快樂小藥師 Im pharmacist nichts glücklich

Editor's Note:
The Centers for Disease Control and Prevention estimates that up to 50 million US adults have some form of arthritis, including one half of those older than 65 years. With lifestyle modification and pharmacotherapies often only providing partial relief, many patients turn to complementary and alternative medicine (CAM) therapies, despite limited efficacy and safety data on many such approaches. Medscape recently asked rheumatologists Nathan Wei, MD, and Jonathan Kay, MD, to participate in the following email debate exploring what CAM data do exist and addressing the role of alternative treatments in the management of arthritic conditions.

Your Patient's Taking What?

Dr. Wei: My patients ask me about any number of CAMs on a daily basis. The ones they ask about most frequently are glucosamine sulfate/chondroitin sulfate, chiropractic, anti-inflammatory herbs, yoga, and acupuncture.

The data on glucosamine sulfate/chondroitin sulfate are mixed, and its use remains controversial. Nonetheless, many patients continue to take it, and many report excellent outcomes. Although some assume the National Institutes of Health (NIH) GAIT trial[1,2] might have put the nail in the coffin of this preparation, after looking at the results of the study (particularly in the moderate to severe cases), I'm not so sure. I am probably not the best person to refute its benefits, because I take it myself -- hedging my bets, so to speak.

Chiropractic is a CAM that the American Medical Association called "snake oil" -- until a Supreme Court ruling came down in favor of the chiropractors. There's little question in my mind that chiropractic works, particularly for acute musculoskeletal pain. Also, chiropractors know musculoskeletal anatomy better than most rheumatologists.

The beneficial effects of anti-inflammatory herbs and supplements have been demonstrated in multiple studies.[3-43] Although these effects appear to be relatively modest, they seem to be effective.

Yoga is an excellent CAM that I would refer to as a "body/mind experience." In addition to flexibility, stretching, and breathing, there is also a mental aspect to it that seems to trigger endorphin release.[44] My wife got me into yoga 2 years ago, and I look forward to each session. It complements vigorous exercise, which I engage in regularly.

Acupuncture is another CAM that has its advocates. Although acupuncture has yielded mixed results in studies,[45-48] I think that it is helpful in some cases of musculoskeletal pain. In the hands of a skilled practitioner, acupuncture appears to be less toxic than the pharmaceutical alternative.

I know I haven't delved into other CAMs, but I think this is a good start.

Dr. Kay: Many of my patients also inquire about CAMs. Some patients new to my practice are already taking glucosamine sulfate/chondroitin sulfate, irrespective of their underlying diagnosis. Although it is more often recommended for patients with osteoarthritis (OA), many patients with rheumatoid arthritis (RA) also take glucosamine sulfate/chondroitin sulfate because it is advertised as a remedy for "arthritis," without mention of the specific type.

Recently, I saw a physician who works in medical research. Despite his regular adherence to evidence-based science and medicine, he told me that he takes glucosamine sulfate/chondroitin sulfate to treat degenerative arthritis of his fingers and that he has perceived an improvement in his symptoms since beginning to take this nutritional supplement.

As you point out, the NIH-sponsored GAIT trial demonstrated no significant benefit of glucosamine sulfate/chondroitin sulfate as a treatment to reduce pain in patients with symptomatic OA of the knee who had radiographic evidence of osteophytes.[1,2] However, a subgroup analysis of this large, well-designed, randomized, controlled clinical trial found this nutritional supplement to be significantly better than placebo in reducing pain among participants with moderate to severe pain at baseline. A limitation of this study was that it did not include patients with milder degrees of knee OA, among a greater proportion of whom one might expect glucosamine sulfate/chondroitin sulfate to be beneficial. Regardless, as for any medication, we cannot confirm its benefit until positive results have been achieved when studied directly in the population of interest.

A skilled chiropractor who performs appropriate manipulation to treat back pain might be as effective as some physical therapists. However, I am not aware of any large, well-designed clinical trials in which chiropractic treatment of back pain has been compared with conservative medical management using physical therapy modalities. There is little credible scientific basis to support chiropractic manipulation as treatment for systemic diseases, such as diabetes mellitus.

I am unaware of any well-controlled study of yoga in pain amplification syndromes, such as the fibromyalgia syndrome, or in other conditions that might be encountered by a rheumatologist. However, disciplined meditation and stretching exercises certainly would benefit patients with pain amplification syndromes.

Acupuncture has been shown to stimulate the release of endorphins into cerebrospinal fluid.[49,50] Thus, this traditional Chinese therapy triggers analgesia by a mechanism that has been validated using the scientific method.

Many patients eat cherries or take cherry extract to prevent and treat attacks of gout. A recent Internet-based study, published in Arthritis & Rheumatism in 2012, found that patients experienced fewer attacks of gout over a 2-day period during which they consumed more cherries or used cherry extract, compared with a 2-day period during which they did not.[51] Cherry consumption may have a urate-lowering effect, but this would not explain a reduction in acute attacks with short-term increased cherry intake. Cherries contain anthocyanins, which exert anti-inflammatory effects. Thus, there is a plausible scientific basis for the efficacy of this alternative approach to treating gout. However, until this therapy is subjected to a prospective, controlled clinical trial, its potential efficacy can only be surmised.
When Is a CAM No Longer a CAM?

Dr. Wei: As usual, you bring very good information, as well as fodder for discussion. Another therapy some of my people use is balneotherapy (spa therapy). Of note, this has been an integral part of the European approach to arthritis treatment for centuries. Although balneotherapy does not halt the progression of RA, it helps patients to feel better whether they have RA, OA, ankylosing spondylitis, or whatever...and feeling better is important, is it not?

Dr. Kay: Balneotherapy is used in Europe, where some government-subsidized health plans cover the cost of treatment in a spa, especially during the holiday month of August. Specialists in physical medicine and rehabilitation and rheumatologists in Europe have developed skill and expertise in recommending treatments in sulfur-laden hot springs. However, I would not go so far as to say that this is "an integral part of the European approach to arthritis treatment." Balneotherapy remains an adjunct to traditional antirheumatic drug therapy. No one would claim that spa treatment in Baden-Baden or Wiesbaden in Germany or in Karlovy Vary in the Czech Republic halts the structural progression of RA.

Purified capsaicin cream, which is derived from hot peppers, may reduce the pain associated with OA of the fingers and, occasionally, of the knee. However, this cream may no longer be viewed as a CAM, because McCarthy and McCarty[52] published a placebo-controlled study that demonstrated the efficacy of capsaicin cream 0.075% as a treatment for OA of the fingers in the Journal of Rheumatology in 1992.

This raises the question as to what CAM is. If a natural substance is studied in an appropriately designed clinical trial, is it no longer an "alternative medicine"? Once the medication becomes "mainstream" and is recommended by allopathic physicians, is it no longer "complementary"? Are CAMs only those natural substances that are used as remedies for ailments, but which have not undergone the rigorous clinical testing that the US Food and Drug Administration (FDA) would be require for approval of a new drug?

A single-blind, randomized, controlled trial of t'ai chi for the management of the fibromyalgia syndrome, published in the New England Journal of Medicine in 2010, demonstrated clinically important effects compared with a standardized education program.[53] Thus, are acupuncture and t'ai chi no longer "alternative" therapies, because the results of these studies that support their use have been published in high-impact journals?

Dr. Wei: Sure, yoga and t'ai chi don't have a long list of studies to support their efficacy; nonetheless, there are small studies showing that there is benefit, and both disciplines involve more than simply stretching.

You raise a great point: When is a CAM no longer a CAM, but just another therapy? If foxglove wasn't used first, we wouldn't have digitalis. And if willow bark wasn't recognized by Hippocrates as having analgesic and antipyretic properties, would aspirin still have been discovered?

In addition to the usual suspects, one growing area of CAM that I would like to expand upon is that of herbal medicines. Examples include but are not limited to ASU (not Arizona State University, but avocado soy unsaponifiables), bioflavonoids, blackcurrant oil, borage oil, bromelain, boswellia, boron, cat's claw, Chinese herbs, curcumin, devil's claw, dimethyl sulfoxide (DMSO), feverfew, flaxseed, frankincense, green-lipped mussels (delicious with garlic and tomatoes, I might add), guggul, methylsulfonylmethane (MSM), S-adenosylmethionine (SAMe), stinging nettle, and white willow bark. Each of these has been used at one time or another by at least one of my patients, and each has some scientific "cred" to support its use.[3-43]

The problem I see is that these herbs may have potential side effects and drug interactions with the medicines we use. On the one hand, I don't mind patients taking them; on the other, it makes me nervous.
Primrose, Thunder God Vine, and Side Effect Concerns Dr. Kay: Thank you very much for identifying other CAMs that patients use and about which they inquire. You list an alphabetical menagerie of herbal medicines that your patients have tried. I am aware of a small, placebo-controlled trial of gamma-linolenic acid, which is a component of evening primrose and borage seed oils, conducted by Robert Zurier and colleagues[7] in patients with RA.Persons treated with gammalinolenic acid in this 24-week study exhibited a modest reduction in the number of swollen and tender joints, which was significantly greater than that among placebo-treated participants. I am also familiar with another small, randomized, controlled trial, conducted by Peter Lipsky and colleagues,[54] in which an extract of the medicinal plant Tripterygium wilfordii Hook F ("thunder god vine") was compared with sulfasalazine in patients with active RA.Approximately one half of the patients randomly assigned to each study drug in this 24-week trial discontinued therapy. However, of the remaining patients who continued study drug treatment for 24 weeks and could also use stable doses of oral prednisone and nonsteroidal anti-inflammatory drugs, a significantly greater proportion of those treated with Tripterygium wilfordii Hook F extract achieved ACR 20, ACR 50, and ACR 70 responses than did those treated with sulfasalazine. Of course, sulfasalazine, which was the active comparator in this trial, is a relatively ineffective disease-modifying antirheumatic drug compared with methotrexate or biological agents. I too am concerned that herbal preparations may interact with the antirheumatic drug therapies that we prescribe. As with any medication, an herbal concoction may have potential side effects. However, because most of these herbs have not been subjected to rigorous study and are not produced according to good manufacturing practices, we know much less about their potential toxicities and drug interactions than we do about those medications that are approved and regulated by the FDA. An exception to this concern relates to extract of willow bark, the active ingredient of which has been available since 1897, when the chemist Felix Hoffman synthesized aspirin. Hoffman was encouraged by his father to synthesize a more palatable form of salicylic acid, because both salicylic acid and willow bark itself have a bitter taste. With aspirin being both widely available and relatively inexpensive, I cannot imagine what might motivate any patient to use white willow bark instead. Scientific advances over the past century have allowed us to treat arthritis effectively without the need to hike into the forest and peel the bark off of trees! Dr. Wei: My mention of willow bark was merely to direct your attention to the origin of aspirin and certainly not to suggest traipsing into the forest. Who wants to risk contracting a bad case of poison ivy just to take care of a headache?
Your Neighborhood Witch Doctor

Dr. Kay: You have provided me with an extensive bibliography and mention that each of the herbal preparations "has some scientific 'cred' to support" its use, but you do not elaborate on the quality of such evidence. Many of the publications that you cite are either abstracts from meetings or articles in relatively obscure journals with low impact factors. As you well know, it is important to differentiate well-designed and carefully executed studies from those that are of lesser quality. I would appreciate your specific comments regarding the articles, among those that you list, which you find to be most interesting and of the best quality.

Dr. Wei: Do I detect a bit of sarcasm here? Granted, the journals cited don't have the cachet of more "scientific" journals. However, I'm amused and sometimes frustrated by smug academics. It reminds of the New Yorker cover depicting how New Yorkers view New York compared with the rest of the country. The attitude that comes across is, "If it wasn't published in the New England Journal of Medicine, it's not worth reading." It goes without saying, in some instances, that breakthroughs have been reported initially in obscure journals.

I grant that the data on herbal remedies have not been subjected to the same scrutiny as those drugs that have been approved by the FDA. Could it because there are no big dollars available for research into these potential remedies? Yes, some of the citations that I've provided come from obscure journals and report observations and individual case reports -- obviously not the rigorous fodder found in "scientific" journals. Nonetheless, empirical evidence, which often is based on an individual's perspicacity, can be instructive.

I disagree with your assertion that a treatment should be considered legitimate only after it has been scientifically scrutinized and proven to work in rigorous scientific studies. We're only as good as our science is right now. In a thousand years, I bet doctors will look back and say, "How could those doctors in 2013 have been so ignorant?"

With advances in quantum physics and other disciplines, what once appeared impossible is now considered doable. What is now considered hocus-pocus may someday be considered the norm. Even Einstein said, "Imagination is more important than knowledge"[55] -- and he had a lot of knowledge!

Barry Marshall, an obscure internist from Western Australia, was ridiculed for his theory that peptic ulcer disease was caused by an infectious agent. I can remember a grand rounds lecture that I attended at which he was literally booed off the stage. This episode, of course, occurred before his winning the Nobel Prize in Medicine.

Dr. Kay: We can only evaluate existing therapies according to current knowledge. Certainly, information gained in the future may change the assessment of treatments that presently are considered to be state of the art. However, it is impossible to judge current practice according to a future paradigm.

Dr. Wei: The reason that clinical trials are double-blind as well as placebo-controlled is because of the subtle signals that a practitioner can send out regarding the presumed efficacy of an administered treatment. In days of yore, that subtle signal often helped patients to improve. Why is it that witch doctors and medicine men can heal? Could it be because their remedies actually work, or because they prescribe placebo and that their patients have faith in their healing powers? Now, we have treatments that are more effective than those of your neighborhood witch doctor. But before these treatments came along, that was all there was -- and it often worked. How is that unethical?
The Ethics of Placebo Dr. Kay: What objective evidence is there that witch doctors and medicine men heal diseases in the same way that allopathic physicians do? If one is to consider the treatments of shamans to be equivalent to those of allopathic physicians, they must be subjected to the same degree of rigorous study using similar objective outcome measures. I am unaware of such studies and would appreciate your pointing me toward them. I suspect that you and my other colleagues in rheumatology would consider it below the appropriate standard of care if I were to attempt to treat a patient with active seropositive RA by performing a rain dance in the examination room, rather than initiating treatment with methotrexate or another disease-modifying antirheumatic drug. Were I to begin treating patients in such a manner, I expect that this practice would be deemed to be unethical. Dr. Wei: No, please don't do a rain dance for an RA patient. As you and I both know, it won't work, and you're not Fred Astaire. My point about shamans was not to put them head to head against allopathic physicians. It was merely to suggest that in the days before allopathic medicine, they were all that there was and sometimes the power of belief was enough to heal, sort of like the Wizard of Oz. Believe me, if I'm sick, I'll take a cushy private room in a modern hospital any day of the week. Of course, I'll also make sure I have relatives, friends, and other advocates there to protect me from the numerous hospital errors that occur on a daily basis in this country. (In fact, a local hospital recently made an error that nearly cost one of my family members their life.) There are abundant stories, perhaps apocryphal, of old-time general practitioners using sugar pills -- the original placebos -- to treat "disease." In rheumatology, we know that the placebo effect in clinical trials can be as high as 40%. Placebo might be the ultimate CAM. Dr. Kay: You mention the potential use of placebo to treat disease. The clinical improvement observed among placebo-treated patients in clinical trials of antirheumatic drugs most likely reflects the natural course of RA, with periods of flare and remission. Most of these clinical trials have been conducted in patients who had been inadequately responsive to background antirheumatic drug therapy. The observed placebo response rate also may reflect additional clinical response to background drug therapy that can occur during the course of the trial, if study participants had not been compliant with background antirheumatic drug therapy before entering the trial. However, the intentional prescription of a placebo as a CAM to treat a patient with any disease is completely unethical. Dr. Wei: Please stop sending me your emails in the evening. I had difficulty sleeping last night because one of your sentences kept haunting me: "The intentional prescription of a placebo as a CAM to treat a patient with any disease is completely unethical." A few years ago, Bruce Moseley and colleagues at the Houston Veterans Affairs Medical Center performed a placebo-controlled, double-blind study[56] comparing arthroscopic debridement of the joint for OA. One group received the real thing, and the other group received a sham procedure. The outcomes were similar for both groups. As you might guess, this study shook up the orthopods. My question: Was this unethical? Any time we perform a placebo-controlled study, we are intentionally prescribing a "sugar pill" for treatment. Dr. Kay: I did not mean for you to lose any sleep about the use of placebo in institutional review board (IRB)-approved clinical trials. When a study has been designed to assess the efficacy of a treatment in a double-blind manner and employs a placebo to maintain this blinding, it is certainly ethical to do so. Before approving such a study, the members of an IRB review the protocol for its risk/benefit ratio and the ethical equipoise of its design. In a clinical trial, participants are followed closely and objective outcomes are measured. As long as the potential risk of the placebo treatment does not outweigh the potential benefit that might be derived from ascertaining the efficacy or lack of efficacy of the experimental therapy, it is appropriate to use placebo in this context. Most important, subjects provide informed consent to participate in a placebo-controlled study. If "placebo" were administered as a treatment in clinical practice, the patient would have been misled to believe that he or she was receiving an active drug. Such an act violates the prescribing physician's Hippocratic Oath.
RCTs, Laughter, and a Need for "Sham Prayer"?

Dr. Wei: I agree we do have much better methods now for protecting patients who participate in clinical trials. Thank goodness, because it wasn't that long ago "modern medicine" allowed the Tuskegee experiment to occur.

While we're on the topic of randomized clinical trials, no less an authority than Eric Topol, Editor-in-Chief of Medscape, brought this gem to our attention, published in the Mayo Clinic Proceedings: "A Decade of Reversal: An Analysis of 146 Contradicted Medical Practices."[57] The authors concluded, "After 65 years of randomized trials, ineffective, harmful, expensive medical practices are being introduced more frequently now than at any other time in the history of medicine."

Why is that? This isn't the first time that the validity of the randomized clinical trial, which is the backbone of scientific inquiry, has been brought into question. If it isn't the randomized clinical trial, what else is going to decide what constitutes an effective CAM?

Dr. Kay: A recurring theme in this discussion has been that lack of scientific evidence to support the safety and efficacy of a potential therapeutic agent appears to be the common denominator in defining a CAM. Once any therapeutic agent has been subjected to rigorous study with application of the scientific method, it no longer is either "complementary" or "alternative." If the treatment is shown to be significantly better than placebo or an active comparator, it becomes an effective component of the allopathic therapeutic armamentarium. However, if the agent cannot be demonstrated to be more effective than placebo, it should no longer be administered to any patient with the expectation of therapeutic benefit.

Dr. Wei: There are other activities that some might consider to be hocus-pocus, but they are also CAMs: for example, guided imagery, meditation, hypnosis, and even prayer. Do these pass scientific scrutiny? Probably not. Are they helpful? I would posit that they are.

Certainly prayer is an activity that I bet many physicians engage in. I certainly do. As far as I know there have been no clear-cut scientific studies proving the existence of God. Does that mean He or She doesn't exist? Maybe all the churches, synagogues, temples, and mosques should just close their doors.

Dr. Kay: The existence or nonexistence of God has no impact on the potential contribution of prayer to healing. In 1999, Harris and colleagues[58] published a randomized, controlled, double-blind, parallel-group clinical trial in the Archives of Internal Medicine that compared prospectively the effect of remote intercessory prayer with usual care on the outcomes of patients hospitalized in the coronary care unit (CCU) of a large metropolitan hospital. Using a "CCU course score" and retrospective chart review, they found that patients who received remote intercessory prayer had slightly lower scores, which were statistically significant at P = .04. Although one could raise questions regarding the methodology used to assess the outcomes of these patients, this intriguing study suggested that there might be benefit to remote intercessory prayer. However, no "sham prayer" was included in this study.

Dr. Wei: My bringing up the subject of God was to underline the fact that there is no scientific proof of His or Her existence. Does this mean that supplications to a higher being (a CAM) should be abandoned? Physician-scientists shouldn't pat themselves on the back too hard -- they might develop a nasty case of whiplash.

And I forgot another one: laughter, described by Norman Cousins. Cousins was an editor of the Saturday Review. He suffered from what many now believe to have been ankylosing spondylitis. During his time as a patient, he kept a journal which eventually was the basis for his book Anatomy of an Illness. In it, he described his use of laughter, watching humorous videos to "prime the pump," as a therapy for his arthritic condition. He recommended 10 minutes a day of laughter.[59]

Have you heard the one about the minister, the priest, and the rabbi who walk into a bar?

Dr. Kay: That's a classic one! The bartender looks at them and says, "What is this, a joke?"

Our discussion of CAMs has prompted me to wonder why patients are so often willing to take a substance as a potential therapy, when that substance has never been proven to be either safe or effective. Because CAMs have not been approved by regulatory agencies, such as the European Medicines Agency or the FDA, they do not require prescription by a licensed provider. Thus, a patient can choose of his or her own free will to take a CAM. Such freedom empowers the patient and frees him or her of dependence upon a licensed healthcare provider. The ability that CAMs provide for patients to control their medical destiny probably accounts for much of their appeal, even if these treatments are less likely to be effective than traditional allopathic drugs that have been studied extensively.

Dr. Wei: In closing, we can agree to disagree. I share your thoughts regarding why patients take CAMs. Another issue is the ever-widening divide between modern medical technology and the lack of connection to patients at a deeper emotional level. I know that when I see a doctor who has his or her nose buried in their laptop and there is no eye contact, it makes me feel like a piece of meat.

We must continue our search for truth through rigorous application of the scientific method; however, we must realize the limitations of what constitutes our science today. It is also important to understand the deeper emotional needs of our patients and to keep an open mind about simple unorthodox remedies that just might have something to them.

Dr. Kay: I really enjoyed our back-and-forth discussion and hope that you didn't consider any of my banter to be meant as a personal attack. Now you can (CAM) get some rest and sleep comfortably, without being haunted by any more of my comments!