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Proof or promise? Get the facts on CAM

Growing evidence base helps doctors advise patients about alternative therapies

From the November/December ACP Observer, copyright © 2007 by the American College of Physicians.

By Jessica Berthold

It seems barely a week passes without a new study being released on the effect, or lack thereof, of some form of complementary or alternative medicine (CAM), which is used by at least 36% of U.S. adults in a given year, according to the most recent survey by the CDC.

The challenge for internists is to keep up with the latest evidence so they are not caught off guard when patients announce they have been taking St. John's wort for depression, for example, or treating their low back pain with acupuncture.

Fortunately, while earlier studies lacked the rigor of standard scientific trials, the quality of research has greatly improved in recent years, according to Barak Gaster, MD, associate professor of medicine at the University of Washington in Seattle, who gave a well-attended talk on CAM research at Internal Medicine 2007.

"The academic community has responded to the public interest in CAM with an explosion of studies, which have a higher level of rigor now than five to 10 years ago," Dr. Gaster said.

CAM encompasses a huge number of treatments ranging from dietary supplements to massage to hypnosis. Thus far, the remedies that show the strongest clinical evidence of potential benefit or harm are acupuncture, glucosamine/chondroitin, ginkgo biloba and St. John's wort, Dr. Gaster said.

A needling issue

Acupuncture has the largest body of research supporting it, said Brent A. Bauer, FACP, director of the Complementary and Integrative Medicine Program at the Mayo Clinic in Rochester, Minn.

"The evidence is not uniformly positive, but for things like pain and nausea associated with chemotherapy, as well as for dealing with anxiety and stress, it's fairly solid," Dr. Bauer said.

High-quality, randomized controlled trials from the last few years have also found acupuncture may slightly reduce neck pain, but it isn't effective in treating fibromyalgia or migraine headaches, Dr. Gaster said.

The National Institutes of Health has funded the largest-ever study examining the effect of acupuncture on chronic low back pain, said Richard Nahin, senior adviser for scientific coordination and outreach at the National Center for Complementary and Alternative Medicine (NCCAM), an NIH unit. The study is complete and data are being analyzed, he added. The trial was prompted by several smaller trials that suggested acupuncture may reduce low back pain; a meta-analysis of those studies was in the April 15, 2005 Spine.

Until recently, the most promising application for acupuncture seemed to be for treating the pain of knee osteoarthritis, Dr. Gaster said. A 2004 Annals of Internal Medicine study of 570 patients with the condition found that acupuncture seemed to improve function and provide pain relief as an adjunctive therapy compared with sham acupuncture and education control groups. Interestingly, it seemed to take two to four months for the acupuncture to have the strongest effect, Dr. Gaster noted. There were no reported side effects.

In June 2007, however, Annals published a meta-analysis of nine trials (including the 2004 study) that concluded that the observed benefits of acupuncture in past studies were probably the result of placebo or expectation effects.

"The meta-analysis was not very persuasive for the case of acupuncture," Dr. Gaster said. "It spoke mostly to the issue that, although we may find some statistically significant effects of the treatment, it's less clear how clinically significant they are."

The final verdict on acupuncture is still out, however, the authors of the 2007 Annals study said. Three large, sham-controlled trials on the treatment are either ongoing or are currently in pre-publication, and these should have a major impact on the evidence either way, they wrote in their study.

Osteoarthritis, take two

Glucosamine, a supplement made from crab and fish shells, and chondroitin, made from bovine or shark cartilage, are also popular for treating knee osteoarthritis. U.S. sales of the supplements, which have few side effects and no reported drug interactions, jumped from $619 million in 2000 to $818 million in 2006, according to the Nutrition Business Journal.

Based on preliminary research indicating glucosamine and chondroitin improved pain and function, as well as narrowed joint space, for knee ostearthritis sufferers, the NIH funded a trial in 2000 that ran nearly four years. The double-blind, randomized controlled study followed 1,583 knee osteoarthritis patients for six months in 16 sites. They were randomized to placebo, glucosamine, chondroitin, a combination of the two, or the non-steroidal anti-inflammatory drug celecoxib (Celebrex).

Though the celecoxib group had significant pain relief versus placebo, no other group did. However, for the glucosamine/chondroitin group, a subset of patients with moderate to severe pain did see a significant pain reduction over placebo - about 79% had a 20% or greater reduction in pain versus about 54% for placebo.

Further, in 2004, a new criterion for measuring response to osteoarthritis treatment was established that combined pain reduction, functional gait and patient self-assessment. By this new measure, all subjects from the study who took glucosamine/chondroitin improved compared with those taking single-supplement therapies, and did about as well as those on celecoxib. And patients with moderate to severe disease actually did better on the combination therapy than on celecoxib. Results were published in the Feb. 23, 2006 New England Journal of Medicine.

More information will be revealed in a follow-up trial, currently under way, in which about half of the patients in the NIH trial will be observed for another two years, Dr. Gaster said.

Supplements for the mind

Ginkgo biloba, which comes from the dried green leaves of the ginkgo tree, has shown some benefit compared with placebo in patients with dementia, but the benefits have been small, Dr. Gaster said. The treatment is usually well-tolerated, though there have been dozens of reports of cerebral hemorrhage related to ginkgo, and the drug shouldn't be used in combination with warfarin, aspirin or other drugs that can cause bleeding, he said.

"It may be modestly effective for dementia, but data are limited and trials are inconsistent," Dr. Gaster said. "The improvement is similar to that of donepezil (Aricept), but the data for donepezil is far more robust. Ginkgo is one-tenth the cost, however."

The NIH is funding a nine-year, multi-site trial to test whether ginkgo affects dementia, with abstract results expected next spring or summer, Dr. Nahin said. The 3,074 participants are at least 75 years old, with no signs of dementia. All are taking 120 milligrams in the morning and again at night, based on past studies showing that patients who progressed up to 240 milligrams of ginkgo per day saw a steady increase in effectiveness. The trial will also examine drug interactions, Dr. Nahin said.

"We are cataloguing every prescription, over-the-counter and herbal product these people are taking. So every time they come into the clinic they bring in their medicine cabinet," Dr. Nahin said. "At some point we'll be looking at interactions to see if using any prescription drug and any kind of dietary supplement leads to more events than you'd expect."

St. John's wort, a weed with a yellow flower used to treat depression, has had a huge number of positive studies in Europe - at least 23, with 1,757 patients, Dr. Gaster said. Yet two major studies published in the U.S. found the supplement worked no better than placebo at treating depression, he said.

A possible explanation for the discrepancy is that the level of depression in the U.S. study subjects was more severe than it was for the European patients. To test this possibility, the NIH is currently funding a multi-center study that will study the effectiveness of St. John's wort in only mildly depressed patients, Dr. Nahin said.

"They haven't yet gotten the 300 patients they need. Once the last patient is finished with the dose regimen, which will start at 1,200 milligrams daily and bump up to 1,800 mg/day if needed, then there will be a three-month follow-up," Dr. Nahin said. "It's going to be awhile before any results are available."

In general, Europeans studies tend to show more positive results from CAM than do U.S. studies, several experts noted.

"It may have to do with the quality of the research or with publication bias in one or both places," Dr. Gaster said. "But it is definitely one of the biggest mysteries in CAM research."

Though studies have yet to definitely prove whether or not CAM treatments work, there's no denying their popularity, which the government has responded to by imposing new regulations on herbal supplements. Last December, Congress passed legislation requiring manufacturers to notify the FDA of adverse reactions to supplements. In August, the FDA ordered dietary supplement manufacturers to follow new rules, called Good Manufacturing Practices, so their products don't contain impurities or contaminants and are labeled correctly.

"The FDA rules are being phased in at different times for different-sized companies, but by 2010, every herb in the U.S. has to reach Good Manufacturing Practices," Dr. Bauer said. "That means they will be much more like an over-the-counter drug in terms of purity and the accuracy of the label."

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