After spending the first 21 years of life in New Jersey and Philadelphia, I ventured to the University of Florida for graduate school. For those who don’t know, UF is in the north-central Florida city of Gainesville – culturally much more like idyllic south Georgia than flashy south Florida.
It was in Gainesville – “Hogtown” to some – that I first encountered the analgesic powder. I believe it was BC Powder, first manufactured just over 100 years ago within a stone’s throw of the Durham, NC, baseball park made famous by the movie, Bull Durham. I remember sitting with my grad school buddy from Kansas City watching this TV commercial with hardy men possessing strong Southern accents enthusiastically espousing the benefits of BC. I looked at Roger – a registered pharmacist – and asked, “what in the hell is an analgesic powder?”
Despite the variety of health systems across hundreds of different countries, one feature is near-universal: We all depend on private industry to commercialize and market drug products. And because drugs are such an integral part of our health care system, that industry is generally heavily regulated. Yet despite this regulation, little is publicly known about drug development costs. But aggregate research and development (R&D) data are available, and the pharmaceutical industry spends billions per year.
Steven Salzberg, a friend of this blog and Director of the Center for Bioinformatics and Computational Biology at the University of Maryland, is on the editorial boards of three of the many journals published by BioMed Central (BMC), an important source of open-access, peer-reviewed biomedical reports. He is disturbed by the presence of two other journals under the BMC umbrella: Chinese Medicine and BMC Complementary and Alternative Medicine. A couple of days ago, on his Forbes science blog, Dr. Salzberg explained why. Here are some excerpts:
The Chinese Medicine journal promotes, according to its own mission statement, studies of “acupuncture, Tui-na, Qi-qong, Tai Chi Quan, energy research,” and other nonsense. Tui na, for example, supposedly “affects the flow of energy by holding and pressing the body at acupressure points.”
Right. What is this doing in a scientific journal?… I support BMC…But their corporate leaders seem to care more about expanding their stable than about maintaining the integrity of science. Chinese Medicine simply does not belong in the company of respectable scientific journals.
Forming a scientific journal whose goal is to validate antiquated, unproven superstitions is simply not science, whatever the editors of Chinese Medicine claim.
BMC should be embarrassed to be publishing journals that promote anti-scientific theories and otherwise muddy the literature. By supporting these journals, they undermine the credibility of many excellent BMC journals. They should cut these journals loose.
Science-based medicine depends upon human experimentation. Scientists can do the most fantastic translational research in the world, starting with elegant hypotheses, tested through in vitro and biochemical experiments, after which they are tested in animals. They can understand disease mechanisms to the individual amino acid level in a protein or nucleotide in a DNA molecule. However, without human testing, they will never know if the end results of all that elegant science will actually do what it is intended to do and to make real human patients better. They will never know if the fruits of all that labor will actually cure disease. However, it is in human experimentation where the ethics of science most tend to clash with the mechanisms of science. We refer to “science-based medicine” (SBM) as “based” in science, but not science, largely because medicine can never be pure science. Science has resulted in amazing medical advances over the last century, but if there is one thing that we have learned it’s that, because clinical trials involve living, breathing, fellow human beings, what is the most scientifically rigorous trial design might not be the most ethical.
About a week ago, the AP reported that experiments and clinical trials that resemble the infamous Tuskegee syphilis study and the less well known, but recently revealed Guatemala syphilis experiment were far more common than we might like to admit. As I sat through talks about clinical trial results at the Society of Surgical Oncology meeting in San Antonio over the weekend, the revelations of the last week reminded me that the intersection between science and ethics in medicine can frequently be a very tough question indeed. In fact, in many of the discussions, questions of what could or could not be done based on ethics were frequently mentioned, such as whether it is ethically acceptable or possible to do certain followup trials to famous breast cancer clinical trials. Unfortunately, it was not so long ago that such questions were answered in ways that bring shame on the medical profession.
I have a mental basket of drugs that I suspect may be placebos. In that basket were the topical versions of non-steroidal anti-inflammatory drugs (NSAIDs). When the first products were commercially marketed over a decade ago, I found the clinical evidence unconvincing, and I suspected that the modestly positive effects were probably due to simply rubbing the affected area, or possibly due to the effects of the cream or vehicle itself. Frankly, I didn’t think these products worked. So when I recently noticed a topical NSAID appear for sale as an over-the-counter treatment for muscle aches and pains (seemingly only in Canada, for now), I was confident it would make a good case study in bad science.
It’s not that I’m partial to the oral NSAIDs. Yes, they’re among the most versatile, and probably most well-loved drugs in our modern medicine cabinet. They offer good pain control, reduce inflammation and can eliminate fever. We start using it in our sick and feverish infants, through childhood and adulthood for the aches and pains of modern life, and into our later years for the treatment of degenerative disease like osteoarthritis, which affects pretty much everyone as we age. An astonishing 17 million Americans use NSAIDs on a daily basis, and this number is expected to grow as the population ages. In the running groups I frequent, ibuprofen has the affectionate nickname “Vitamin I”, where it’s perceived as an essential ingredient for dealing with the consequences of training.
But NSAIDs have a long list of side effects. Not only do they cause stomach ulcers and bleeding by damaging the gastrointestinal mucosa, there are heart risks, too. It was the arrival (and departure) of the drugs Bextra and Vioxx that led to documentation of the potential for cardiovascular toxicity. And now there’s data to suggest that these effects are not limited to the “COX-2″ drugs – almost all NSAIDs, including the old standbys we have used for years, seem capable of raising the risks of heart attacks and strokes.
So despite my initial skepticism, I took another look at the topical NSAIDs. The data were not what I expected.
It has long been recognized that there are substantial multifactorial placebo effects that create real and illusory improvements in response to even an inactive treatment. There is a tendency, however (especially in popular discussion), to oversimplify placebo effects – to treat them as one mind-over-matter effect for all outcomes. Meanwhile researchers are elucidating the many mechanisms that go into measured placebo effects, and the differing magnitude of placebo effects for different outcomes.
For example, placebo effects for pain appear to be maximal, while placebo effects for outcomes like cancer survival appear to be minimal.
A recent study sheds additional light on the expectation placebo effect for pain. The effect is, not surprisingly, substantial. However it does not extrapolate to placebo effects for outcomes other than pain, and the results of this very study give some indication why. From the abstract:
The effect of a fixed concentration of the μ-opioid agonist remifentanil on constant heat pain was assessed under three experimental conditions using a within-subject design: with no expectation of analgesia, with expectancy of a positive analgesic effect, and with negative expectancy of analgesia (that is, expectation of hyperalgesia or exacerbation of pain).
What they found was that the positive expectation group reported twice the analgesic effect as the no expectation group, and the negative expectation group reported no analgesic effect. This is a dramatic effect, but not surprising.
Ear infections used to be a devastating problem. In 1932, acute otitis media (AOM) and its suppurative complications accounted for 27% of all pediatric admissions to Bellevue Hospital. Since the introduction of antibiotics, it has become a much less serious problem. For decades it was taken for granted that all children with AOM should be given antibiotics, not only to treat the disease itself but to prevent complications like mastoiditis and meningitis.
In the 1980s, that consensus began to change. We realized that as many as 80% of uncomplicated ear infections resolve without treatment in 3 days. Many infections are caused by viruses that don’t respond to antibiotics. Overuse of antibiotics leads to the emergence of resistant strains of bacteria. Antibiotics cause side effects. A new strategy of watchful waiting was developed.
What does honey bee colony collapse disorder have to do with a potential new cancer treatment?
They both relate – in a convoluted manner – to an old antibacterial drug called nitroxoline.
True to my devotion as a natural product pharmacologist, I’m proud to say that new life would not have come to nitroxoline had not a fungal natural product called fumagillin been studied as an antiangiogenic anticancer drug – one that inhibits the formation of new blood vessels.
Working in pharmacies where supplements are sold alongside traditional (over-the-counter) medications, I’m regularly astonished at the different perceptions consumers can have about the relative efficacy and safety of different types of products. Once, speaking with a customer about a medical condition she wanted to treat, I indicated that there were no effective non-prescription therapies — she needed to see a physician for access to an effective treatment by prescription — and I gestured behind the counter. “Back there?!” she pointed. “That’s where you keep the stuff that kills people! I want something natural!” Suggesting that my patients with heart disease or HIV had a somewhat different perspective, I tried (unsuccessfully) to talk her out of a questionable-looking supplement (Hint: avoid anything from a company with a P.O. box as a mailing address.) This appeal to nature, combined with a perception that natural products are safe, and conventional drugs are unsafe, is pervasive. (more…)
In discussing “alternative” medicine it’s impossible not to discuss, at least briefly, placebo effects. Indeed, one of the most common complaints we at SBM voice about clinical trials of alternative medicine is the lack of adequate controls — meaning adequate controls for placebo and nonspecific effects. Just type “acupuncture” in the search box in the upper left hand corner of the blog masthead, and you’ll pull up a number of discussions of acupuncture clinical trials that SBM bloggers have written over the last three years. If you check some of these posts, you’ll find that in nearly every case we spend considerable time and effort discussing whether the placebo or sham control used was adequate, noting that, the better the sham controls, the less likely acupuncture studies are to have a positive result.
Some of the less clueless advocates of “complementary and alternative medicine” (CAM) seem to realize that much of what they do relies on placebo effects. As a result, they tend to argue that what they do is useful and good because it’s “harnessing the placebo effect” for therapeutic purpose. One problem that advocates of SBM (like those of us at SBM who have taken an interest in this topic) tend to have with this argument is that it has always been assumed that a good placebo requires on some level at least some deception of the patient by either saying or implying that he is receiving an active treatment or medicine of some kind. This, we have argued, is a major ethical problem in using placebos in patients, and advocates of placebo medicine appear to agree, because they frequently argue that placebo effects can be harnessed without deception. Indeed, just last week there was an example of this argument plastered all over multiple news outlets and blogs in the form of stories and posts with headlines and titles like:
Except for one, every one of these articles or blog posts discussing a new study in PLoS ONE that purports to have found that placebo effects can be elicited in irritable bowel syndrome (IBS) without deception buys completely into that very thesis. For example, here is an example, taken from the Reuters story about this study:
Placebos can help patients feel better, even if they are fully aware they are taking a sugar pill, researchers reported on Wednesday on an unusual experiment aimed to better understand the “placebo effect.”
Nearly 60 percent of patients with irritable bowel syndrome reported they felt better after knowingly taking placebos twice a day, compared to 35 percent of patients who did not get any new treatment, they report in the Public Library of Science journal PLoS ONE.
“Not only did we make it absolutely clear that these pills had no active ingredient and were made from inert substances, but we actually had ‘placebo’ printed on the bottle,” Ted Kaptchuk of Harvard Medical School and Beth Israel Deaconess Medical Center in Boston, who led the study, said in a statement.