Life without COX 2 inhibitors

Doctors need to broaden their approach to pain in older patients because cyclo-oxygenase-2 inhibitors have the potential to affect the heart, argue Allen F Shaughnessy and Andrea E Gordon

Several cyclo-oxygenase-2 inhibitors (COX 2 inhibitors) have been withdrawn from sale in many countries. The use of other drugs in this class is being limited by their potential to cause cardiac effects. As Kearney and colleagues show,^w1 this concern is valid, since they have been associated with an increased risk of myocardial infarction with prolonged use as compared with placebo or other non-steroidal anti-inflammatory drugs.^w2

Have we lost a truly superior option? Probably not. Although COX 2 inhibitors were marketed as being less likely to cause gastrointestinal distress and ulceration, there is good evidence that other pharmacological and non-drug options may be reasonably effective, equally safe, and less costly.

COX 2 inhibitors rose to market prominence on the basis of premarketing and postmarketing studies showing less ulceration, on endoscopy, of the gastrointestinal tract. However, ulceration is neither intrinsically harmful nor a surrogate marker for harm associated with use of non-steroidal anti-inflammatory drugs (NSAIDs).^w3

Gastroduodenal damage found on endoscopy in clinical studies does not lead in most patients to the serious adverse effects sometimes known as POBs—gastric Perforation, outlet Obstruction, and Bleeding.^w4 In addition, the presence of gastroduodenal ulcers is not related to symptoms of dyspepsia; many ulcers are asymptomatic, and patients with dyspepsia associated with drug treatment often do not have signs of mucosal damage. This distinction—between the disease-oriented outcome of ulceration and the patient-oriented outcome of symptoms and serious adverse effects—was shown in studies that found little or no difference in the incidence of adverse effects or dyspepsia symptoms in patients taking COX 2 inhibitors as compared with the older NSAIDs.^w5 The common assumption that COX 2 inhibitors are safer than other NSAIDs has not been borne out.^w6

If older people with pain need NSAIDs, misoprostol is effective at preventing the serious adverse effects (POBs) and should be offered as a co-treatment to patients at high risk.^w7 Diarrhoea is a relatively common side effect of misoprostol, but this might be less bothersome to older patients for whom constipation is the predominant bowel habit. Histamine-2 antagonists and proton pump inhibitors are not consistently effective at preventing serious adverse effects of treatment^w8 or symptomatic ulcers.w7 They should not be used routinely except by patients who develop peptic ulcer while receiving anti-inflammatory treatment. Topical NSAIDs such as diclofenac offer short term pain relief for knee osteoarthritis and their low absorption may limit their effect on the gastrointestinal tract.^w9

For many older patients, paracetamol offers an effective and safe treatment for general musculoskeletal pain, including osteoarthritis.^w10 Patients should always be offered paracetamol at sustained doses before resorting to other analgesics, owing to its relatively high safety margin except in overdose. (It should be limited to 4 g a day in adults, and less if the patient has liver disease or high alcohol intake.)

As a last pharmacological resort, opioids can be used. These are suboptimal for treating chronic problems, although concerns about addiction are largely unfounded. Dependence—experiencing withdrawal symptoms if drugs are withdrawn—can be expected, however. Fear of dependency and addiction is not sufficient justification to fail to relieve pain. Low potency opioids such as dextropropoxyphene and tramadol, however, offer little analgesic advantage over paracetamol.

Non-drug options are also effective in older people. Several small studies have shown that unloader braces (which reduce the pressure on the knee joint by pushing it into a valgus position) and therapeutic taping are effective in treating pain from osteoarthritis of the knee. Multiple systematic reviews, including a Cochrane review, have found exercise to reduce hip and knee pain while improving function, with benefit increased in those who continue the exercise regimen.^w11 Several dietary supplements have been studied to assess their potential to decrease pain in osteoarthritis.

Systematic reviews have found that glucosamine sulfate is superior to placebo in treatment of osteoarthritis pain,^w12 and a meta-analysis has shown S-adenosylmethionine (SAMe) to be as useful as NSAIDs in reducing pain and functional limitation in patients with osteoarthritis.^w13

Recent research has defined the role of several complementary and alternative approaches in treating pain in older people. Medical acupuncture has been documented useful for pain due to knee osteoarthritis though it has not been as effective for other painful problems.^w14 There is limited evidence of the efficacy of other, less well known therapies in painful arthritis of the knee. These include therapeutic touch (an energy modality), which showed benefit in a single blind randomised controlled trial,^w15 and electrical stimulation, which a Cochrane review of three studies found to have a small to moderate effect on outcomes.^w16 These modalities may be used in conjunction with more conventional approaches.

PHOTOS.COM

Rather than lamenting the loss of COX 2 inhibitors—an intervention that was more popular than proved—we will best serve our patients by thinking creatively about other approaches to their pain. Presenting a menu of possible treatments and working with patients to choose those that best suit their lifestyle and health beliefs is the optimal way to find solutions for their often chronic pain. Patients may not have to live with pain if they can live with the solutions that we explore with them.

1. Kearney PM, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ 2006;332:1302-8.
2. Kearney PM, Baigent C, Godwin J, Emberson JR, Patrono C. Do coxibs and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ 2006;332:1302-5.
3. Goldkind L. Medical officer’s gastroenterology advisory committee briefing document. Division of anti-inflammatory, analgesic and ophthalmologic drug products: HFP-550. 12 Jun 2000. www.fda.gov/ohrms/ dockets/ac/01/briefing/3677b1_05_gi.doc (accessed 22 Mar 2006).
4. Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs. N Engl J Med 1999;340:1988-99.
5. Shaughnessy AF. Right ballpark, wrong base: assessing safety of NSAIDs. J Fam Pract 2002;51:538.
6. Hrachovec JB, Mora M. Reporting of 6-month vs 12-month data in a clinical trial of celecoxib. JAMA 2001;286:2398.
7. Hooper L, Brown TJ, Elliott RA, Payne K, Roberts C, Symmons D. The effectiveness of five strategies for the prevention of gastrointestinal toxicity induced by non-steroidal anti-inflammatory drugs: systematic review. BMJ 2004;329:948-52.
8. Rostom A, Dube C, Wells G, Tugwell P, Welch V, Jolicoeur E, et al. Prevention of NSAID-induced gastroduodenal ulcers. Cochrane Database Syst Rev 2006;(1):CD002296.
9. Roth SH, Shainhouse JZ. Efficacy and safety of a topical diclofenac solution (Pennsaid) in the treatment of primary osteoarthritis of the knee: a randomized, double-blind, vehicle-controlled clinical trial. Arch Intern Med 2004;164:2017-23.
10. Towheed TE, Maxwell L, Judd MG, Catton M, Hochberg MC, Wells G. Acetaminophen for osteoarthritis. Cochrane Database Syst Rev 2006;(1):CD004257.
11. Fransen M, McConnell S, Bell M. Exercise for osteoarthritis of the hip or knee. Cochrane Database Syst Rev 2006;(1):CD004286.
12. Towheed TE, Maxwell L, Anastassiades TP, Shea B, Houpt J, Robinson V, et al. Glucosamine therapy for treating osteoarthritis. Cochrane Database Syst Rev 2006;(1):CD002946.
13. Soeken KL, Lee WL, Bausell RB, Agelli M, Berman BM. Safety and efficacy of S-adensylmethionine (SAMe) for osteoarthritis. J Fam Pract 2002;51:425-30.
14. Ezzo J, Hadhazy V, Birch S, Lao L, Kaplan G, Hochberg M, et al. Acupuncture for osteoarthritis of the knee: a systematic review. Arthritis Rheum 2001;44:819-25.
15. Gordon A, Merenstein JH, D’Amico F, Hudgens D. The effects of therapeutic touch on patients with osteoarthritis of the knee. J Fam Pract 1998;47:271-7.
16. Hulme JM, Judd MG, Robinson VA, Tugwell P, Wells G, de Bie RA. Electromagnetic fields for the treatment of osteoarthritis. Cochrane Database Syst Rev 2006;(1):CD003523.

       

           

	EDITORIALS Life without COX 2 inhibitors       Allen F Shaughnessy, Andrea E Gordon (July 2006)
	Yasmeen Khan (July 17th, 2006)       Fifth Year Medical Student,University of Birmingham Medical School yasmeen789@hotmail.com
	Your July 2006 Editorial "Life without COX-2 inhibitors" made excellent reading as it succinctly detailed the various approaches to pain management now that the reputation of this drug class has been tarnished (1). Vioxx - which was withdrawn in September 2004 for increasing the risk of heart attacks - is the most notorious drug within this therapeutic class and Merck - who manufactured Vioxx - faces greater than 10,000 lawsuits in the US (2). The impact of the scandal surrounding COX-2 inhibitors on pain management is minimal when one looks at the bigger picture. The Vioxx debacle will have a huge effect on the drug regulation landscape and, in turn, clinical practice. The US Food and Drug Administration (FDA) is expected to exhibit stricter drug approval standards following the scandal surrounding COX-2 inhibitors. This is because the FDA has been accused of not effectively evaluating the safety of Vioxx post licensing. What does this means for clinical practice? The expected outcome is that pioneering drugs will take longer to reach the market as approval will not be given without the presence of exceedingly detailed safety data. As a result patients who would have benefited from novel treatments may have to wait longer to gain access to potentially life-saving drugs. This is bad news for patients and doctors, especially considering that the number of ground-breaking medicines approved in recent years is already nowhere near the highs enjoyed last decade (3). Confidence in the pharmaceutical industry has been rocked. Both the public and physicians are now quite sceptical about the industry and its underlying objective. Which comes first: making money for shareholders or drugs for the sick. The view that profits come before people is widely held, and drug companies will have to work hard to regain the trust which has been lost. Patients must, obviously, not be exposed to unacceptable risks from drugs. We need to ensure medicines are not harmful to patients - after all, this is the first ethical principle that we, as doctors, learn. We, however, need to be mindful that ground-breaking drug development is not jeopardised due to the scandal surrounding COX-2 inhibitors. Holding back pioneering drug development will in the long run hurt the advancement of medical science and, consequently, patient care. This is especially true considering that with the arrival of the genomic revolution, we are on the brink of entering a period of great innovation in drug development. Shaughnessy AF, Gordon AE. Life without COX 2 inhibitors. studentBMJ 2006 July. Available at URL: http://www.studentbmj.com/issues/06/07/editorials/267.php (Accessed 15 July 2006) Merck Wins Vioxx Case in New Jersey. The New York Times 2006 July 14. Available at URL: http://www.nytimes.com (Accessed 15 July 2006) US Food and Drug Administration. CDER 2004 report to the nation: improving public health through human drugs. Rockville, MD (USA): US Food and Drug Administration 2005. Available at URL: http://www.fda.gov/cder/reports/rtn/2004/rtn2004.PDF (Accessed 15 July 2006)