Vying for the Vioxx Market: Natural Meds Step into the Breach

[Guest guest]

This is a long article . . . but please read through.

Very interesting info for all! - Rogene

------------------------

http://www.citizens.org/news/newsletter/2005/march/articles/vioxx.cfm

Vying for the Vioxx Market: Natural Meds Step into the

Breach

By L. Goldman, Editor in Chief, Holistic Primary

Care

When Vioxx got axed two months ago, roughly 20 million

Americans with arthritis and other chronic pain

problems suddenly found themselves shopping around for

new forms of relief. While many simply shifted over to

Celebrex, others are questioning the pharmaceutical

approach, and turning instead to botanical medicines,

nutraceuticals, and homeopathic remedies.

There are indeed many naturally occurring compounds in

foods and medicinal plants that can reduce

inflammation, lessen pain, and improve quality of life

for patients with chronic pain syndromes. Many of them

affect cyclooxygenase-2 (COX-2), the same enzyme

inhibited by Vioxx (Rofecoxib) and the other COX-2

inhibitors. Some natural therapies, like Assalix, an

extract of white willow bark, have actually compared

favorably with Vioxx in head-to-head trials (see

related story P. 12).

Merck's voluntary withdrawal of Vioxx on September 30,

owing to increased incidence of cardiovascular and

cerebrovascular events, was front-page news worldwide.

According to a report in the November 1 edition of

Fortune, the former blockbuster drug brought in around

$2.5 billion a year. The recall cost Merck over $27

billion in capital almost overnight—and that's not

including what is expected to be a tidal wave of class

action lawsuits.

Who Knew What, and When?

There has been considerable ink spilled over whether

Merck's research directors and executives knew about

the potential CV risk prior to the September release

of data from the Adematous Polyp Prevention on Vioxx

(APPROVe) study. APPROVe showed a 2-fold greater

incidence of heart attacks and strokes in patients on

Vioxx versus placebo for longer than 18 months.

At a press conference in New York on October 13, Dr.

Kim, Merck's Director of Research and

Development, insisted that the company acted

ethically, swiftly and decisively once definitive

evidence—the data from the now-halted APPROVe

study—came to light. He held that earlier studies,

including the Vioxx Gastrointestinal Outcomes Research

(VIGOR) study showing a 4-fold increased rate of heart

attacks in patients on Vioxx versus those on naproxen,

were equivocal or insufficient to warrant a drug

recall.

The VIGOR data, published in 2000, " were of concern to

us, " said Dr. Kim. " All data from previous studies

demonstrated no difference in the CV event rate

between VIOXX and placebo or between VIOXX and

non-naproxen NSAIDS. Because VIGOR compared two drugs

and did not contain a placebo arm, it was not possible

to conclude based on this study alone whether naproxen

was having a beneficial CV effect or whether VIOXX was

having a detrimental CV effect. "

Merck steadfastly maintained its position that

naproxen, owing to its inhibition of platelet

aggregation, is cardioprotective. Dr. Kim argued that

in the absence of any other data, the VIGOR results

did not constitute grounds for pulling Vioxx. However,

the VIGOR findings were sufficient to prompt FDA and

Merck to work together to revise the Vioxx prescribing

information

In attempting to put APPROVe in perspective, Dr. Kim

stressed that the CV event rates were still fairly

low—15 events per thousand Vioxx patients and 7.5

events per thousand on placebo—and the differences

only emerged after 18 months of continuous therapy. He

maintained that if Merck had designed APPROVe as a

12-month trial, the CV effects might not have come to

light. In short, the company holds that until APPROVe,

there was no solid evidence Vioxx was dangerous.

A November 1 Wall Street Journal report, however,

tells a different story. As early as 1997, two years

before FDA approved Vioxx, Merck's upper eschelon,

including the company's revered research director, Dr.

Ed Scolnick, were aware that Vioxx increased blood

clots and had potential CV side effects. According to

the Wall Street Journal, Merck's sales training

documents instruct company reps on how to dodge

difficult questions on Vioxx's potential adverse

effects.

Several clinical researchers, including Gurkipal

Singh, MD, and Fries, MD, of Stanford Medical

School, M. Stillman, MD of the University of

Minnesota, and Lee Simon, MD, of Beth Israel Deaconess

Medical Center have come forward stating that Merck

used intimidation tactics to suppress scientific

discussion of potential CV risk in the years prior to

APPROVe.

J. Topol, MD, Chief Academic Officer of the

Cleveland Clinic, and one of the nation's leading

research cardiologists, called for a full

Congressional investigation of the Vioxx affair. In a

scathing editorial in the October 21 New England

Journal of Medicine, Dr. Topol said, " Considering the

tens of millions of patients who were taking

Rofecoxib, we are dealing with an enormous public

health issue. Even a fraction of a percent excess in

the rate of serious CV events would translate into

thousands of affected people. "

He charged Merck executives with putting profit ahead

of safety, adding that " FDA's passive position of

waiting for data to arrive is not acceptable given the

strong signals that there was a problem and the vast

number of patients exposed. "

A Class Effect?

The issue of who knew what and when will keep lawyers

and regulators busy for years to come. In the

meantime, the medical community must figure out what

specifically about this COX-2 inhibitor led to the

observed rise in CV events, and whether this is a

class effect.

Merck's executives certainly hope not: the company's

second COX-2 inhibitor, Arcoxia, is sold in more than

40 countries worldwide, and it is pending FDA approval

here. Executives at Pfizer, maker of celecoxib

(Celebrex), are also hoping the problem was

Vioxx-specific. Pfizer is betting that Celebrex will

prove to be cardioprotective. Three weeks after the

Vioxx recall, Pfizer announced plans for a

placebo-controlled study of Celebrex in patients with

osteoarthritis (OA) and pre-existing heart disease.

Preliminary work suggests that while Celebrex has the

same anti-inflammatory effect as Vioxx, it affects the

endothelium quite differently.

Given the emerging picture of how inflammation

contributes to the pathogenesis of myocardial

infarction, Vioxx's adverse heart effects seem

somewhat surprising. If inflammation is a key driver

of atherosclerosis and vessel occlusion, why would a

powerful and highly specific anti-inflammatory like

Rofecoxib increase the infarction rate? No one is sure

yet, and it is a question that will likely receive a

lot of research attention in the coming years.

From a holistic medical perspective, the demise of

Vioxx isn't so surprising. " This is just another in a

long line of pharmaceutical disasters. I wasn't

surprised by this—I'm never surprised when there's a

drug recall, " said Carol , MD, director of

Wellness Works, a Tampa-area holistic medical clinic,

and President-Elect of the American Holistic Medical

Association.

" Most of the testing of pharmaceuticals is done

post-approval. And it is only after 5 or 10 years that

we find out what we should have known in the

beginning. I've been practicing for a long time and

seen many recalls. And every time, people seem

surprised. They wonder how this could have happened.

The point is, putting people on drugs that suppress

natural processes for long periods of time can be very

dangerous. Keeping someone on a suppressive drug for a

long time is simply not a good idea, " Dr. told

Holistic Primary Care.

The Holistic Viewpoint

To her mind, the situation with Vioxx underscores one

of the core problems with conventional medicine: its

sometimes myopic focus on eliminating symptoms through

pharmaceutical interventions.

" The whole conventional medical mindset about chronic

illness—that a disease is here to stay, and never

going away, and that the best you can hope for is

symptom relief—is not a mindset to which I subscribe.

That mind set is based on training patients to believe

in pills, and training doctors to believe in pills. It

is part of the medical training process. As young

physicians, we are intellectually immunized against

every other way of looking at things because we are

ridiculed if we ask about anything else. As a result,

conventional medicine has become very good at rescues,

but very poor at treating chronic conditions. "

Regardless of the specific treatment modalities a

practitioner uses, the holistic viewpoint is about

looking for root causes of problems. With regard to

chronic pain problems, Dr. said there are a

limited number of root causes: trauma (new or old),

immune system imbalances leading to chronic

inflammation, dietary imbalances, food allergies.

" People need to realize that food allergies can and do

cause joint pain. Toxicities, particularly heavy metal

toxicities can cause joint pain. On the other hand,

mineral deficiencies can also lead to joint pain. The

point is, we need to look at why someone's having

chronic pain, not just mask the pain with

pharmaceuticals. It's fine to provide temporary pain

relief, but you don't want to continue with pain drugs

forever and ever. "

Several years ago, rheumatologists at the Mayo Clinic

assessed cellular immunity in 51 people with

rheumatoid arthritis and 47 healthy controls. They

found that rheumatoid arthritis patients consistently

show a premature exhaustion of their cellular immune

systems. Normal immune cells are not produced at

normal rates, and existing cells begin attacking the

body's own tissues (Koetz K, et al. Proc Natl Acad

Sci. 2000; 97(16):9203–8).

According to Cornelia Weyand, MD, the principle

investigator, the findings strongly suggest that

clinicians must be very careful in selecting

treatments for rheumatoid arthritis. " We have

aggressively treated the symptoms of rheumatoid

arthritis with medications that suppress the immune

system. While this practice offers relief of the

painful symptoms, it also puts patients at greater

risk for infections and cardiovascular disease—the two

leading causes of death among these patients. " Dr.

Weyand's study was published four years before Vioxx

was recalled.

Natural Medicine Steps to the Plate

Leaders in the natural products field view the

situation as a prime opportunity to step up and show

what botanical medicines and nutritional supplements

have to offer. And indeed, there are a number of

promising products for the treatment of arthritis, low

back pain, and chronic inflammatory conditions.

One can certainly make a case for increased intake of

omega-3 fatty acids, which reduce the production of

proinflammatory cytokines. In effect, omega-3's quiet

chronic inflammation, leading to gradual improvement

of a host of inflammatory disorders including some

forms of arthritis. Unlike 'coxibs, there's no risk of

cardiac side effects; the data are nearly unanimous in

support of omega-3s as cardioprotective.

The combination of glucosamine and chondroitin also

makes a lot of sense for individuals with

osteoarthritis or other types of joint pain, the prime

customers for Vioxx and the other COX-2 inhibitors.

Glucosamine stimulates new cartilage production, while

chondroitin sulfate inhibits enzymes involved in the

breakdown of collagen. Together, they slow the

degeneration of collagen in the synovial spaces while

stimulating new collagen formation. There are a number

of strong early clinical studies showing that

consistent use of glucosamine/chondroitin can improve

joint collagen and reduce joint pain. A good review of

this topic was published by Deal and Moskowitz in

Rheumatic Disease Clinics of North America in 1999.

Cosamin DS, a patented combination of glucosamine

hydrochloride and chondroitin sulfate made by Nutramax

Laboratories (www.nutramaxlabs.com) is probably the

most well-known product in this category. Recently,

Cargill introduced a non-shellfish derived form of

glucosamine called Regenasure.

The role of glucosamine and chondroitin in treatment

of arthritis will become far more clear this Spring,

with publication of a massive NIH-sponsored, 5-arm

trial involving nearly 1,600 arthritis patients

randomized to placebo, celecoxib, glucosamine alone,

chondroitin alone, or a combination of glucosamine and

chondroitin. In light of the Vioxx recall, this study

couldn't be more timely.

Zyflamend's Checks and Balances

A very strong contender in the botanical alternatives

department is Zyflamend, NewMark's combination of

anti-inflammatory herbs. The product combines whole

herb extracts of ginger, turmeric, rosemary, green

tea, oregano, skullcap, and several other herbs, all

of which have strong anti-inflammatory effects. Green

tea, ginger, and turmeric, in particular, contain many

compounds that can downregulate COX-2, as well as

COX-1, though none are selective COX-2 inhibitor.

The COX-2 inhibition effect of Zyflamend is being

studied by Katz, MD, of the Center for Holistic

Urology, Columbia Presbyterian Medical Center, New

York. He and his colleagues are midway through a Phase

I trial of the botanical formula in the treatment of

prostate intraepithelial neoplasia (PIN). He began the

trial after preliminary work showed pre-neoplastic and

malignant prostate cancer cells produce COX-2, and

that inhibition of the enzyme can slow growth of

malignant cells in vitro. (For more information on

Zyflamend, visit: www.new-mark.com.)

If the Vioxx phenomenon proves to be a class effect,

will herbs like those in Zyflamend cause similar heart

problems? In an interview, Dr. Katz stressed, " No one

really knows at this point. " His trial will test

whether Zyflamend can prevent progression of PIN to

prostate cancer, and will not directly evaluate CV

effects. Still, he will eventually have 2 years of

follow-up data on 48 patients routinely taking a

botanical COX-2 inhibitor, so it could provide some

insight.

Herbalist Schulick, founder of NewMark and

formulator of the Zyflamend combination doesn't expect

problems. " Vioxx was so specific and so selective, it

inhibited COX-2 versus COX-1 by an extremely high

ratio ratio. None of the compounds in the herbs making

up Zyflamend have nearly that kind of selectivity, " he

said in an interview.

" The pharmaceutical development model holds that

greater specificity is desirable, and this ideal

guides drug development. But extreme selectivity is

not always a good thing, " Mr. Schulick continued.

" The principles of botanical medicine take an entirely

different view. Medicinal plants are biochemically

complex, and they provide many checks and balances.

Ginger, green tea and turmeric also inhibit

lipoxygenase. When you inhibit COX, there is a

biochemical shift, and the arachidonic acid—the

substrate for many inflammatory mediators—gets shunted

down the LOX pathways. Anti-inflammatory herbs provide

a more complete but less extreme downregulation of

more of the enzymes and pathways involved in the

inflammatory cascades. Pharmaceuticals can be much

more powerful and rapid, but they don't provide the

checks and balances that whole herbs can provide. "

Zeel and the Homeopathic Approach

Several homeopathic medications have proven quite

effective in treating arthritis. The most impressive

evidence is for a product called Zeel, a combination

of homeopathic preparations of Rhus toxicodendron,

Solanum dulcamara, Sanguinaria canadensis, Arnica

montana, and several other herbs: Zeel compared

favorably with both rofecoxib and celecoxib in the

treatment of osteoarthritis.

The study involved 592 women and men with stage I or

II OA of the knee. They were seen by a total of 127

physicians. Half of the participating physicians were

only permitted to prescribe Zeel, while the other

group were permitted to prescribe a 'coxib of their

choice. There were 323 patients treated with the

homeopathic drug, 109 treated with celecoxib, 100–200

mg per day, and 160 treated with Rofecoxib, 12.5 or 25

mg per day. All were treated for 10 weeks.

The investigators measured 4 key symptoms: initial

pain with movement, continued pain during movement,

pain when fatigued, and joint stiffness. There were

significant improvements from baseline in all 3

groups. Those treated with the 'coxibs experienced a

more pronounced effect in the first weeks, indicating

a faster onset of action, the net WOMAC scores were

more or less equivalent by the 6th week. By the end of

the study, 79% of those in the Zeel group rated their

treatment as good or very good, compared with 86% in

the combined 'coxib groups (Birnesser H, et al. Der

Allgemeinarzt. 2003; 25(4): 261–4).

The authors, from the Institute for Antihomotoxic

Medicine, Baden-Baden, noted that, " because the COX-2

isozyme plays an important role in healing processes

(including ulcer healing), and in maintaining

homeostasis with regard to blood pressure and

vasoregulation, kidney function, CNS function and bone

metabolism, inhibiting COX-2 is not completely

unproblematic. A more physiologically sound

therapeutic approach is to reduce the concentration of

proteolytic enzymes (serine proteinases and

metalloproteinases) that support inflammation in the

extracellular matrix. "

Though the mechanism is far from understood, in vitro

studies indicate that the Zeel formula inhibits the

release of leukocyte elastase, a proteolytic enzyme

that is released during inflammation. A previous study

of Zeel, which is made by Heel (www.heel.com), showed

it to be equivalent to diclofenac, a widely used COX-1

inhibitor in Europe, for mild to moderate knee

arthrosis (Maronna U, et al. Orthopadische Praxis.

2000; 29(3): 157–158).

Stress Reduction, Exercise & Physical Approaches

In the wake of Vioxx's demise, there will inevitably

be a lot of scrambling to find alternative substances

to help patients relieve pain. But clinicians

interviewed for this article stressed the importance

of approaches like stress reduction, biofeedback,

acupuncture, osteopathic or chiropractic manipulation,

dietary changes and exercise. Pills and capsules, be

they pharmaceuticals, vitamins or herbal preparations,

are convenient and can be highly effective. But

inflammation and chronic pain are complex

psychophysiological processes.

In helping chronic pain patients cope with life after

Vioxx, bear in mind that a complex physiological state

can only be truly rectified through a comprehensive

multimodal approach. No single enzyme or chemical

compound is entirely responsible for a complex

disorder like arthritis, and no one therapy is " the

answer. " That may very well be one of the most

important lessons to emerge in the wake of Vioxx.