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January 2005, Vol. 15, No. 1
Table of Contents
ACA's New CCGPP Guidelines • An Opinion of Shortcomings CBP® • ASHN: Chiropractic Enemy • CBP® fosters international Research Collaboration • CBP® Research Corner • Contraction/Expansion Mentally • COX Inhibitors and the FDA • Counter Point • Do You Practice CBP®? • Don's Opinion • European Spine Accepts CBP® Clinical Control Trial • Regarding the Use of Body Weighting • SAC Reaffirms Life University's Accreditation • Spine Accepts CBP® Research • The Diminishing Return Triangle • Traction Details • Validity of PosturePrint™
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COX Inhibitors and the FDA
by Daniel J. Murphy, DC, FACO
Vice President of ICA
Dan Murphy graduated magna cum laude from Western States Chiropractic College in 1978, and has more than 20 years of practice experience. He received Diplomat status in Chiropractic Orthopedics in 1986. Since 1982, Dr. Murphy has served part-time as undergraduate faculty at Life Chiropractic College West, currently teaching classes to seniors in the management of spinal disorders.
Dr. Murphy is on the post-graduate faculty of several chiropractic colleges. His post-graduate continuing education classes include “Whiplash and Spinal Trauma” and “Pain Neurology.” Dr. Murphy is the coordinator of a year-long certification program in “Chiropractic Spinal Trauma,” now (2000) in its twelfth year of being offered. This year, the program is being offered through the International Chiropractors Association of California. He has taught more than 700 post-graduate continuing education seminars.
Dr. Murphy is a contributing author to the book Motor Vehicle Collision Injuries, published by Aspen, 1996; and to the book Pediatric Chiropractic, published by Williams & Wilkins, 1998. He writes a quarterly column in the Journal of Clinical Chiropractic.
In 1987, 1991 and 1995 Dr. Murphy received the Post-graduate Educator of the Year award, given by the International Chiropractic Association. In 1997, he received The Carl S. Cleveland, Jr., Educator of the Year award, given by the International Chiropractic Association of California.
Eicosanoids are short-lived hormonal-like compounds that have powerful influences on physiology. All eicosanoids are derived from 20-carbon long fatty acids.
Prostaglandin E2 (PGE2) is a pro-inflammatory eicosanoid derived from the 20-carbon long omega-6 fatty acid arachidonic acid. PGE2 receives a lot of press because studies have linked it to:
Pain
Degenerative Joint Disease
Intervertebral Disc Herniation
Rheumatoid Arthritis and Other
Autoimmune Diseases
Asthma and Allergies
Immune System Dysfunction
Cardiovascular Disease
Cancer
Alzheimer’s Disease
Free Radical Production
Historically, PGE2 is most associated with increased pain. Recent estimates confirm that as many as 70 million Americans suffer from chronic daily pain.1
PGE2 is derived from arachidonic acid through the action of enzymes called cyclo-oxygenase, or cox.
Therefore, when dealing with pain, there are several options, including:
1) Reduce consumption of arachidonic acid (found abundantly in most animal food products). Most Americans are unwilling to take this option.
2) Reduce consumption of arachidonic acid precursors (corn oil, sunflower seed oil, safflower oil, cottonseed oil, peanut oil, etc.). This option is difficult because these oils are used abundantly in our commercially available foods.
3) Increase consumption of omega-3 fatty acids. Omega-3 fatty acids enzymatically compete with omega-6 conversion to PGE2. Increasing omega-3 fatty acids in the diet reduces the production of PGE2. This option is simple with the availability of omega-3 oil supplements.
4) Take drugs that inhibit the body’s production of cyclo-oxygenase (cox) enzymes. These drugs are referred to as non-steroidal anti-inflammatory drugs, or NSAIDs. Taking these NSAIDs has become the option of choice because taking drugs is simple. Cox inhibiting drugs are sold both over-the-counter and by prescription. People like this option because they can habitually eat cheap proinflammatory foods and suppress their deleterious effects by taking a pill. Food companies like this option because profits are higher when they fill our food with government subsidized cheap pro-inflammatory omega-6 derived foods (“How To Get Fat Without Really Trying”, ABC News, Peter Jennings, December 8, 2003). Drug companies like this option because they make tens of billions of dollars yearly selling cox inhibiting drugs to Americans.
However, there are some important problems associated with option #4. NSAIDs are associated with numerous side effects, especially when they are consumed on a regular basis.
Historically, NSAIDs (like aspirin and ibuprofen) inhibit both the cox-1 and cox-2 enzymes. This is unfortunate because cox-1 enzymes protect the lining of the gastrointestinal system.
As Giles and Muller2 note, “Gastrointestinal toxicity induced by NSAIDs is one of the most common serious adverse drug events in the industrialized world.” Studies suggest that over-the-counter NSAIDs will kill approximately 20,000 Americans per year from fatal gastrointestinal bleeds.3 Prescription NSAIDs will conservatively kill an additional 16,500 Americans per year from fatal gastrointestinal bleeds.4, 5 This totals 36,500 deaths per year from fatal gastrointestinal bleeds from NSAIDs.
In an effort to reduce fatal gastrointestinal bleeding and other gastrointestinal complications, drug companies proceeded to develop and patent drugs that only inhibited the cox-2 enzyme and not inhibit the cox-1 enzyme. Theoretically, this should provide pain relief without compromising the health of the gastrointestinal tract. These cox-2 inhibitors were approved by the FDA for consumer consumption in 1999. The brand names best known by consumers are Vioxx (from Merck), Celebrex (from Pfizer), and Bextra (from Pfizer). These cox-2 inhibitor drugs had about $6 billion in sales in 2004.6 These pain-relieving drugs are heavily promoted by direct to consumer advertising.7 In 2000, Merck spent $160 million in direct to consumer advertising of Vioxx. In comparison, that year Pepsi spent $125 million in advertising and Budweiser spent $146 million.7 Overall, drug marketing costs about $25 billion per year.7
By 2000, the FDA noted that the reduction in gastrointestinal bleeding was only about 1%, and so they informed the makers of these cox-2 inhibitors that they could not longer advertise reduced gastrointestinal complications as a benefit of taking these drugs. The FDA also noted at that time that these drugs should carry a warning regarding increased risk for cardiovascular events.8,9
On September 30, 2004, Merck stopped selling Vioxx because a study showed a significant increased risk of heart attacks and stroke by those taking the drug. Official estimates are that in just over 4 years of consumption, Vioxx resulted in as many as 139,000 heart attacks and strokes, and as many as 55,600 were fatal. It is important to emphasize that this is damage caused by one FDA approved drug in a period of less than 5 years. An article written in the British Medical Journal, titled “FDA is incapable of protecting US ‘against another Vioxx’ notes:10
“The approval of rofecoxib (Vioxx) by the US Food and Drug Administration has led to the ‘single greatest drug safety catastrophe in the history of this country or the history of the world,’ charged one of the agency’s own experts, Dr. David Graham, in US Senate hearings last Thursday.”
“Dr. Graham, associate director in the FDA’s Office of Drug Safety, said an estimated 88,000 to 139,000 Americans had heart attacks and strokes as a result of taking rofecoxib. The number, he said, far exceeds earlier disasters such as the 100 children killed in the United States by an elixir of sulfanilamide in the 1930s and the 5000 to 10,000 children born in the 1960s with birth defects related to thalidomide.”
“Senator Grassley charged that the FDA ‘has lost its way when it comes to making sure drugs are safe’ and that its relationship with drug companies was ‘too cosy’.”
Dr. Graham’s data was to be published in The Lancet “but was pulled at the last minute after Dr Graham had a warning from his FDA supervisor about the publication.”
“Dr. Gurkipal Singh, adjunct clinical professor of medicine at Stanford University, testified that as early as November 1996 Merck scientists ‘were seriously discussing a potential [heart attack] risk of Vioxx’.”
“Merck’s failure to undertake a study of cardiovascular outcomes was a ‘marketing decision’ designed to minimise the possibility of finding cardiovascular adverse events, said Dr Singh. He added: ‘It would be better to kill the drug than to kill the patient’.”
An editorial comment made in the British Medical Journal on November 27, 2004, notes:11
“Something is rotten at the heart of the FDA. The United States Food and Drug Administration, mired in controversy over the last 12 months, now faces an extraordinary charge of attempting to discredit a whistleblower. As this week’s issue reveals, David Graham, the FDA’s associate director of drug safety, was so bothered about the difficulties of presenting his data on rofecoxib (Vioxx) in the Lancet that he took his case to the Government Accountability Group, a public interest group that protects whistleblowers.”
“What was extraordinary was that an FDA manager then called the accountability group to rubbish Graham’s account and accuse him of scientific misconduct. In a quandary, the accountability group checked both sides of the story, and found that Graham’s version was perfectly credible, while the FDA agent’s version failed every test of credibility. It says something of the turmoil within the FDA that when Graham returned to work after giving his damning testimony at Senate hearings — he described the approval of [Vioxx] as the ‘single greatest drug safety catastrophe in the history of the world’ — he received a standing ovation from his colleagues.”
“His testimony raises serious questions about the ability of the FDA to fulfill its role as regulator.”
“The dangers of [Vioxx] were apparent eight years ago and not acted upon, the harms suppressed.”
The FDA is accused of being too close to the drug industry.
“When will [the FDA] show that their primary role is to protect the public and not to protect [the drug] industry?”
A news item in the British Medical Journal on December 4, 2004, notes:12
“The US Food and Drug Administration, rocked by controversy in recent months, has now admitted that a senior management official secretly contacted a whistleblower group. That official attempted to discredit Dr David Graham, the FDA’s scientist who criticised the agency during US Senate hearings, saying that the FDA failed to protect the public when it approved rofecoxib (Vioxx, Merck) — despite evidence suggesting that the drug caused heart attacks and strokes.”
Dr. Graham’s attorney, Tom Devine, “told the BMJ that Steven Galson, acting director of the FDA’s Center for Drug Evaluation and Research, ‘engaged in the extraordinary move of personally contacting the Lancet editor, Richard Horton, to block publication of the Vioxx study’.”
“Dr. Graham told the BMJ that when another drug safety officer, Dr Andrew Mosholder, concluded that selective serotonin reuptake inhibitor antidepressants caused increased suicidal tendency among teens, the FDA prevented him from presenting his findings at an advisory meeting and suppressed his report. When the report was leaked ‘the FDA’s reaction was to do a criminal investigation into the leak. I was named as one of the targets of the investigation along with Dr Mosholder’.”
“Dr. Graham said a culture of intimidation and fear permeates the [FDA], making it difficult for drug safety officers to protect the public.”
The FDA “continued to try to catch the leaker even after the inquiry showed that Dr. Mosholder’s findings were correct. It’s extraordinary. The FDA is in a class by itself for its almost obsessive intolerance of dissent. Other agencies fire their dissenters. The FDA launches criminal investigations.”
“‘The public is very vulnerable,’ said the officer, who called for provisional approvals of drugs with reviews two years after the release of a new drug.”
Then, on December 12, 2004, the cox-2 inhibiting drug Bextra, produced by Pfizer, added a warning on its label about cardiovascular and blood-clotting problems.13 In a letter to the editor of the New England Journal of Medicine (December 23, 2004),14 it is pointed out that 7 million patients are taking Bextra. The authors also point out the maker of Bextra, Pfizer, initially felt that it was unethical to test Bextra on patients with high risk of heart disease. The authors also pointed out that most of the people who have musculoskeletal reasons to take Bextra, also have baseline risk of cardiovascular events. Apparently, Pfizer felt it more ethical to not do appropriate testing and appropriate label warnings, while potentially risking the health and lives of thousands of patients. Most would consider such an approach illogical and driven by profit motive.
As noted above, PGE2 is also associated with cancer. Therefore, reducing the production of PGE2 potentially could also reduce incidences of certain types of cancer. Therefore, in an effort to expand market uses of the cox-2 drug Celebrex, Pfizer initiated a study of Celebrex for the prevention of colon cancer. The study was sponsored by the US National Cancer Institutes (a taxpayer funded group). The study was suppose to span 5 years, but was suspended in less than 3 years because those taking 400-800 mg of Celebrex per day had a 2.5-3.4 fold increase of major cardiovascular events compared with placebo.15
This means that all three cox-2 inhibitors that have been approved by the FDA since 1999 have been shown to be quite dangerous, and have subsequently been removed from the market, had serious warnings added to their labels, or are be investigated for sanctions.
Lastly, as noted above, PGE2 is also associated with Alzheimer’s Disease. Again, reducing the production of PGE2 potentially could reduce the incidence of Alzheimer’s Disease. Another NSAID that reduces the production of PGE2 is Naproxen (prescription Naprosyn, over-the-counter Aleve). Naprosyn has been on the market since 1976. Aleve has been on the market since 1994. On December 21, 2004, the National Institutes of Health (another taxpayer funded organization), announced that those taking Aleve in the Alzheimer’s risk study, also had significant increased risk of heart attack and stroke.16 The FDA, now quick to respond, advises “no more than 2 pills per day, and do not take it for longer than 10 days.16
In light of all of this information coming to light in the last 3 months, one wonders at the gall used by those who would caution against chiropractic spinal adjusting for fear of vascular accidents. The only numbers I found in these articles are from Dr. Graham on Vioxx: up to 139,000 heart attacks and strokes, with as many as 56,000 being fatal, in a period of time of less than 5 years. Again, this is from just one of these drugs.
Incredibly, there is only one randomized clinical trial comparing the cox-2 inhibitors Vioxx/Celebrex/Bextra to chiropractic spinal adjusting for the treatment of chronic spinal pain.2 It was published in July 2003 in Spine, the world’s number one orthopedic journal. Astonishingly, chiropractic spinal adjusting was better than 5 times more effective in treating chronic spinal pain than were the cox-2 inhibitors Vioxx/Celebrex/Bextra. Interestingly, the drugs resulted in more patients experiencing adverse reactions than becoming asymptomatic during the study period. Chiropractic spinal adjusting resulted in far superior results, with no adverse reactions. You can sign-up for my review of this article2 and many others at my website, www.danmurphydc.com.
REFERENCES
1) Liz Szabo, Tough choice: Pain of risk? Celebrex patients searching for answers, USA Today, Dec 23, 2004.
2) Lynton G. F. Giles, DC, PhD; Reinhold Muller, PhD; Chronic Spinal Pain: A Randomized Clinical Trial Comparing Medication, Acupuncture, and Spinal Manipulation; Spine July 15, 2003; 28(14):1490-1502.
3) The Back Letter, Lippincott, August, 1997.
4) Gurkirpal Singh, George Triadafilopoulos; Epidemiology of NSAID induced gastrointestinal complications. J Rheumatol 1999 Apr;26 Suppl 56:18-24
5) M. Michael Wolfe, M.D., David R. Lichtenstein, M.D., Gurkirpal Singh, M.D. GASTROINTESTINAL TOXICITY OF NONSTEROIDAL ANTIINFLAMMATORY DRUGS The New England Journal of Medicine, June 17, 1999.
6) Craig Moon (editor), More drug-safety questions increase doubts about FDA, USA Today, December 20, 2004.
7) Sabin Russell, Ads in the spotlight, drugs under a cloud, San Francisco Chronicle, December 22, 2004.
8) Kevin McCoy, Merck faces first hearing on Vioxx today as lawsuits mount, Merrill Lynch says drug giant’s liability could hit $18 billion; USA Today, November 18, 2004.
9) Eric J. Topol, MD, Arthritis Medicines and Cardiovascular Events-”House of Coxibs” JAMA. Dec 28, 2004, 2005;293
10) Jeanne Lenzer, FDA is incapable of protecting US “against another Vioxx” BMJ November 27, 2004;329:1253
11) Kamran Abbasi, acting editor, Is drug regulation failing? BMJ, November 27, 2004;329.
12) Jeanne Lenzer, Crisis deepens at the US Food and Drug Administration BMJ, December 4, 2004;329:1308.
13) Rita Rubin, “Arthritis drug add warning label, Bextra gets heart, clotting caution,” USA Today, December 12, 2004.
14) Wayne A. Ray, Ph.D., Marie R. Griffin, M.D., M.P.H., C. Michael Stein, M.B., Ch.B. Cardiovascular Toxicity of Valdecoxib, NEJM, December 23, 2004,Volume 351:2767.
15) Scott Gottlieb, Warnings issued over COX 2 inhibitors in US and UK BMJ, January 1, 2005;330:9.
16) Rita Rubin, Aleve is latest pain reliever facing questions, Study links drug to higher risk of heart attack, stroke, USA Today, December 21, 2004.
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