NON STEROIDAL ANTI-INFLAMMATORY DRUGS

A Physician Guideline.
by
drdoc on-line


"The weeping willow" by Monet

Weeping willow1.jpg (27051 bytes)willow.jpg (69323 bytes)The use of the bark from the Willow, utilized over centuries, for the relief of pain and inflammation was described in 1763 by Rev Edmond Stone, and was followed in 1860, with the synthesis of salicylic acid. Aspirin was discovered in 1898 as acetyl salicylic acid1. It was, ultimately, together with its associated compounds, to become the mainstay of therapy for inflammation and the principal pharmacological agents for the management of the rheumatic diseases. These non steroidal anti-inflammatory drugs (NSAIDs), now constitute perhaps the most frequently prescribed class of medications2.They are frequently misused and abused, and are available in multiple formats, including "over the counter " preparations. They can be classified into several groups, illustrated in Figure 1.:

nsa.gif (8082 bytes)

The main mechanism of action of NSAIDs was clarified by Sir John Vane3 in 1971. He noted the inhibition by aspirin, of prostaglandin synthesis.

It was noted that cells synthesized prostaglandins in response to tissue injury. Inhibition of these prostaglandins inhibited inflammation. Whilst the prostaglandin hypothesis is generally accepted as being the most important, we now know that the mechanisms are more complex4 and involve additional non-prostaglandin dependent pathways. In the prostaglandin mediated process, cyclooxygenase metabolises arachidonic acid to form prostaglandin endoperoxides, (Figure 2.). These include the prostaglandins, prostacycline and thromboxane.

nsb.gif (11345 bytes)

Blocking of the cyclooxygenase enzyme results in a reduction in the formation of prostaglandins. The prostaglandins in fact are both physiologically important and potentially pathologically harmful. PGE2 is the principal eicosanoid formed from arachidonic acid. It is a crucial mediator of inflammatory changes.5

With the usefulness of the NSAIDs, came a significant side effect profile, including in particular, gastrointestinal and renal problems.

The costs of the side effects are enormous 6,7. Such costs include not only the cost of therapy, but also the cost of treating induced gastroduodenal damage.

The appearance of symptoms and lesions vary as a function of the product itself, as well as the dose and duration of therapy.

It is estimated that prevalence of NSAID induced gastric or duodenal ulcers, varies between 14.6% and 43.9%8. Gabriel and Bombardier estimated the absolute risk of gastric ulceration to be approximately 20%9. The absolute risk for hospitalization for serious complications was between 0.2% and 4%. In a study looking at consecutive cases of patients hospitalized for life-threatening complications of peptic ulceration, 60% of these patients were taking non steroidal anti-inflammatories compared to 9.9% in a hospital controlled group. Mortality in NSAID users versus non-users was 43.3% versus 18.1%. 10

Studies have shown a multiplied coefficient of 1.36 to 3, to the cost of the NSAID medication, because of the costs of treating the adverse side effects of the drugs. This relates to the treatment of the secondary effects, and does not include indirect costs, such as loss of work.6,

Meta-analysis of risk of gastrointestinal complications of NSAIDs show risk of serious gastrointestinal events are three times greater in NSAID users. Risk is increased within the first three months of starting therapy.11
It is important to realize that NSAID induced gastropathy may be completely asymptomatic.12

There are several options to reduce the incidence of the complications of anti-inflammatory drugs:

 

Firstly: Effective adjunctive preventative therapy

Several studies have consistently shown the effectiveness of misoprostol for the prevention of NSAID induced, gastric and duodenal ulcer disease.13,14,15,16

It is reasonably confirmed that the use of misoprostol is cost effective, in that there is a clear reduction in the incidence of complications of peptic ulcer disease.

Antacids have not been shown to prevent NSAID related peptic ulcers.
At standard doses, ranitidine and other H2 antagonists have been shown to reduce duodenal ulceration, but have not been shown to prevent NSAID induced gastric ulcers. Famotidine at high dose, but not at normal dose, has been shown to have some efficacy in reduction of both duodenal and gastric ulceration 17.

There is some evidence that use of H2 antagonists or antacids with NSAIDs, may actually increase probability of a serious gastrointestinal event, possibly by giving a false sense of security through suppression of symptoms.18

Gastric acid proton pump inhibitors have shown effectiveness in the therapy of NSAID induced ulcers, but remain unproven in terms of primary prevention of NSAID induced gastric ulcers.19,20.

Secondly: Appropriate prescribing.

Fries et al showed with The Arthritis, Rheumatism and Ageing Medical Information System (ARAMIS) database, of over 17 000 patients in 37 centres in the US and Canada, that there is considerable morbidity and mortality from arthritis. They confirm, as have other researchers, that NSAIDs are not all the same but rather, have different toxicity profiles.21,22,23. They illustrated appropriately, that the disease modifying drugs (DMARDs), used in the therapy of inflammatory arthritis, have an acceptable side effect profile. They showed that the toxicity profile of these drugs used appropriately was of similar scale to the NSAIDs 24.

Therefore correct diagnosis and treatment of the underlying condition with DMARDs where appropriate, is essential.

Guidelines from the American College of Rheumatology, 25 regarding the treatment of osteoarthritis of the hip and the knee, have included recommendations for initial use of analgesics such as acetaminophen. Recommendation is made for conservative measures such as weight loss, exercise, aquatherapy, use of a cane where appropriate, and judicious use of corticosteroid injections where indicated. Thereafter it is recommended that appropriate NSAID therapy may be instituted. Misoprostol is recommended in particular for those at risk of peptic ulceration.

Risk factors for peptic ulceration have been elucidated by Fries et al. Those studies demonstrate greater risk with:
a. Persons aged 65 or older.
b. A history of previous gastrointestinal symptoms associated with NSAIDs.
c. Concomitant use of oral corticosteroids
d. High NSAID doses
e. A high disability index.

Thirdly: Prescribing the appropriate NSAID.

Whilst many NSAIDs are considered to have equivalent efficacy, there is now no doubt that NSAIDs have different side effect profiles 8,22.

The explosion of knowledge about the different cyclooxygenase enzymes has given us a more fundamental understanding of the actions and side effects of these drugs.

In the 1980’s Needleman showed that COX enzyme was increased in inflamed tissue and that COX was stimulated by interleukin-1 (IL-1) on cultured human dermal fibroblasts. They showed a dose-dependent response curve. This suggested IL-1 dependent transcriptional regulation. 26

In 1990 he demonstrated the induction of COX by endotoxin. An increase in COX was prevented by glucocorticoids. However it was noted that Dexamethasone did not affect baseline prostaglandin formation.

They therefore postulated a second COX enzyme. In 1991 the second COX isoform was cloned. This represented what is now known as COX-2. COX-1 is now known to be present in most tissues as the housekeeper enzyme. COX-2 is inducible by inflammation. It is not present at baseline, but increases in response to inflammation including arthritis. It has 60% homology with COX-1. Both have the same affinity to convert arachidonic acid to prostaglandin. COX-1 maintains normal gastric mucosa and influences kidney function. The inhibition of COX-1 is therefore undesirable. The inhibition of COX-2 on the other-hand is a desirable effect. (Figure 3)

nsc.gif (11462 bytes)

The concept of the COX-2 to COX-1 ratio provides us with a mechanism to assess the balance of inhibition of the inducible COX-2. Analysis of these ratios and side effects of the older conventional non-steroidal anti-inflammatories show that the lower the ratio, the lower the COX-1 inhibition, and the lower the overall side effect profile. In the guinea pig macrophage model of Engelhardt, Meloxicam had a ratio in the order of 0.33, diclofenac, 2.2 and piroxicam 33. (Figure 4.) 27.

These agents are not truly selective, as COX-1 inhibition does occur at therapeutic dose.

nsd.gif (8703 bytes)

Truly specific COX-2 inhibitors are NOW commercially available in some countries, with the approval and release of Celecoxib (Celebrex, Pfizer) and Valdecoxib (Pfizer) and Arcoxa (Etoricoxib) (MERCK) in some countries.

Rofecoxib (Vioxx Merck USA) was also approved by the Federal Drug Administration in the USA. However the drug was controversially withdrawn by MERCK as the drug appeared to increase risk of myocardial infarction in selected studies.

Development and trials of these true COX-2 inhibitors have been under way for several years. Results from these studies show a clear reduction or even absence of gastrointestinal side effects. Celecoxib for example, is 375 fold more selective for COX-2 compared to COX-1. It does not inhibit COX-1 at therapeutic doses in contrast to standard NSAIDs currently available. Studies show effective benefit with no gastrointestinal adverse effects compared to placebo. 28,29 Other COXIBs in development include etoricoxib - Arcoxa (Merck) and Lumiracoxib (Novartis)

These new agents are have changed our prescribing habits and perhaps, where available, should be our first choice of anti-inflammatory drug. However in the case of Cardiac risk factors, cardioprotection with low dose aspirin is required.

However, if a Coxib is not tolerated or not available, we can make certain recommendations:

  1. Appropriate diagnosis and treatment of the underlying condition, including DMARDs where appropriate.
  2. Appropriate conservative measures and patient education.
  3. Use of appropriate analgesics, but where required, a conventional NSAID, with a desirable COX-2 to COX-1 ratio, with or without an additional therapeutic agent such as misoprostol, in the absence of contraindication or side effect.

References

  1. Weissman G. Aspirin. Sci Am 1991; January:84-90
  2. Baum C, Kennedy DL, Forbes MB. Utilization of nonsteroidal anti-inflammatory drugs. Arthritis Rheum. 1985 28:686-92.
  3. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature New Biol 1971;231:232-5.
  4. Abramson SB, Weissmann G. The mechanisms of action of nonsteroidal anti-inflammatory drugs. Arthritis Rheum 32,1:1-9,1989
  5. Portanova J, Zhang Y, Anderson GD et al. Selective neutralization of prostaglandin E2 blocks inflammation, hyperalgesia and IL-6 production in vivo. J Exp Med. 1996;184:883-891.
  6. De Pouvourville G. The economic consequences of NSAID – induced gastropathy: the French context. Scand J Rheumatol 1992 (Suppl 96):49-53.
  7. Bloom BS. Risk and cost of gastrointestinal side effects associated with nonsteroidal anti-inflammatory drugs. Arch Inter Med 1989;149:1019-1022
  8. Geis GS, Stead H, Wallermark C-B, et al. Prevalence of mucosal lesions in the stomach and duodenum due to chronic use of NSAIDs in patients with rheumatoid arthritis or osteoarthritis and interim report on prevention by misoprostol of diclofenac associated lesions. J Rheumatol 1991; 18(Suppl 28):11-14.
  9. Gabriel SE, Bombardier C. NSAID induced ulcers. An emerging pandemic? J Rheumatol 1990;17:1-4
  10. Armstrong CP, Blower AL. Non steroidal anti-inflammatory drugs and life threatening complications of peptic ulceration. Gut 1987;28:527-532.
  11. Gabriel SE, Jaakkimanen L, Bombardier C. Risk for serious Gastrointestinal complications related to use of nonsteroidal anti-inflammatory drugs. A meta-analysis. Ann Intern Med1991;115:787-796
  12. Larkai EN, Smithe JL, Lidsky MD, Graham DY. Gastroduodenal mucosa and dyspeptic symptoms in arthritic patients during chronic nonsteroidal anti-inflammatory drug use. AmJ Gatroenterol, 1987;82:11,1153-8
  13. Graham DY, Agrawal NM, Roth SH. Prevention of NSAID induced Gastric ulcer with misoprostol. Multicentre double blind placebo-controlled trial. Lancet. 1988;2:1277-80.
  14. Silverstein FE, Graham DY, Senior JR et al. Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs. A Randomized, double blind, Placebo controlled trial. Ann Intern Med 1995;123:241-249
  15. Simon LS, Hatoum HT, Bittman RM, et al. Risk factors for serious nonsteroidal-induced gastrointestinal complications: Regression analysis of the MUCOSA trial. Fam Med 1996;28(3):204-210.
  16. McKenna F. Efficacy and Gastroduodenal safety of a fixed combination of diclofenac and misoprostol in the treatment of arthritis. Br J Rheumatol 1995:34(Suppl.1):11-18.
  17. Taha AS; Hudson N; Hawkey CJ et al. Famotidine for the prevention of gastric and duodenal ulcers caused by nonsteroidal antiinflammatory drugs. N Engl J Med, 1996 ; 334:22, 1435-9
  18. Singh G, Ramey DR, Morfeld D, et al. Gastrointestinal tract complications of nonsteroidal anti-inflammatory drug treatment in rheumatoid arthritis. A prospective observational cohort study. Arch Intern Med, 1996;156:1530-1536.
  19. Agrawal NM. Epidemiology and prevention of non-steroidal anti-inflammatory drug effects in the gastrointestinal tract. Br J Rheumatol 1995;34(suppl. 1):5-10
  20. Hawkey C, Karrasch J, Szczepanski L, et al. Omeprazole compared with misoprostol for ulcers associated with nonsteroidal antiinflammatory drugs. N Engl J Med 1988;388:727-34.
  21. Mitchell DM, Spitz PW, Young DY et al. Survival, prognosis and causes of death in Rheumatoid Arthritis. Arthritis Rheum 1986;29:706-714.
  22. Fries JF, Williams CA Bloch DA. The relative toxicity of non-steroidal anti-inflammatory drugs. Arthritis Rheum 1991;34:1353-1360
  23. Fries JF, Spitz PW, Williams CA et al. A toxicity index for comparison of side effects among different drugs. Arthritis Rheum 1990;33:121-130
  24. Fries JF, Williams CA, Ramey DR et al. The relative toxicity of disease modifying anti-rheumatic drugs (DMARDs). Arthritis Rheum 1993;36:297-306.
  25. Hochberg MC, Altman RD, Brandt KD, et al. Guidelines for the medical management of osteoarthritis. Arthritis Rheum;1995;38:1535-1546.
  26. Raz A, Wyche A, Siegel N, Needleman P. Regulation of fibroblast cyclooxygenase synthesis by interleukin-1. J Biol Chem. 1988;263:3022-3028
  27. Engelhardt G, Homma D, Schlegel K et al. Anti-inflammatory, analgesic, antipyretic and related properties of meloxicam, a new nonsteroidal anti-inflammatory agent with favourable gastrointestinal tolerance. Inflamm Research 1995,44:422 – 433
  28. Lipsky PE, Isakson PC. Outcome of specific COX-2 inhibition in rheumatoid arthritis. J Rheum 1997;(suppl 49)24:9-14.
  29. Lane NE. Pain Management in OA: The role of COX-2 inhibitors. J Rheum 1997;(suppl 49)24:20-24
  30. Internet resource : The Arthritis pages of drdoc on-line : http://www.arthritis.co.za

Original Article - copyright protected
March 1999
Revised
Jan 05

Dr David Gotlieb
MBChB FCP(SA)
Rheumatologist
Constantia Arthritis Clinic
Cape Town
South Africa
Internet:
drdoc on-line

Go to drdoc on-line homepage
Go to drdoc on-line NSAIDs
Go to cox-1 / cox-2 page
Go to arthrotec page
Go to misoprostol page
Go to meloxicam page
Go to drugs page
Celecoxib page
Rofecoxib page