions in Anesthesiology 1994; 7: 465–469.

Insel PA . Analgesic-antipyretic and antiinflammatory agents and drugs employed in the treatment of gout. In: Hardman JG , Limbird LE eds. Goodman and Gilman's the pharmacological basis of therapeutics, 9th edn. New York: McGraw-Hill, 1996: 617–657.

Cashman JN . The mechanisms of action of NSAIDs in analgesia. Drugs 1996; 52(suppl 5): 13–23.

McCormack K , Brune K . Dissociation between the antinociceptive and anti-inflammatory effects of the nonsteroidal anti-inflammatory drugs. A survey of their analgesic efficacy. Drugs 1991; 41: 533–547.

Yaksh TL , Dirig DM , Malmberg AB . Mechanism of action of non-steroidal anti-inflammatory drugs. Cancer Investigation 1998; 16: 509–527.

10.

Thomson SW , King AE , Woolf CJ . Activity dependent changes in rat ventral horn neurones in vitro; summation of prolonged afferent evoked post-synaptic depolarizations produced a D-2-amino-5-phosphonovaleric acid sensitive wind-up. Eur J Neurosci 1990; 2: 638–649.

11.

Choi DW , Visekul V . Opioids and non-opioid entantiomers selectively attenuate N-methyl-D-aspartate neurotoxicity on cortical neurons. Eur J Pharmacol 1988; 155: 27–35.

12.

Hay CH , Trevethick MA , Wheeldon A , Bowers JS , de Belleroche JS . The potential role of spinal cord cyclooxygenase-2 in the development of Freund's complete adjuvant-induced changes in hyperalgesia and allodynia. Neuroscience 1997; 78: 843–850.

13.

Boyce S , Chan CC , Gordon R , Li CS , Rodger IW , Webb JK , Rupniak NM , Hill RG . L-745,337: a selective inhibitor of cyclo-oxygenase-2 elicits antinociception but not gastric ulceration in rats. Neuropharmacology 1994; 33: 1609–1611.

14.

Beiche F , Scheuerer S , Brune K , Geisslinger G , Goppelt-Struebe M . Up-regulation of cyclooxygenase-2 mRNA in the rat spinal cord following peripheral inflammation. FEBS Lett 1996; 390: 165–169.

15.

Dirig DM , Konin GP , Isakson PC , Yaksh TL . Effect of spinal cyclooxygenase inhibitors in rats using the formalin test and in vitro prostaglandin E2 release. Eur J Pharmacol 1997; 331: 155–160.

16.

Wheeler-Aceto H , Porreca F , Cowan A . The rat paw formalin test: comparison of noxious agents. Pain 1990; 40: 229–238.

17.

Malmberg AB , Yaksh TL . Capsaicin-evoked prostaglandin E2 release in spinal cord slices: relative effect of cyclooxygenase inhibitors. Eur J Pharmacol 1994; 271: 293–299.

18.

Dick WC , Franchimont P , Veys E . Double-blind comparison of etodolac and piroxicam in the treatment of rheumatoid arthritis. Clinical Therapeutics 1993; 15: 148–159.

19.

Lonauer G , Tisscher JR , Lim HG , Bijlsma JW . Double-blind comparison of etodolac and diclofenac in patients with rheumatoid arthritis. Curr Med Res Opin 1993; 13: 70–77.

20.

Dore R , Ballard I , Constantine G , McDonald P . Efficacy and safety of etodolac and naproxen in patients with osteoarthritis of the knee: a double-blind, placebo-controlled study. Clin Therap 1995; 17: 656–666.

21.

Perpignano G , Bogliolo A , Puccetti L . Double-blind comparison of the efficacy and safety of etodolac SR 600 mg u.i.d. and of tenoxicam 20 mg u.i.d. in elderly patients with osteoarthritis of the hip and of the knee. Int J Clin Pharmacol Res 1994; 14: 203–216.

22.

Mehlisch DR , Hubbard RC , Isakson PC , Perkins M , Weaver M , Mills S . A single-blind, placebo controlled comparison of the analgesic efficacy of a highly selective inhibitor of COX-2 (SC58635) versus aspirin 650 mg in patients with post-surgical dental pain. Vancouver: International Association for the Study of Pain, 1996: 234.

23.

McMillan DC , O'Gorman P , Fearon KCH , McArdie CS . A pilot study of megestrol acetate and ibuprofen in the treatment of cachexia in gastrointestinal cancer. Br J Cancer 1997; 78: 788–790.

24.

Langman MJ , Weil J , Wainwright P et al. Risks of bleeding peptic ulcer associated with individual NSAIDs. Lancet 1994; 343: 1075–1078.

25.

Murray MD , Black PK , Kuzmik DD et al. Acute and chronic effects of nonsteroidal anti-inflammatory drugs on glomerular filtration rate in elderly patients. Am J Med Sci 1995; 310: 188–197.

26.

Porro GB , Montrone F , Pretillo M , Caruso I , Imbesi V . Gastroduodenal tolerability of nabumetone versus naproxen in the treatment of rheumatic patients. Am J Gastroenterol 1995; 90: 1485–1488.

27.

Cook ME , Wallin JD , Thakur VD et al. Comparative effects of nabumetone, sulindac and ibuprofen on renal function. J Rheumatol 1997; 24: 1137–1144.

28.

Bjarnason I , Hayllan J , MacPherson AJ , Russell AS . Side effects of non-steroidal anti-inflammatory drugs in the small and large intestine in humans. Gastroenterology 1993; 104: 1832–1847.

29.

Gabriel SE , Jaakkimainen L , Bombardier C . Risk for serious gastrointestinal complications related to use of nonsteroidal anti-inflammatory drugs: a meta-analysis. Ann Intern Med 1991; 115: 787–796.

30.

Valentini M , Cannizzaro R , Poletti M et al. Nonsteroidal anti-inflammatory drugs for cancer pain: comparison between misoprostol and ranitidine in prevention of upper gastro-intestinal damage. J Clin Oncol 1995; 12: 2637–2642.

31.

Hawkey CJ , Karrasch JA , Szczepanski L et al. Omeprazole compared to misoprostol for ulcers associated with non-steroidal anti-inflammatory drugs. N Engl J Med 1998; 338: 727–734.

32.

Chan FK , Sung JJ , Chung SC et al. Randomized trial of eradication of Helicobacter pylori before nonsteroidal anti-inflammatory drug therapy to prevent peptic ulcers. Lancet 1997; 350: 975–979.

33.

Westlund K . Mortality of peptic ulcer patients. Acta Med Scand Suppl 1963; 402: 1–110.

34.

Baillie P , Millar F , Morrison S , Pratt A . Gastric ulceration in tumor bearing rats. J National Cancer Inst 1967; 38: 939–946.

35.

Bonnevie O . Causes of death in duodenal and gastric ulcer. Gastroenterology 1977; 73: 1000–1004.

36.

Clive DM , Stoff JS . Renal syndromes associated with non-steroidal anti-inflammatory drugs. N Engl J Med 1984; 310: 563–572.

37.

Wong F , Massie D , Hsu P , Dudley E . The effect of misoprostol on indomethacin-induced renal dysfunction in well compensated cirrhosis. J Hepatol 1995; 23: 1–7.

38.

Bakris GL , Starke V , Heifets M , Polack D , Smith M , Leurgan S . Renal effects of oral prostaglandin supplementation after ibuprofen in diabetic subjects: a double-blind, placebo-controllled multicenter trial. J Am Soc Nephrol 1995; 5: 1684–1688.

39.

Bruera E , Pereira J . Neuropsychiatric toxicity of opioids. In: Jensen TS , Turner JA , Wiesenfeld-Hallen Z eds. Proceedings of the eighth world congress on pain, progress in pain research and management, Vol 8. Seattle, WA: IASP Press, 1997: 717–738.

40.

Potter JM , Reid DB , Shaw RJ , Hackett P , Hickman PE . Myoclonus associated with treatment with high doses of morphine: the role of suppplemental drugs. Br Med J 1989; 299: 150–153.

41.

Bruera E , Chadwick S , MacDonald N , Fox R , Hanson J . Study of cardiovascular autonomic insufficiency in advanced cancer patients. Cancer Treat Rep 1986; 70: 981–983.

42.

Forster HS . Naproxen reversal of nortriptylineinduced orthostatic hypotension. J Clin Psychiat 1989; 50: 356.

43.

Imaizumi T , Takeshita A , Ashihara T , Nakmura M , Tsuji S , Shibazati H . Increase in reflex vasoconstriction with indomethacin in patients with orthostatic hypotension and central nervous system involvement. Br Heart J 1984; 52: 581–584.

44.

Kochar MS , Itskovitz HD , Albers JW . Treatment of orthostatic hypotension with indomethacin. Am Heart J 1979; 98: 271.

45.

Hoppman, RA , Peden JG , Obert SK . Central nervous system side effects of nonsteroidal anti-inflammatory drugs. Arch Intern Med 1991; 151: 1309–1313.

46.

Holecher C . Prostaglandins play a role in memory consolidation in the chick. Eur J Pharmacol 1995; 294: 253–259.

47.

Goodwin JS , Regan M . Cognitive dysfunction associated with naproxen and ibuprofen in the elderly. Arthritis and Rheumatism 1982; 25: 1013–1015.

48.

Wysenbeek AJ , Klein Z , Nakar S , Mane R . Assessment of cognitive function in elderly patients treated with naproxen: a prospective study. Clin Exp Rheumatol 1988; 6: 399–400.

49.

Bruce-Jones PN , Crome P , Kalra L . Indomethacin and cognitive function in healthy elderly volunteers. Br J Clin Pharmacol 1994; 38: 45–51.

50.

Pereira J , Hanson J , Bruera E . The frequency and clinical course of cognitive impairment in patients with terminal cancer. Cancer 1997; 79: 835–842.

51.

Lorenz J , Beck H , Bromm B . Cognitive performance, mood and experimental pain before and during morphine-induced analgesia in patients with chronic non-malignant pain. Pain 1997; 73: 369–375.

52.

Bruera E , Macmillan K , Hanson J , MacDonald RN . The cognitive effects of the administration of narcotic analgesics in patients with cancer pain. Pain 1989; 39: 13–16.

53.

Szczecklik A . Analgesics, allergy and asthma. Drugs 1986; 32: 148–163.

54.

Eisenberg E , Berkey CS , Carr DB , Mosteller F , Chalmers TC . Efficacy and safety of non-steroidal anti-inflammatory drugs for cancer pain: a meta-analysis. J Clin Oncol 1994; 12: 2756–2765.

55.

Pellegrini A , Massida B , Pellegrini P et al. Effect of IV indoprofen on cancer pain and serum prolactin and growth hormone levels. A controlled pharmacological study versus IM morphine and placebo. Int J Clin Pharmacol Ther Toxicol 1983; 21: 483–486.

56.

Stambaugh JE . Analgesic efficacy, safety and acceptibility of zomepirac sodium in comparison to morphine sulphate in the treatment of pain secondary to malignancy. Curr Ther Res 1982; 31: 922–929.

57.

Sunshine A , Olson NZ . Analgesic efficacy of ketoprofen in post partum, general surgery and chronic cancer pain. J Clin Pharmacol 1988; 28: S47–54.

58.

Coombes RC , Munro-Neville A , Gazet J-C et al. Agents affecting osteolysis in patients with breast cancer. Cancer Chemother Pharmacol 1979; 3: 41–44.

59.

Bennett A . The role of biochemical mediators in nociception and bone pain. Cancer Surv 1988; 7: 55–67.

60.

Stambaugh JE , Drew J . The combination of ibuprofen and oxycodone/acetaminophen in the management of chronic cancer pain. Clin Pharmacol Ther 1988; 44: 665–669.

61.

Levick S , Jacobs C , Loukas DF , Gordon DH , Meyskens FL , Uhm K . Naproxen sodium in the treatment of bone pain due to metastatic cancer. Pain 1988; 35: 253–258.

62.

Sachetti G , Camera P , Rossi AP . Injectable ketoprofen versus acetylsalicyclic acid for the relief of severe cancer pain: a double blind crossover trial. Drug Intell Clin Pharm 1984; 18: 403–406.

63.

Benahmed M , Wibault P , Court B , Kple Faget P , Ammarguellat H , Pichard E . [Efficacy of diclofenac continuous perfusion in hyperalgesic bone metastases. Apropos of 20 cases treated at Gustave Roussy Institute]. Bulletin du Cancer 1988; 75: 571–572.

64.

Ferrer-Brechner , Ganz P . Combination therapy with ibuprofen and methadone for chronic cancer pain. Am J Med 1984; suppl 78–83.

65.

Bjorkman R . Ullman A , Hedner J . Morphine-sparing effect of diclofenac in cancer pain. Eur J Clin Pharmacol 1993; 44: 1–5.

66.

Arunasalam S , Siegel RJ . Rapid resolution of symptomatic acute pericarditis with ketolcan tromethamine: a parenteral nonsteroidal anti-inflammatory agent. Am Heart J 1993; 125: 1455–1458.

67.

Morimoto S , Katch S , Inoue K , Terashima S , Tatsukawa H , Ida K . The efficacy of indomethacin in the treatment of uremic pericarditis. Jap J Nephrol 1995; 37: 140–144.

68.

Patwarhan RV , Heilpern RJ , Brewster AC , Darrah JJ . Pleuropericarditis: an extraintestinal complication of inflammatory bowel disease. Report of three cases and review of the literature. Arch Intern Med 1993; 143: 94–96.

69.

Lorell BH . Pericardial diseases. In: Braunwald E ed. Heart disease: a textbook of cardiovascular medicine. Philadelphia, PA: WB Saunders, 1997: 1478–1484.

70.

Dellemijn PL , Verviest HB , van Vliet JJ , Roos PJ , Vecht CJ . Medical therapy of malignant nerve pain. A randomized double-blind explanatory trial with naproxen versus slow-release morphine. Eur J Cancer 1994; 30A: 1244–1250.

71.

Max MB , Schafer SC , Culnane M , Dubner R , Gracely RH . Association of pain relief with drug side effects in post-herpetic neuralgia: a single dose study of clonidine, codeine, ibuprofen and placebo. Clin Pharmacol Therap 1988; 43: 363–371.

72.

Camp Herrero J , Artigas Roventos V , Milla Santos J , Allende Honorato L , Dominguez Granadas R , Mareno Carretoro E . The efficacy of inectable fluriprofen in the symptomatic treatment of biliary colic. Medicina Clinica 1992; 98: 212–214.

73.

Akrividis EA , Hatzigavriel M , Kapnias N , Kirimlidis J , Markantas A , Garyfallos A . Treatment of biliary colic with diclofenac: a randomized, double-blind, placebo controlled study. Gastroenterology 1997; 113: 225–231.

74.

Cordell WH , Larson TA , Lingeman JE , Nelson DR et al. Indomethacin suppositories versus intravenously titrated morphine for the treatment of ureteral colic. Ann Emerg Med 1994; 23: 262–269.

75.

Olsen UB , Magnussen MP , Eillertssen E . Prostaglandins, a link between renal hydro- and haemodynamics in dogs. Acta Physiol Scand 1976; 97: 364.

76.

Johnson JR . The efficacy of choline magnesium trisalicylate (CMT) in the management of metastatic bone pain: a pilot study. Palliat Med 1994; 8: 129–135.

77.

Myers KG , Trotman IF . Use of ketorolac by continuous subcutaneous infusion for the control of cancer-related pain. Postgrad Med J 1994; 70: 359–362.

78.

Blackwell N , Bangham L , Hughes M , Melzack D , Trotman I . Subcutaneous ketorolac – a new development in pain control. Palliat Med 1993; 7: 63–65.

79.

Mercadante S , Sapio M , Caligara M , Seretta, Dardanoni G , Barresi L . Opioid-sparing effect of diclofenac in cancer pain. J Pain Symptom Manage 1997; 14: 15–20.

80.

Weingart WA , Sorkness CA , Earhart RH . Analgesia with oral narcotics and added ibuprofen in cancer patients. Clin Pharmacol 1985; 4: 53–58.

81.

Lomen PL , Samai BA , Lamborn KR , Sattler LP , Crampton SL . Flurbiprofen for the treatment of bone pain in patients with metastatic breast cancer. Am J Med 1986; 80(suppl. 3A): 83–87.

82.

Bruera E , Macmillan K , Hanson J , MacDonald RN . The Edmonton staging system for cancer pain: preliminary report. Pain 1989; 37: 203–209.

83.

Folstein MF , Folstein S , McHugh PR . ‘Mini-mental state’: a practical method for grading the cognitive state of patients for the clinician. J Psych Res 1975; 12: 189–198.

84.

Watanabe S , Bruera E . Corticosteroids as adjuvant analgesics. J Pain Sympt Manage 1994; 9: 442–445.