Jay S. Cohen M.D.       http://medicationsense.com      1337 Camino Del Mar   Suite C       Del Mar, CA 92014       Phone: 858.345.1760       Fax: 858.509.8944


What Now for Users of Vioxx, Celebrex, and Bextra?

How to Use Anti-Inflammatory Drugs (NSAIDs) More Safely -- and Natural Alternatives That Work.

Vioxx is now history.  Bextra, another "COX-2 inhibitor" anti-inflammatory drug, is under suspicion after Pfizer issued a new warning on October 13, 2004.  Celebrex is the third and last COX-2 inhibitor that remains untarnished, but many experts and the FDA are wondering whether it too causes increased risks of heart attacks and strokes.

More than 10 million people were using a COX-2 anti-inflammatory drug on Sept. 30, 2004, when Merck announced Vioxx's withdrawal.  In 2003, Vioxx, Celebrex, and Bextra reaped more than $6 billion in sales, driven by $400 million in advertising targeting doctors and consumers.  Celebrex, the first COX-2 inhibitor, received one of the most aggressive launches and media buildups of any drug I've ever seen.  With claims that COX-2 anti-inflammatory drugs were safer than older NSAIDs such as Motrin, Voltaren, and Naprosyn -- claims that have still not convinced many experts -- COX-2 NSAIDs quickly became top-sellers.

I've had a problem with Celebrex and Bextra from the start.  These COX-2 NSAIDs are no more effective against pain than older NSAIDs.  And unlike Motrin, Voltaren, Naprosyn, and many other older NSAIDs that come in several sizes, Celebrex and Bextra are one-size-fits-all for osteoarthritis, the most common form of arthritis.  Osteoarthritis is the arthritis of injury or aging, and millions of older people require ongoing anti-inflammatory therapy.  With Bextra and Celebrex, your 90-year old grandmother with arthritic hands will receive the very same, super-strong dosage as Shaquille O'Neal will receive for his arthritic toe.

What should you do if you were taking Vioxx?  What should you do if you are taking Celebrex or Bextra?  Is there a safer way to use these two COX-2 NSAIDs?  Should you switch to an older NSAIDs?  Are there natural alternatives that work?  Here are some objective answers to these important questions.

What About Bextra?
From the day Bextra hit the market, I knew there would be problems, and it did not take long for them to surface.  Reports soon came in linking Bextra to severe, rare skin reactions that caused hospitalizations and deaths.  Bextra could also evoke reactions in people allergic to sulfa drugs.  In 2003, Public Citizen issued a safety alert about all NSAIDs including the COX-2 inhibitors:

"All members of the NSAID family of drugs can cause gastrointestinal toxicity that can lead to gastrointestinal bleeding and hospitalization or death.  The risk of gastrointestinal toxicity from these drugs increases with increasing doses and the length of treatment."1

Dosage is key: the risk of serious side effects can be minimized by using the lowest NSAID dosage required by each person.  In fact, the Celebrex package insert states: "For osteoarthritis and rheumatoid arthritis, the lowest dose of Celebrex should be sought for each patient."2  The same applies to all NSAIDs.  This is because stomach bleeding, kidney injury, skin eruptions, and most other NSAID side effects are dose-related: the lower the dose, the fewer the risks.  It is also important to individualize drug doses because people differ so greatly in their responses to medications.  According to the American Medical Association, the range of response to a drug can vary from one person to another by four to forty-fold.3  This is not surprising considering the differences in people's ages, sizes, absorption and metabolism of medications, other concomitant medical disorders and/or other medications, and innate sensitivities to medications.

Medical science supports using the lowest, safest, proven-effective doses of drugs, particularly NSAIDs, yet such individualization is not possible with one-size-fits-all Bextra.  Whether you are 25 or 95 years old, 100 or 300 pounds, your doctor will prescribe 10 mg of Bextra for your osteoarthritis.  This is not only bad medicine, but also defies published studies on Bextra:

In a large multicenter, randomized, double-blind, placebo-controlled study of people with moderate to severe osteoarthritis of the knee, 5 mg of Bextra was significantly superior to placebo over the 12-week study.4

In a multicenter, randomized, double-blind study of people with osteoarthritis of the hip, 5 mg of Bextra was significantly superior to placebo over 12 weeks of study.5

In a review article of ten large, well-controlled, randomized trials of Bextra, doses of 2.5 and 5 mg/day were significantly superior to placebo for osteoarthritis of the knee.  5 mg of Bextra was effective for osteoarthritis of the hip.6

Your doctor is unlikely to know any of this, because it isn't mentioned in the package insert or Physicians' Desk Reference.

What About Celebrex?
Celebrex suffers from many of the same problems as Bextra: it is contraindicated in people with sulfa sensitivities, and it is a super-strong one-size-fits-all drug for people with osteoarthritis.  How strong are Celebrex and Bextra?  Check their advertising in which Pfizer boasts about how strong these drugs are.  But more is not necessarily better with medications.  Extra-strength also means extra risks.

How strong are Celebrex and Bextra?  Both are equivalent in pain relief to the strongest dose of Naprosyn: 500 mg twice-daily.  But here's the problem.  In the 20 years I treated patients, I often prescribed Naprosyn (naproxen).  It comes in 3 sizes: 250, 375, and 500 mg, all taken twice-daily.  I always started people with 250 mg twice-daily, which was enough for most people.  Some people required the 375 mg dosage, and a few required the 500 mg dosage.  By approaching it this way, each person got the lowest dosage that worked for them.  In fact, some people got sufficient relief with over-the-counter Aleve, which contains 200 mg of naproxen.  In contrast, with Celebrex and Bextra, you get the equivalent of the strongest prescription dose of Naprosyn from the start.  It doesn't matter how old you are or how much you weigh or how many other medications you may be taking: you will still get maximum strength Celebrex or Bextra -- with maximum risks.  This is what Pfizer recommends, this is what doctors prescribe, this is what the FDA allows -- and this explains why we see so many problems with these drugs.

Pfizer's recommended dosage of Celebrex for osteoarthritis is 200 mg once daily (or 100 mg twice-daily).  Yet, lower doses of Celebrex work.  in a large study conducted by the Mayo Clinic of older people with severe osteoarthritis, 50 mg twice-daily of Celebrex provided significant pain relief in comparison to placebo on all efficacy measures.  Equally important, the lower dosage caused fewer side effects than higher Celebrex doses, and the lower dosage did not cause any renal toxicity.7

If 50 mg twice-daily of Celebrex is effective in people with severe osteoarthritis, would an even lower dose be effective for  people with mild arthritis?  Very likely.  My guess is that within a decade we will see low-dose Celebrex marketed as an over-the-counter remedy at 25 and 50 mg/day.  However, if these lower doses work, just like over-the-counter Motrin and Aleve do, why must we wait for more than a decade before having access to these effective, safer preparations?  Why must people with mild osteoarthritis receive the same super-strong doses of Celebrex and Bextra has people with severe osteoarthritis?

What about the Older NSAIDs: Motrin, Naprosyn, Voltaren, and Others?
Mainstream doctors are now debating the use of older NSAIDs instead of Bextra and Celebrex.  "These drugs have been heavily promoted as wonder drugs for arthritis and pain," Dr. Joel Hyatt, assistant medical director for the Southern California region of Kaiser Permanente, told the Los Angeles Times in regard to Vioxx, Celebrex, and Bextra.  "But they are really no more effective than Motrin or Naprosyn."8

For many people, he may be correct, yet we should not forget that the first generation of NSAID drugs caused major problems too.  In a 1999 analysis, NSAIDs accounted for more than 16,000 deaths and 100,000 hospitalizations each year.9  The PDR states: "Serious gastrointestinal toxicity such as bleeding, ulceration, and perforation, can occur at any time, with or without warning symptoms, in patients treated chronically with nonsteroidal anti-inflammatory drugs."2  These are also dose-related problems, and although you won't find the information in package inserts or the PDR, lower doses of Motrin, Naprosyn, and Voltaren work for many people.10

Some experts believe that taking an acid-suppressing drug like Prilosec (omeprazole) with an older NSAID reduces the risk of gastric bleeding.  However, other risks remain, include renal injury.  One advantage of older NSAIDs is that they usually come in multiple sizes, allowing for individualization of dosage.  Unlike Vioxx, Bextra, and possibly Celebrex, older NSAIDs are not associated with increased risks of heart attacks or strokes.  In fact, older NSAIDs may actually reduce these risks slightly.

At Special Risk: Women and Seniors
Celebrex and Bextra present special problems for women and seniors.  Plasma concentrations of Celebrex rise to much higher concentrations in older patients, especially older females, and adverse effects occur more frequently in this group.  This should have led Pfizer to market a lower dosage of Celebrex for seniors, but Pfizer didn't do so and the FDA didn't require it.  Subsequently, the FDA has received reports of fatal gastrointestinal events and acute renal failure in seniors taking Celebrex.2  Similarly, plasma concentrations of Bextra rise to significantly higher levels in seniors, yet they still get the same strong, one-size-fits-all dosage as young adults.  For more information on seniors, women, and other at-risk groups with NSAIDs, see the Sept.-Dec. 2003 MedicationSense newsletter article: "Seniors, Side Effects, and Celebrex: Does This Strong, One-Size-Fits-All Drug Put Seniors, Women, And Others At Unnecessary Risk?"

More than 75% of all medication side effects are dose-related.11  Just like with coffee and alcohol, most side effects are a function of the amounts taken, not of the drugs themselves.  Moreover, many other side effects are caused by drug interactions, many of which would not occur if people were taking the lowest effective dosages of their medications.  Again and again, medical science supports the principle of using the lowest, safest, proven-effective doses of medications.  The rub is that the methods of the drug industry and FDA are outdated, and the drug industry makes so much money, it is not about to initiate major changes.

Natural Alternatives
Most of my work pertains to medications: how to maximize the benefits of medications while minimizing their risks.  Over recent years, I have had the opportunity to research and try a variety of non-drug alternatives for a variety of medical conditions including pain and inflammation.  There are several natural alternatives that can provide anti-inflammatory effects, and there is considerable scientific evidence supporting their use.  In some cases, natural therapies have allowed people with arthritis to reduce or discontinue their prescription anti-inflammatory drugs.  These natural alternatives include: curcumin, glucosamine with chondroitin, borage oil (containing high doses of gamma linolenic acid), or high doses of omega-3 fish oils.

Final Considerations
There is no easy answer to the question "Which NSAID is safest?" because no NSAID provides an ideal ratio of effectiveness vs. risk.  All NSAIDs can cause gastrointestinal bleeding, kidney injury, and other side effects, and all can raise blood pressure and block the effects of some antihypertensive drugs.  Vioxx was withdrawn due to increased risks of heart attacks and strokes.  Now Bextra has been linked to the same.  Many experts suspect that Celebrex is no different, but this has not been proven yet.  Older NSAIDs were never considered particularly safe drugs, and this has not changed.  NSAIDs should not be taken in conjunction with aspirin.

Because all of the serious side effects of NSAIDs are dose-related, you can minimize your risk by using the very lowest, proven-effective dosage of any NSAID.  For Celebrex, this is 50 mg twice-daily or 100 mg once-daily.  For Bextra, this is 2.5 or 5 mg.  For Motrin, this is 200 mg every 4 to 6 hours.12-15  For Naprosyn, 200 or 250 mg twice-daily.16  For Voltaren, 25 mg twice or three-times-a-day.17-20

The older NSAIDs all come in lower doses.  Bextra is a tablet that can be split.  Celebrex comes in a 100 mg capsule.  If you require 50 mg twice-daily of Celebrex, some pharmacists will make this size for you for a fee.  Compounding pharmacies make individualized dosages: you can find a local compounding pharmacy via the Professional Compounding Centers of America (800-331-2498; 281-933-6948).

For people wanting to avoid problems altogether with NSAIDs, consider the natural alternatives I listed above.  In January 2005, I am going to make myself available one afternoon for in-person or telephone consultations for people seeking input about better methods with medications or alternatives that work.  I will issue more information about this in December, at which time interested people can contact us for scheduling.  In the meantime, there is a lot of good information on the Internet about the natural alternatives I listed above, and you may find everything you need.  Because doctors are so limited in time and in their sources of information, it is important for you to do your own research about medications.  This is the only way you will obtain the full range of information you need and deserve.  When you have obtained the information you need, share it with your doctor, with whom you should discuss any changes in your prescription drug regimen or doses.  If your doctor is not acquainted with the low-dose data presented in this article, take a copy to him and point out the studies listed in the reference section.  This is good evidence, and more and more doctors today are adherents of "evidence-based medicine," so good doctors should be very open to this information.

Referencesbr> 1.  Wolfe, SM.  New safety warning added to the arthritis drug valdecoxib (Bextra).  Worst Pills, Best Pills News, Jan. 2003;9:1-2.
2.  Physicians' Desk Reference, 58th Edition.  Montvale, N.J.: Medical Economics Company, 2004.
3.  American Medical Association.  AMA Drug Evaluations, Annual 1994.  Chicago: American Medical Association, 1994.
4.  Kivitz, A, Eisen, G, Zhao, WW, Bevirt, T, Recker, DP.  Randomized placebo-controlled trial comparing efficacy and safety of valdecoxib with naproxen in patients with osteoarthritis.  Journal of Family Practice 2002;51(6):530-7.
5.  Makarowski, W, Zhao, WW, Bevirt, T, Recker, DP.  Efficacy and safety of the COX-2 specific inhibitor valdecoxib in the management of osteoarthritis of the hip: a randomized, double-blind, placebo-controlled comparison with naproxen.  Osteoarthritis & Cartilage 2002;10(4):290-6. 
6.  Ormrod, D, Wellington, K, Wagstaff, AJ.  Valdecoxib.  Drugs 2002;62(14):2059-71.
7.  Bensen WG, Fiechtner JJ, McMillen JI, et al.  Treatment of osteoarthritis with celecoxib: a randomized controlled trial.  Mayo Clinic Proceedings 1999;74(11):1095?]105.
8.  Marsa, L.  What Now for Pain: with Vioxx off the Market, Consumers Face Tough Questions.  Los Angeles Times, Oct. 11, 2004:www.latimes.com.
9.  Wolfe, MM, Lichtenstein, DR, Singh, G.  Gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs.  New England Journal of Medicine 1999;340(24):1888?]99.
10.  Cohen, JS.  Over Dose: The Case Against The Drug Companies.  Prescription Drugs, Side Effects, and Your Health.  Tarcher/Putnam, New York: October 2001.
11.  Lazarou, J, Pomeranz, BH, Corey, PN. Incidence of adverse drug reactions in hospitalized patients: a meta?]analysis of prospective studies.  JAMA 1998;279(15):1200?]5.
12.  Chalmers, TM. Clinical experience with ibuprofen in the treatment of rheumatoid arthritis.  Annals of Rheumatic Diseases 1969;28:513-517.
13.  Brooks, CD, Schmid, FR, Biundo, J, et al.  Ibuprofen and aspirin in the treatment of rheumatoid arthritis; a cooperative double-blind trial.  Rheumatology and Physical Medicine 1970;10(suppl):48-63.
14.  Thompson M, Bell D.  Further experience with ibuprofen in the treatment of arthritis.  Rheumatology and Physical Medicine 1970;10(suppl):100-103.
15.  Hingorani, K. Double-blind crossover trial comparing ibuprofen with flufenamic acid in rheumatoid arthritis. Rheumatology and Physical Medicine 1970;10(suppl):76-82.
16.  Helzner, EC, Fricke, J, Cunningham, BG.  An evaluation of ibuprofen 200mg, ibuprofen 400mg and naproxen 200mg and 400mg in postoperative oral surgery pain.  Clinical Pharmacology and Therapeutics, 1992; 51(2):122.
17.  Durrigl, T, Vitaus, M, Pucar, I, Miko, M. Diclofenac sodium (Voltaren): Results of a multi-centre comparative trial in adult-onset rheumatoid arthritis.  Journal of International Medical Research 1975;3:139-144.
18.  Mutru O, Penttila M, Pesonen J, Salmela P, Suhonen O, Sonck T.  Diclofenac sodium (Voltaren) and indomethacin in the ambulatory treatment of rheumatoid arthritis: A double-blind multicentre study.  Scandinavian Journal of Rheumatology 1978;(suppl)22:51-56.
19.  Ciccolunghi, SN, Chaudri, HA, Schubiger, BI.  The value and results of long-term studies with diclofenac sodium (Voltarol).  Rheumatology and Rehabilitation 1979;(suppl2):100-115.
20.  Ciccolunghi, SN, Chaudri, HA, Schubiger, BI, Reddrop, R. Report on a long-term tolerability study of up to two years with diclofenac sodium (Voltaren).  Scandinavian Journal of Rheumatology 1978;(suppl)22:86-96.



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