The road from an idea to a useful drug is a long one, and in cancer it is often particularly long. One reason is that to be able to tell whether a given treatment is effective against cancer often takes several years at a minimum, in order to determine if patients receiving the new treatment are surviving their disease longer than those who are not. Surrogate endpoints are usually not enough. Tumor shrinkage in response to a drug often does not correlate with prolongation of survival, although the converse (i.e., lack of tumor shrinkage in response to a new drug) does strongly correlate with failure of a treatment to prolong survival. In other words, effects observed on surrogate endpoints are not enough to judge whether a cancer therapy is working or not.

Three years ago, predating the existence of this blog by nearly a year, I became aware of a story that involved many of the issues in bringing a compound from the laboratory to the clinic. The case was unusual in that is is very rare to see the scientific process by which new drugs progress through the stages of cancer research, from concept to testing in cell culture to testing in animals to testing in humans challenged so strongly by patients themselves. The reason that this normally doesn’t occur is that new cancer treatments are almost always the product of either university-conducted research, pharmaceutical company-conducted research, or partnerships between the two. This case was markedly different in that it involved a chemical that was not only easy to synthesize, but cheap and long out of patent. Even more intriguing, it targeted a metabolic abnormality found in many cancer cells, an abnormality first described nearly 80 years before by Otto Warburg in 1928. This latter aspect of the drug gave it every appearance of a “rediscovery” of old wisdom that big pharma had ignored for 80 years, and that only added to its mystique.

The chemical was dichloroacetate (DCA), and three years ago it created a world-wide sensation. Last week, it created a sensation again, as breathless news reports once again overhyped its promise. Since I’ve been following the story since early 2007, I appear to be in as good a position as anyone to tell the story thus far and put the new findings into context. To begin that process, let’s head back to January 2007.

“The cure for cancer big pharma doesn’t want you to know about”

The DCA saga began in January 2007, when I started noticing a bunch of posts by various bloggers as well as news stories that all had similar titles, such as Cheap, safe drug kills most cancers, Objectively pro-cancer, Gotta pay, When promising cures are ignored, and, my personal favorite, Potential cheap, safe cure for cancer: Will Big Pharma Allow It? These stories described some intriguing work by University of Alberta researcher Evangelos Michelakis regarding this old/new drug that showed great promise in cell culture and rodent models of cancer (more on that shortly) that was published in Cancer Cell. Typical quotes I saved at the time:

• “Big Pharma won’t put up the dough to fund human research and enable this drug to come to market, there’s no money in it. In fact, it wouldn’t surprise me to discover that they had an interest in actively preventing the research so as to maintain demand for more expensive less effective drugs. This drug looks to be extremely promising, and I can’t imagine that it won’t get government funding for human trials, but that said, it doesn’t pay to underestimate the power of Big Pharma…” (unfortunately the original link is gone, but the text lives on)
• “And here I thought the pharmaceutical companies had to charge such high prices because of all the research they were doing. Seems without the possibility of future revenue they can’t be bothered. Of course, a cheap cure for cancer would cut into profits in so many ways, wouldn’t it?” (From Digby, who really, really should have known better, but didn’t.)
• “It seems to good to be true. A cheap, effective cancer cure that BigPharma doesn’t own. If further research proves effective in humans, it could be the answer to many peoples prayers. I’ve always thought something simple, rather than the current convoluted regimen of surgery, radiation and chemicals would be the cure for cancer. Again, if proven effective, will we ever see it in use in this country? Will patients have to take ‘DCA tours’ to Canada for treatment?” (Source: Randular’s diary.)
• “Here’s the big catch. Pharmaceutical companies probably won’t invest in research into DCA because they won’t profit from it. It’s easy to make, unpatented and could be added to drinking water. Imagine, Gatorade with cancer control.” (Source; this particular editorial was truly overwrought.)
• “My bet is that the dichloroacetate news will fade into the background very quickly. Because neither the US government, nor any major university, nor any private company (pharma or otherwise) will have the least bit of interest in funding further studies. There will be a small handful of tiny, underfunded studies, and that will be that. Indeed, already those with vested financial and personal prestige issues will be doing their best to put the brakes on anyone who takes this development seriously. Not because the megacomplex of big government and big business wants to kill people–it doesn’t, there are few if any mustache-twirling villains–but because of the age old factors of bureaucracy, personal pettiness, ego, and conflicts of interest.” (Source: Dean Esmay, scroll down for post.)

Note that there were two assumptions here three years ago. First, these bloggers and pundits assumed that the cell culture and animal work were definitive evidence that DCA might be a “cure” for cancer. Second, the assumption was that, because the drug was out of patent and very cheap to make, neither the government nor pharmaceutical companies would be interested in funding it, thus condemning thousands, maybe millions, of people to die of cancer unnecessarily. Unfortunately, the New Scientist article and articles in the Edmonton Sun featured headlines to that effect and quotes by the investigator Evangelos Michelakis lamenting how he had had difficulties finding funding to do the next step, clinical trials in cancer. As a result of these sensationalistic stories, unscrupulous “businessmen” sought to bring DCA to the masses.

DCA and the Warburg effect

DCA is a very simple molecule, deceptively simple. Basically, it is an analog of acetic acid in which two of the three hydrogen atoms of the methyl group have been replaced by chlorine atoms. Interestingly, it is only one chlorine atom off from trichloroacetic acid (TCA), a chemical we routinely use in the laboratory to precipitate nucleic acids and proteins from solution. The structure of DCA is depicted below.

DCA has been around for a long time (which is why is it no longer under patent) and has primarily been used for inherited diseases of mitochondrial metabolism. Mitochondria are often (and correctly) referred to as the “powerhouses” or the “batteries” of the cell, because it is in the mitochondria that the main energy-containing molecule, ATP, is produced using byproducts of glycolysis and the Krebs citric acid cycle to generate a proton gradient across the mitochondrial membrane, which supplies the energy for the enzyme ATP synthase, which, true to its name, synthesizes ATP for use in the cell as a chemical source of energy. The key thing to remember about oxidative phophorylation is that it requires oxygen, whereas glycolysis does not. When there is insufficient oxygen, the end products of glycolysis end up being turned into lactic acid, which is one of the things that make muscles feel tired after a rapid workout that exceeds the capacity of the body to deliver oxygen to the tissues. The primary activity of DCA in cells is to inhibit the enzyme pyruvate dehydrogenase kinase. The result, to boil it down (and not to have to stress my knowledge of the basic biochemistry of glycolosis, the Krebs cycle, and oxidative phosphorylation too much) is to shift the metabolism of pyruvate from glycolysis towards oxidation in the mitochondria. To boil it down even further, DCA shifts the cell’s metabolism from anaerobic to aerobic metabolism.

The three components of glucose metabolism are shown below in simplified illustrations:

Why, then, would such an activity be useful as an anticancer therapy?

It all boils down to something known as the Warburg effect, which Otto Warburg first described way back in 1928 and reported in Science back in 1956. Over the last five years or so, cancer researchers have been increasingly coming to appreciate the role of abnormalities in metabolism, in particular the mitochondria, in cancer. To put it briefly, many cancers (approximately 60-90%) favor glycolysis, even in the presence of adequate oxygen for oxidative phosphorylation, leading to a voracious appetite for glucose. Indeed, it is this very avidity of cancer cells for glucose that is the basis of the PET scan, which detects the high uptake of a radiolabeled form of glucose by cancer cells relative to the surrounding normal cells.

Over the last few years, there has been a sort of “chicken or the egg” argument about what is more important and what is the first abnormality leading to cancer. The traditional view has long been that mutations in DNA lead to the activation of protooncogenes into cancer-initiating and causing oncogenes and to the shutdown of tumor suppressor genes. Under this model, mutations leading to cancer also lead to the observations of abnormalities in metabolism. In the wake of the DCA furor, there have been data reported suggesting that the metabolic derangements may actually occur first or simultaneously with the mutations. p53, for instance, the granddaddy of tumor suppressor genes, can trigger the Warburg effect when mutated. Whatever the case, it is now fairly clear that abnormalities in cancer cell metabolism are very important in driving cancer growth and could well represent targets for cancer therapy. AS a result of these new data, studying the metabolism of cancer cells has become a much hotter topic of research than it has been in the past. Everything old is new again, it seems. Why cancer cells might have an advantage due to the Warburg effect is a matter of debate, although, given how tumors frequently outgrow their blood supply, being able to maintain themselves in low oxygen situations would be advantageous.

This fascinating basic science met the public in January 2007, when Michelakis and his colleagues at the University of Alberta in Edmonton published a seminal paper in Cancer Cell. In the study, DCA was tested in multiple cell culture and rodent models of cancer. In rats, tumor weights in animals treated with DCA were approximately 60% lower than the tumors in the untreated control groups. The drug increased apoptosis, decreased proliferation, and inhibits tumor growth by acting on a critical enzyme that controls the switch between aerobic and anaerobic metabolism without harming non-cancerous cells. Even better, DCA had already been FDA-approved for mitochondrial disorders, meaning that using it in humans would be an “off-label” use of an already existing drug to test it in humans. Thus, the regulatory requirements were considerably easier to meet for early drug trials in cancer.

The “Pet DCA” phenomenon

The media coverage of the Michelakis study unleashed the proverbial perfect storm of conspiracy mongering about big pharma. Never before (at least that I can recall) had a chemical that was so cheap and so easy to synthesize, not to mention already used in patients for another indication, been reported as being a “cure” for cancer. This hype, of course, neglected what those of us who do cancer research as part of our living, namely that many are the candidate drugs that show a great deal of promise in animals but fail in humans and that at present there is no such thing as a “cure for cancer.” I like to think of the example of angiogenesis inhibitors, which I’ve been studying for 13 years now. Part of what attracted me to the study of these compounds were the amazing results of the late Dr. Judah Folkman in mice, which I’ve described on this blog before. However, the amazing results in mice did not translate to humans. That’s not to say that angiogenesis inhibitors don’t work, but in humans they did not produce anywhere near as dramatic results as they did in Dr. Folkman’s mouse experiments. That’s why, rather than being a “magic bullet” for cancer, angiogenesis inhibitors entered our armamentarium of anti-cancer drugs as a useful, but not miraculous, new addition. Avastin, for instance, has increased the five year survival rates in colorectal cancer metatastic to the liver and several other cancers, when added to the current standard of care, but it has not resulted in the cure of any metastatic cancer.

That being said, I can understand how cancer patients incurable with standard therapy would leap at this drug as their last hope. Unfortunately, there were unethical “entrepreneurs” who were more than eager to supply DCA to them. The most famous of these who appeared in the months following the publicity surrounding Michelakis’ study was a pesticide dealer named Jim Tassano, who leapt to create a website known as TheDCASite.com and BuyDCA.com (the latter of which appears to be unreachable at the moment). His way of getting around the FDA? To market his DCA as “Pet DCA,” to be sold for pets dying of cancer. It was as disingenuous an approach as could be imagined, because not only did Tassano openly admit that he knew that people were buying the drug for themselves but he blithely dismissed the possibility of serious side effects in adults. Although children could take the drug with few side effects, adults who took the drug often developed serious severe peripheral neuropathy. Since peripheral neuropathy is a side effect of some commonly used cancer chemotherapeutics, taking DCA with these cancer chemotherapies has the potential to do serious harm. Moreover, when asked about the source of DCA, the webmaster Heather Nordstrom replied:

In my opinion, it is not that difficult to get, but that may be because my step father has connections with manufacturers since we invent and sell tools for our family business. We know of a chemical company in China that makes DCA. It is pharmaceutical grade. More information on the quality and source will be posted on the website that sells it.

Naturally, I was…skeptical. Worse, scammers were hyping DCA as not being “chemotherapy,” when, if it works for cancer, that’s exactly what it is.

Meanwhile, cancer patients and their families flooded the discussion boards of TheDCASite.com to write about their self-experimentation. Here are a couple of posts that I saved (the DCASite.com purged many of its forums when it started to get into legal trouble):

My husband has been using DCA since early February. He has Glioblastoma, an aggressive brain cancer that DCA is proposed to target. The naDCA he is using was made in a private lab. We turned away from our medical community, realizing that we would not receive blessings from them, since they considered him a “dead man walking”. From what I have read here, my husband seems to be the earliest “labrat”. We obtained the DCA in early February, started at a 5% dose,(to test toxicity or side effects, I suppose) and after 4 days , he insisted on taking 25mg per kg. He takes a liquid dose twice a day( totaling 25mg per kg). He has been taking DCA since Feb 7, 2007, with full dose as of Feb 11. No side effects to report as yet. Though side effects of DCA(numbness in fingers and appendages) are also symptoms of his disease, there are none to report at this time. He is also taking 100mg per day of thiamine. He is also on CCNU, Heparin, and 16 mg steroid. So far, so good. I am taking weekly urine samples to check his billyrubin, ph , etc. He still sees an oncologist, and takes chemo( CCNU). His doctors do not know that he is taking DCA. I do not trust them, they have not been terribly compassionate through this, and I do not feel that they would be as knowledgable as those of us that are in these desparate situations. I pray for all of us that I can report great news in the weeks to come. I still can’t decide at this point if he should take THiamine or not? Any thoughts?

My thought at the time was that this woman’s husband was endangering his life by taking DCA along with his chemotherapy and not telling his doctors about it. Meanwhile, as time went on, someone on the DCASite actually questioned the anecdotes in May 2007:

Maybe I am crazy but it seems like every time I ask this question the admin removes it – if not then where is the question I asked last time?

I am asking this Question -

Do we want to know or not? is this a site for lies or truth? I have DCA and I also sent money in for the clinical trials as well as having my wife dealing with stage four lung cancer currently stable with antioxident regimens. Today we go in with DCA to see if her oncologist will support her using it.

Some news here would sure be great but NO ONE who has been CT scanned after using DCA for a couple months is talking or coming back except for squareb who gave us bad news. What is going on here? are we participating in a venting session where these folks are linked with those folks selling us DCA? what exactly is going on – our lives and our loved ones lives are on the line and not ONE CT SCAN in 4 months!!!! or the TRUTH is being removed from the site and people who had scans did post bad results so it was also removed like my questions are.

I am not happy about this admin – gee sorry I lost everything sorry – what? didn’t this happen last month on another persons testimony who DIED!! while using DCA. Something is definitely missing here and I am starting to think its THE TRUTH.

I believe in DCA but I am starting to think these admins are manipulating the information to suit them which is pretty typical for us trying to survive to run into. Sorry but these admins need to either post it ALL or explain why they are not allowing CT scan results to be listed on this site. Folks just think about it – Jan, Feb, March, April and now May – 4 months and nothing – come on folks lets get real here – do you really think its a coincidence?.

It is too bad that more people didn’t ask questions like this. squareb, by the way, was an early adopter of DCA whose tumor progressed on the drug.

Unfortunately, Jim Tassano wasn’t alone. For example, a family physician in Toronto named Dr. Humaira Khan, even though agreeing with the warnings not to use DCA outside the auspices of a clinical trial, decided to start selling DCA for $150 a week, using arguments of “health freedom” and wanting to “supervise” patients who would take the drug anyway. Dr. Khan’s webpage on DCA appears not to have been updated since 2008 but is claiming a high response rate. Odd, though, I haven’t seen this published anywhere in the peer-reviewed scientific literature, and a PubMed search turns up…nothing, at least nothing by Dr. Khan or anyone associated with her. Jim Tassano himself also tried to do a “clinical trial” of DCA that was basically nothing more than a questionnaire that–I kid you not–included questions like:

• Do you think DCA is working for you? Why or why not? Scans? Examinations? Blood level testing? Here, I encourage you to freeform answer.
• How do you rate your health compared to when you started DCA? 1. Much better; 2. Somewhat better; 3. About the same; 4. Somewhat worse; 5. Much worse

I trust that SBM readers will immediately recognize why such questions are worse than useless. Basically, they are doing nothing more than soliciting testimonials, and testimonials in cancer are often highly misleading, and that’s all TheDCASite has now. This is just as true for something like DCA as it is for any alternative medicine cancer therapies. Fortunately, in July 2007 the FDA finally acted to shut down TheDCASite.com, at least as far as selling DCA went. In response, Tassano shut down BuyDCA.com and morphed TheDCASite.com into an “informational” website. Much of what was on the forums there disappeared. Meanwhile, conspiracy theorists had a field day denouncing the FDA’s action.

Back to the future

Over the last couple of years, my biggest fear was that the activities of “entrepreneurs” like Jim Tassano would taint what is a scientifically fascinating and potentially very useful new cancer therapy with the indelible stain of quackery. DCA is most definitely not quackery. It is, however, unproven in humans and thus may not be effective, which is why self-treatment and treatment by doctors who have no clue what they are doing are not advisable. Fortunately, while ignorant businessmen like Tassano and opportunistic doctors were selling DCA to desperate cancer patients, a clinical trial was beginning by Michelakis and his team, and last week the results were reported in Science Translational Medicine entitled Metabolic Modulation of Glioblastoma with Dichloroacetate.

The first part of the study was something quite fascinating that I don’t recall ever having seen before in a clinical trial. Michelakis and colleagues studied 49 consecutive surgically excised glioblastomas. Glioblastoma is an aggressive form of brain cancer known to exhibit the Warburg effect and thus a good candidate for the first attempts at testing DCA in humans. These tumors were then tested in vitro with DCA. The excised tumors did demonstrate evidence of the Warburg effect, and treatment with DCA resulted in significant reversal of some of these features in the excised tumors, particularly mitochondrial hyperpolarization, while not having any effect on normal tissues excised with the cancers. The second part of the study is what most media and blog reports focused on. Michelakis treated five patients with neuroblastoma with oral DCA. However–and this needs to be emphasized–patients were also treated with temozolomide and radiation, with DCA added to the mix. The DCA dose started at 12.5 mg/kg orally twice a day for 1 month, and then the dose was increased to 25mg/kg orally twice a day. Michelakis then followed a dose de-escalation protocol, decreasing the dose by 50% when dose-limiting toxicity occurred. The patients were followed clinically for up to 15 months. In other words, this appeared to be a combined phase 0/phase I clinical trial.

For those not familiar with the various types of clinical trials, phase I clinical trials are not trials of efficacy. They are designed to determine two things: dose and dose-limiting side effects. They generally use a few patients (although five patients represent a rather small number, even for a phase I trial, which usually requires around 10 or 20), and it is not uncommon to perform a dose escalation. Researchers don’t expect necessarily to see tumor response in a phase I trial, as that is not the purpose of the trial, but it is heartening when tumor shrinkage is observed, for obvious reasons. Phase 0 trials similarly are not therapeutic trials but rather seek to determine if the drug is doing biochemically what it is expected to do based on preclinical studies. The usual design is to take a biopsy of the tumor, test it for biochemical markers in the laboratory, treat the patient with experimental drug, and then resect the tumor. The biochemical markers in the resected tumor are then compared with those measured in the pre-treatment biopsy. The idea is to see whether the drug can recapitulate biochemical changes in actual living tumors in human patients, the idea being that, if it can, then the drug is “hitting the target” (i.e., its molecular target) and therefore “working.” Whether its “working” actually shrinks tumors or results in prolonged patient survival is then the next question that has to be tested.

Michelakis went one further in that he isolated tumor cells from the pretreatment biopsies and produced glioblastoma cell lines. He could do this in three of the patients because he had tissue from their first debulking surgery, and these patients had recurrent glioblastoma that had failed additional chemotherapy (patients 1 through 3). All of them had had multiple rounds of different chemotherapy. Patients #1 and #2 showed signs of improvement or were at least stable for the full 15 months of the study, while patient #3 died three months after starting DCA therapy. Two other patients (patients #4 and #5) had new diagnoses, allowing initial tumor tissue from debulking surgery to be examined. Their treatment was somewhat different. After his first surgery, patient #4 underwent DCA therapy for three months followed by DCA and standard therapy. However, by the end of the third month, the patient showed evidence of progression requiring a second operation. Patient #5 underwent surgery followed by DCA and radiation with temozolomide for six months and then stayed on DCA for nine more months and is doing well.

The reason I mention this is because not only were there only five patients, but they were not all even treated the same way. They were treated with varying regimens of surgery, with drug therapies combining DCA and chemotherapy (mostly temozolomide), some with and some without radiation. Even so, the tissue from these tumors showed signs of metabolic reversion to an oxidative phosphorylation phenotype. The problem is, as both our very own David Kroll pointed out, we don’t know for sure if the DCA was responsible for this effect. As a cancer researcher, I can’t say whether the regressions observed were due to DCA, although the regression of paraventricular masses in patient #1 and the regression observed in patient #5 are certainly fairly suggestive (at least to me) of an anti-tumor effect due to DCA alone. The only side effect Michelakis reported was a reversible change in peripheral nerve function.

So what does this all mean?

I’m frequently asked why we shouldn’t just use DCA now–or even let people use it the way that they were using Jim Tassano’s homemade DCA? What’s the harm? That’s a rather difficult question, because there is always a conflict between wanting to do something now for suffering patients, damn the consequences, and following the scientific method to demonstrate efficacy and safety. Our nation has been at both extremes. Indeed, until 1906, pharmaceutical companies could make essentially any claims and sell essentially anything to the public as a drug without regulation. We all know how well that worked out. Early in the history of the FDA, as Dr Jerome Groopman points out, companies often tested new drugs by sending them to doctors to offer to their patients, asked for little information regarding side effects and complications, and had no standard criteria for efficacy. There was a reason we moved away from such a system.

I think Dr. J. Leonard Lichtenfeld, Deputy Chief Medical Officer for the national office of the American Cancer Society, put it well in writing about this latest DCA study on his blog, Dr. Len’s Cancer Blog:

This research still needs lots of work before we know whether it works or doesn’t work, and whether it is really safe or not when given to patients with cancer under a variety of circumstances.

If that sounds overly cautious, so be it. I have seen too many dashed hopes in my medical career which make me a bit cautious about reports like this. That’s not to say I don’t think it could work—it could, as I mentioned above—but I want to see evidence in well done trials that prove the point that DCA is effective in the treatment of which cancers under what circumstances.

Early in my cancer training there was a substance isolated by a researcher that was supposedly non-toxic and would cure leukemia. The research center where I was working was inundated from people around the globe who wanted this treatment, especially after the lead researcher injected himself on a nationwide morning show to demonstrate its apparent lack of toxicity.

Only grams of this medicine existed. Fortunes were offered in return for getting this miracle drug.

But the miracle drug—after reasonable clinical trials were done—didn’t work after all.

Many are the lists of new “miracle cures” that have met this same fate. The difference today is that the Internet has allowed news of these drugs to be disseminated to more people than ever before–and faster than every before. Moreover, it has linked patients and activists into mutually supportive disease-specific communities, who can inform and educate each other, as well as publicizing research about their disease and lobbying legislators. The dark side of this power, however, is that it can facilitate the spread of false hope and the demand for a drug after only cell culture and animal work, before it even makes it to human trials. Add unscrupulous “entrepreneurs” into the mix, and the potential for harm is great.

One has to remember that cancer is not just one disease. Not only that, but even a single type cancer is often not just one disease. As I have written extensively about before, cancer is incredibly complex. Because of that complexity, it’s incredibly unlikely that any one drug will be any sort of “magic bullet” to cure cancer. Worse, simply using a drug like DCA outside the auspices of well-designed clinical trials will virtually guarantee that we will never know for sure whether the drug actually works. Because of that, as frustrating as it is, as slow as it is, letting science take its course to determine if DCA works, how it works, and for what cancers it works, is the best method to make sure that the most patients are helped and the fewest are harmed. I don’t say this because I want DCA to fail; I say it because I would very much like to see DCA succeed.

Other good posts about DCA:

• Potential cancer drug DCA tested in early trials
• More On Dichloroacetate (DCA) In Cancer Treatment
• DCA And Cancer: More Results
• Dichloroacetate not yet an effective treatment for aggressive brain cancer

Two recent acupuncture studies have received some media attention, both purporting to show positive effects. Both studies are also not clinical efficacy trials, so cannot be used to support any claims for efficacy for acupuncture – although that is how they are often being presented in the media.

These and other studies show the dire need for more trained science journalists, or science blogging – they only make sense when put into a proper context. No media coverage I read bothered to do this.

The first study comes out of South Korea and involves using acupuncture in a rat model of spinal cord injury. The researchers used a standard method of inducing spinal cord injury in rats, and compared various acupuncture locations to no-acupuncture control. They followed a series of metabolic outcomes, as well as the extent of spinal cord injury and functional recovery. They conclude:

Thus, our results suggest that the neuroprotection by acupuncture may be partly mediated via inhibition of inflammation and microglial activation after SCI and acupuncture can be used as a potential therapeutic tool for treating acute spinal injury in human.

The notion that acupuncture will actually improve outcome after acute spinal cord injury is, of course, extraordinary. This goes far beyond a subjective decrease in pain or some other symptomatic benefit. Therefore similarly extraordinary evidence should be required to support such a claim – and this study does not provide that.

In reading through the details of the study several factors caught my attention. The first is that there is no indication that the researchers were blinded. This alone calls the results into serious question. It is all too easy for researchers to allow personal bias to affect study results, even when they seem quantitative. We need look no further than the homeopathy research of Jacques Benveniste to see this (initial impressive results were investigated by Nature and found to be the result, charitably, if inadequate blinding).

Further, the researchers looked at several acupuncture points and then chose the ones that seemed to have an effect. This allowed for retrospective cherry picking – it is possible, in other words, that they received a scattering of random effects and chose the ones that appeared positive.

The effect sizes themselves, while statistically significant, were not clinically impressive. If they were real they would be useful in the treatment of spinal cord injury, but that is the point. Such small effect sizes are easily the product of randomness or bias.

And finally it should be noted that the study is coming out of South Korea. It is well established that countries where acupuncture is culturally important tend to have a much higher positive outcome rate than the same research in Western countries. The motivation to prove acupuncture seems to be a significant bias. Similarly, we recognize that there is a bias in favor of efficacy for pharmaceutical company sponsored research – the principle is the same. The bias of the researchers, even when well-controlled on paper, is measurable.

The bottom line with this study is that it provides weak evidence for a very extraordinary claim. It is of no practical use unless and until it is independently replicated with proper blinding. If you believe what you read in the media, however, you would be led to the conclusion that spinal injured patients could be made to walk again simply by sticking needles into magical locations on their body.

The second study uses quantitative sensory testing (QST) to look at pain threshold at baseline and after acupuncture and “electroacupuncture”. They conclude:

There were congruent changes on QST after 3 common acupuncture stimulation methods, with possible unilateral as well as bilateral effects.

In other words – acupuncture decreases the perception of pain. This small study suffers from the same primary problem as the other – it is described as only single-blinded. The subjects themselves were not blinded to whether or not they were getting “real” acupuncture vs a sham or placebo. The totality of prior acupuncture research has clearly demonstrated that such unblinded studies are all but useless. There is a significant placebo effect from getting poked with needles, and this is sufficient to explain the results of this study.

While QST is quantitative, it is still subjective. In fact, using QST has fallen a bit out of favor in neurological studies because the elaborate procedure is no more reliable as an outcome measure than straightforward sensory testing. QST is still reliant on the subjective report of the subject.

Further, this study mixed acupuncture with “electroacupuncture.” I strongly maintain that there is no such thing as “electroacupunture” – it is, rather, the application of transcutaneous electrical stimulation through an acupuncture needle. This is no more acupuncture than the application of morphine through a hollow acupuncture needle should be considered acupuncture.

It is possible that needling and electrical stimulation do decrease subjective pain perception (although we can’t conclude that based upon this study). One pain or sensory stimulation can certainly distract you from another. There is also the principle of counter-irritation – the inhibition of pain pathways by activating parallel sensory pathways. Bang your elbow and you will rub it to decrease the sharp pain.

Conclusion

Given the state of the acupuncture literature, such small and insufficiently blinded studies are of little value. It has already been established that there is a significant placebo effect surrounding the ritual of acupuncture and there are mechanisms of non-specific effects, such as counter-irritation. None of this can be logically used to support the underlying assumptions of acupuncture – that there is anything special about the designated acupuncture points, or that they can be used to manipulate “chi” or some other mysterious energy.

We are already well past the stage of preliminary studies in acupuncture. Only rigorously controlled studies are of any use. And the term “electroacupuncture” causes only confusion and cannot be meaningfully used. It is the blurring of variables when good science should endeavor to isolate variables.

Also, in a perfect world, the general press would not report on every preliminary study as if they were a definitive medical breakthrough. Such medical news stories should be covered in more focused outlets that have the space and expertise to put the results into a reasonable context.

It is my pleasure to announce the addition of a new SBM blogger. Impressed by his dedication to applying scientific principles to the profession of pharmacy, we have recruited Scott Gavura, who is currently best known for his work on Science-Based Pharmacy. You can find out a bit more about his background at his new page on SBM, and his first post is scheduled for Thursday, May 13. In the beginning he will be posting approximately once every four weeks.

Please join me in welcoming Scott to the SBM team.

For most of human history, doctors have killed their patients more often than they have saved them. An excellent new book, Taking the Medicine: A Short History of Medicine’s Beautiful Idea, and Our Difficulty Swallowing It, by Druin Burch, MD, describes medicine’s bleak past, how better ways of thinking led to modern successes, and how failure to adopt those better ways of thinking continues to impede medical progress.

The moral is not that doctors once did foolish things. The moral is that even the best of people let themselves down when they rely on untested theories and that these failures kill people and stain history. Bleeding and mercury have gone out of fashion, untested certainties and overconfidence have not.

Burch’s conversation with his rowing coach epitomizes the problem:

“I want you to keep your heart rate at 85% of max for the next hour and a half.”
“Why?”
“Because it’s the best way to improve your fitness.”
“How do you know?”
“Because I’ve done it before and it worked. Because that’s what the people who win the Olympics do. I know, I’ve trained some of them.”
“But has anyone actually done an experiment?”
“What on earth are you talking about?”

This book is Burch’s answer to his coach’s question. Medicine’s “beautiful idea” is that we should test all hypotheses and beliefs using the kind of tests that are reliable for determining the truth. Instead of going by tradition, authority, theory, common sense, or personal experience, we now have effective tools to find out for sure whether a treatment really works.

The scientific method developed slowly and there were a lot of hiccups on the way. Researchers frequently misunderstood what constituted evidence.

In an early Chinese experiment, two people were asked to run together. One was given ginseng; the other, who didn’t get ginseng, developed shortness of breath. They thought that was sufficient evidence to prove that ginseng prevented shortness of breath.

Galen gave one of his potions to a lot of patients: some recovered, some died. He thought that was evidence that the potion worked, because

All who drink of this treatment recover in a short time, except those whom it does not help, who all die. It is obvious, therefore, that it fails only in incurable cases.

Galen’s fallacious reasoning is easy to spot, but a 20th century doctor committed a similar error. He gave all his patients aspirin and asserted it was 100% effective in preventing heart attacks. Some of them did have heart attacks, but he didn’t count them because on close questioning he found that they had omitted doses or otherwise didn’t strictly follow the aspirin protocol (which was probably equally true of all his patients).

Even after the importance of randomization was recognized, there were errors in applying the principle. In early trials, randomization was by alternate allocation, where the first subject to enroll is put in group A, the second in group B, the third in group A, etc. But doctors tended to bend the rules to put certain patients in the treatment group. True randomization had to be forced on doctors who thought they knew what was best for their patients and who didn’t even realize they were cheating.

Humility is required of those who have theories rather than evidence. If they design experiments simply to confirm their prejudices, they are in danger of designing bad ones or misinterpreting results. The more researchers want to prove that the results were due to their favored treatment, the more exhaustive should be their search for alternative and equally reasonable explanations.

Burch’s book is a history of medicine with many intriguing stories about people, personalities, penicillin, opium, thalidomide, and the other usual subjects of medical history; but it is also an explanation of the scientific method and a commentary on modern medicine’s failure to rigorously and consistently apply that method.

Despite our increasing acceptance of the scientific method, the term evidence-based medicine (EBM) didn’t appear in the medical literature until 1991. Critics of scientific medicine have unfairly claimed that less than 10% of treatments are EBM. Burch points out that evidence doesn’t just consist of randomized controlled trials (RCTs), and that we have good evidence that parachutes save lives without having to do an RCT on parachutes. The 10% figure is way too low: a recent study estimated that 80% of current treatments are based on evidence.

Testing and experiment have failed to protect us from deluded cures and poisonous remedies. They can’t be relied upon unless they are carried out with method and rigor. Understanding previous mistakes helps us to avoid them.

Burch has some harsh things to say about current medical research and the processes of drug approval. Many treatments accepted as EBM are actually based on poor quality studies. 62% of studies change the definition of what they are studying between ethical approval and publication. Some studies are stopped prematurely because of apparently clear benefits or risks to patients: this is usually a mistake that diminishes the quality of data. It might be better to finish the study as planned and harm a few patients today than to harm thousands of patients later because of a false conclusion.

People worry about withholding new drugs from needy patients while they undergo testing. They worry about the ethics of offering placebos to patients when a new drug offers an apparently effective treatment. But history has shown that the new drugs in these trials are just as likely to harm as to help.

A drug’s effects, even if they are moderately large, can almost never be reliably figured out on the basis of personal experience.

Doctors are still reluctant to trust science when it goes against their prejudices. He tells how cardiologists strongly supported the first Coronary Care Units (CCUs). A study was done comparing CCU treatment to home treatment for heart attacks. The researchers told the cardiologists that there were fewer deaths in the CCU but that the difference didn’t reach statistical significance. The cardiologists all thought this trend was a strong enough reason to insist on CCUs. Then the researchers admitted they had lied: the numbers were correct but reversed. The trend had actually favored home care. Based on the same quality of evidence, the cardiologists now did not consider the data a strong enough reason to insist on home care!

Medicine is becoming more scientific and more evidence-based every day, but we can and should do better.

What is needed is a culture, regulatory and intellectual, where every attempt is made to ensure new medical interventions are used solely in randomized trials. Only when their effects have been determined should they become available for use outside a trial setting. Until then there is a moral obligation on doctors to use unknown drugs and treatments only in such a way as to come to an understanding of them, and a moral obligation on patients to demand treatments that are either supported by sound evidence or only given as part of a trial which will uncover some.

This is good advice for mainstream medicine, and it is even more important for alternative medicine, which Burch doesn’t address. Since by definition “alternative” medicine is medicine that has not been proven effective, following these guidelines would eliminate any use of alternative medicine outside of a clinical trial. I know, the money isn’t there and it would be difficult to implement, but the principle is irrefutably sound. (That’s assuming that we want to avoid using placebos and find out what really works; but I don’t think the general public wants that. I suspect they would resist and prefer to cling to untested beliefs.)  

Here’s a sampling of some of Burch’s quotable words of wisdom:

There is a bitter joke in modern medicine: the violence with which someone makes an argument is inversely proportional to the amount of evidence they have backing it up.

Trials can be full of statistics; difficult to understand and laborious to undertake. They have a loveliness to them all the same, and it comes from their power to uncover parts of the reality we live in.

[It is] our nature to prefer credulity to doubt, confidence to skepticism. We share a tendency to simplify and confuse things, to slip into mental habits that let us down.

The idea that even the most reasonable-sounding theories should be subjected to tests probably has more potential to make the world a better place than all the drugs that doctors possess. Economics, politics, social care and education are full of policies that are based on beliefs held as a matter of principle rather than because they are supported by objective tests. Humility, even more than pills, is the healthiest thing that doctors have to offer.

I highly recommend this book. It’s well-written, entertaining, and provides much food for thought. It’s a great way to learn about fascinating incidents in the history of medicine and a great way to learn what constitutes truly science-based medicine and how to avoid the errors of the past, the errors in thinking that we flawed humans are all susceptible to.

Spring is here.  I don’t say that because of the warmer weather, the blooming tulips in my back yard, or the current effect of the earth’s axial tilt on the Northern hemisphere.  No, in my somewhat warped world of the pediatric ICU seasons are marked by illnesses and injuries with an annual rhythm.  Fall begins with a spike in cases of bronchiolitis, Summer with a near-drowning in a swimming pool.  Winter has arrived when seasonal influenza reappears.  And Spring, well, Spring has several harbingers, including auto vs bicycle accidents, falls from windows, and snakebites.

Sure enough, this week we admitted our first child of the year bitten by a venomous snake who, like most people unfortunate enough to be envenomated by a North American pit viper, has done very well.  This child fell prey not only to our local limbless fauna, but also to one of several common myths or misunderstandings about snakebites that place the victim, rescuer, or both at higher risk for injury and complications.  This post will explore some of the more common mistakes people make during North American snakebite encounters (being limited to snakes native to North America, the following does not necessarily apply to snakes from other areas).

File this post under Science-Based-You’re-Not-Helping-Please-Don’t-Do-That.

Myth #1: You Need to Know the Species / Kill the Snake

North America has around 120 species of snake, over 20 of which are venomous.  With so many species, it may seem important to ID the snake so the docs in the ED can give the appropriate anti-venin.  Fortunately, that isn’t the case.

All venomous North American snakes fall into one of two families, the Elapidae, and the Crotalinae.  Crotalinae encompasses most of the venomous species commonly encountered, including the Copperhead, the Cottonmouth (aka Water Moccasin), and all rattlesnakes.  Elapidae, on the other hand, is represented by only two species in North America, both a type of coral snake.

The close evolutionary relationship of these snakes (except the coral snake) means that the venom of all Crotalinae is very similar.  Venom is a mixture of a variety of different enzymatic proteins and low-molecular-weight polypeptides, in the case of Crotalinae including proteolytic enzymes, collagenase, hyaluronidase, phospholipases, RNase, DNase, phosphodiesterase, lactate dehydrogenase, a thrombin-like enzyme, and more.  It’s nasty stuff.

Though people have tried to label certain venoms as “hematotoxic” or “neurotoxic,” the sheer variety of proteins and their broad range of actions make this labeling somewhat misleading.  Symptoms and findings at the site of the bite include rapid swelling, bruising, pain, and erythema, while systemic symptoms include nausea, vomiting, oral paresthesias (odd sensations) including a metalic taste, low blood pressure, rapid heart rate and breathing, a markedly deranged ability of the blood to clot, kidney damage, altered levels of conciousness, weakness, double vision, and more.  The volume of venom and relative proportions of its component molecules vary species to species and snake to snake.  However, since the molecules themselves are so similar (and in many cases identical), a single antivenin is capable of treating the venom from all species within the family Crotalinae.

This fact mean clinicians need only ensure that the bite A) didn’t come from a zoo or private collection containing a non-North American venomous snake, and B) that it wasn’t a coral snake, before selecting which antivenin to administer.

How can a doc be sure someone wasn’t bitten by a coral snake?  After all, it does require a different and difficult to obtain antivenin from the Crotalinae. Here again we are assisted by happy chance.  Coral snakes have a very limited range, and can be ruled out in the majority of states.  In areas where the coral snake is endemic, it is easily identified by its red/yellow/black coloration at a distance.  Even an un-witnessed bite can frequently be distinguished by the symptoms and physical appearance of the bite on arrival.  Furthermore, coral snakebites while very serious are quite uncommon, making up only ~1% of venomous bites.

Physicians almost invariably have all the information they need to treat North American venomous snakebites from knowing the geographic location where the bite occurred and the patient’s history and physical exam.  No snake corpse is required or desired.

What’s the harm in killing the snake?  I’d think this was obvious were it not for the nearly ubiquitous element of snakebite histories that people went out of their way to kill the offending animal (the family this week did exactly that).  The risk of trying to kill a snake is that you can be bitten too.  Of all venomous snakebites, almost half occur while people are trying to kill a snake.  They place themselves at risk for no benefit to the person already bitten. Oh, and people will frequently then bring the “dead” snake in to the ED.  Is it dead?  Probably, but since the bite reflex can remain intact for a short time after death, I’d rather not risk my life on your skill as the Great White Hunter.

The best plan is to get everyone safely away from the snake and call animal control to get the animal away from your home, don’t try to do it yourself, and don’t bring it to the hospital.  Please.

Myth # 2: Most Snakebites are Rapidly Lethal

I remember speaking to a 12-year-old last year who was 2 days out from his bite and doing well, only to find that he still fully expected to die from the bite.  A snake, after all, had bitten him and snakebites kill you!  It broke my heart that I had allowed him to live with this fear for two days.

I should have anticipated his fear, because his reaction is not at all uncommon.  Most parents (and children old enough to know) are terrified when their child is bitten by a venomous snake.  Though entirely justified, their fears and expectations are usually out of proportion to the actual risk.

The lethality of a bite depends on a vast number of variables including the species and size of the snake, the location of the bite, the number, depth, and duration of bites, the first aid given, and the type and rapidity of medical care received.  In general, for Crotalinae envenomations not given antivenin the mortality is a very respectable 5-25%.

Antivenin (Crotalidae) Polyvalent (ACP) was the first antivenin introduced in 1954, and was produced by exposing horses to low doses of venom to induce antibodies against its component molecules.  IgG antibodies, including those now directed against the venom, were then purified from the horse’s blood and this was injected into humans bitten by Crotalinae species.  The antibodies then bind to the various proteins and enzymes in the venom, rendering them inert.  The use of this antivenin reduced the mortality rate from 5-25% down to 0.5%.

Though effective, ACP had a rather high incidence of anaphylaxis (20-25%) and serum sickness (~50%), driving the development of a better antivenin.  In 2000, CroFab was approved.  Derived from sheep serum, containing far less non-human protein, and being made of a Fab fragment, Crotalidae Polyvalent Immune Fab (Ovine) aka CroFab, has been far better tolerated.  Post-release studies have reported anaphylaxis or severe reactions in 0-19%, and serums sickness in 0-23%, and mortality rates are the lowest they have ever been.  CroFab is currently the only Crotalidae antivenin available.

Presently there are around 8000 venomous bites per year in the US, but less than 12 deaths per year, making current mortality ~0.15%, though another 15-40% of victims sustain some form of permanent injury or disfigurement.

In addition to the fact that most bites are from non-venomous snakes, there is another facet to snakebite lethality to think about: the concept of a  “dry bite,” or a bite from a venomous snake without injection of venom.  It’s surprisingly common, accounting for around 25% of Crotalinae bites and ~50% of coral snake bites.  Given the high rate of dry bites from venomous snakes, large number of bites from non-venomous snakes, and the rather high side-effect profile of even our newest antivenin, it’s reasonable to ask who should get antivenin.

If you have symptoms of envenomation, you need antivenin, period.  However, symptom onset can be delayed, occasionally by hours.  If someone arrives in the ED with a bite but no symptoms other than a couple of small holes, it is reasonable (and standard of care) to watch them in the ED without antivenin.  Should symptoms begin, antivenin should be started immediately, but if there are no symptoms after 12 hours, it is safe to declare the encounter a dry bite, the person lucky, and let them go home.

Remember, all snakebites should be taken seriously and brought to immediate medical attention, but most will not require antivenin, and even those who do will tend to recover well.

Myth # 3: Suck Out the Poison

I love this one.  The idea is self-apparent: venom is in me, I want venom out of me, suck it out through the holes.  You’ve seen it in countless Old West movies, and it still pops up in modern entertainment, older medical literature, and even some out of date professional sites.  There are devices currently marketed to apply a constant negative pressure (~ 1 atmosphere) to the wound and actually do produce fluid, purportedly containing venom, that is then discarded.  As recently as the early 2000’s, these devices were advocated for short durations of time as they were felt to hold some potential benefit but pose little risk of harm.  Time and study has not been kind to this recommendation.

First the question of efficacy.  After needle injection of a radio-labeled fluid into volunteers, one study attempted to then remove it by suction using a popular commercially available pump; they successfully removed only 0.04% of the simulated venom.  In another randomized, controlled study pigs were randomized to receive suction therapy or no suction following injection of real venom.  The suction pump effected no improvement in symptoms in the pigs.  The bulk of the evidence, sparse as it is, indicates that these devices do not work.

Beyond being ineffective, suction devices also cause quite a bit of damage.  Even on normal skin negative pressure quickly forms a “hickey,” which is a bruising and edema of the skin.  Combine that trauma with skin being actively destroyed by the venom, and you simply generate a worse wound without reducing the venom load.  This is precisely what was found in the porcine study discussed earlier, and has been reported in the literature since. Significant harm + no benefit = bad idea.

Suction applied by mouth is even worse.  Not only does it just as ineffective while carrying the same risk as the devices (maybe a bit less, since the suction isn’t sustained), but now you add the oral bacterial flora of the human mouth to a fresh wound.  Snakes’ mouths are far from sterile, but bacterial infections after snakebites are uncommon enough (<3%) that antibiotics are not routinely prescribed, unlike human bite wounds.  Don’t compound the problem by giving the victim cellulitis.

If you are bitten by a snake and someone tries to suck out the poison, kindly go ask them to catch the snake instead.*

* Don’t do that.  Just tell them to call 911.

Myth # 4: Place a Tourniquet

In older survival manuals it was common advice to apply a tourniquet around the bitten limb, the thought being to limit the venom’s spread and to provide time to get to medical care.

There has been at least one animal study that demonstrated a longer survival time in pigs after envenomation with the use of a tourniquet (36 min longer), providing some plausibility to the benefit of tourniquets after snakebites.  However, the same study also showed markedly elevated pressure in the effected limb (43 mmHg higher) and led the authors to discourage the use of tourniquets for snakebites. But better to lose a limb and save a life, right?  Well, yes, if it were effective at saving lives in practice.

The trouble is that in practice tourniquets are fiendishly tricky to apply without causing further injury, and even with training under controlled circumstances professionals aren’t able to place them to the “proper” pressure.  Furthermore, clinical studies have failed to confirm the modest benefit seen in one animal model while demonstrating multiple serious complications from their use (tourniquets too easily become ligatures and compound the injury of the venom).

Tourniquets have their place in medicine, but it isn’t in the management of a venomous snakebite.

Myth # 5: Apply Ice

One of the hallmarks of a Crotalinae envenomation is swelling, pain, bruising, and often a burning sensation.  This superficially resembles other traumatic injuries, like a badly twisted ankle commonly treated with ice packs, so it makes some sense people are inclined to try cooling a snakebite.

Though there is a degree of hyperemia (increased blood flow) with envenomations that ice will reduce, the swelling is due more to the direct tissue injury of the venom. That direct injury also causes increasing pressure, clotting, and vascular damage all of which impede and at times stop blood flow to the tissue.  Anything done that further reduces blood flow (like ice or tourniquets) can make such injuries much worse.  Animal modeling has failed to show a benefit from cooling of the injury, and clinical studies have suggested that people may have more complications if their bites are iced.

There is, of course, also the more obvious risk of ice, in that it tends to be rather cold, and can cause injury to even healthy tissue if not closely monitored.  Yet again, we have little hope of benefit with clear risk of harm.  No ice.

Myth # 6: Taze Me, Bro! (Electrotherapy)

In 1986 the Lancet published the first paper in the medical literature where Dr. Guderian advocated high voltage electric shock of the envenomated site as a first aid technique. Subsequent studies in both animals and humans failed to show any benefit, and there has not been any significant presence of this intervention in the medical literature since 2001, which was a paper condemning its use.

Of course, this hasn’t stopped people from adding insult to injury by tazing their buddies who were just struck by a rattlesnake.  Yes, really.  Let that image sink in for a moment… there you go.  Dr. Guderian, or someone posing as him, puts forth the argument for electrotherapy of envenomations here.  As this is already a lengthy post, I’ll address this gem of a site and its specific claims at a later time.  Suffice it to say that beyond a very crude form of pain control, electrotherapy holds no plausible benefit, has significant risk of harm (like electrocution and burns), and has the existing literature stacked firmly against it.

If you are bitten by a snake and someone tries to taze you, kindly go ask them to go catch and taze the snake instead.*

* Again, don’t do that.  Just tell them to call 911, then re-assess your choice of friends.

What You Should Do

Odds are that neither you nor anyone you know will ever be bitten by a snake.  However, if you happen to find yourself joining those unlucky few, the best things you can do are incredibly simple:

1)    Calm the victim and calm yourself.

2)    Call 911.

3)    Immobilize the limb like you would a fracture and await medical assistance.

4)    Report any symptoms, no matter how odd or minor, to medical providers immediately as they occur.

What if you are days out in the wilderness, is it worth trying these interventions in a desperate situation?  No.  Being away from help doesn’t make useless and harmful interventions any less useless or harmful.  Instead, be responsible and have an evacuation plan for any medical emergency, including snakebites.  Now go enjoy the Spring!

Imagine you’re an FDA reviewer looking at a new drug application. Drug A relieves a symptom, but doesn’t cure any disease. It doesn’t conflict with other medications. It’s considered safe in pregnant and breastfeeding women. At normal doses, there are virtually no side effects. There’s one unfortunate problem: If you take ten times the dose, liver damage is very likely and may be fatal. In other countries, Drug A is the number one cause of acute liver failure.

Should Drug A be available without a prescription?

Now consider another drug. Drug B also treats a symptom, but can also be used to treat a number of acute and chronic conditions, some of which require monitoring by specialist physicians. Drug B should generally be avoided in children, as it is associated with a rare but fatal toxicity. Even at normal doses, it can cause an array of side effects, and severe digestive system toxicity, resulting in hospital admission, is not uncommon. It interacts with other prescription drugs, and can be fatal in overdose situations.

Should Drug B be available without a prescription?

What factors influence if a drug can be purchased without a prescription? Drug A is acetaminophen (Tylenol), a safe drug when used at appropriate doses, but highly toxic in overdose – one in three overdoses are fatal, and linked to 500 deaths per year (USA). Drug B is aspirin (acetylsalicylic acid/ASA), with well established benefits for a number of conditions, but also an impressive side effect profile, including stomach ulcers, multiple drug interactions, and an associated risk of Reye’s syndrome when given to children.

Acetaminophen and aspirin are among the oldest drugs that continue in regular use. Both were first marketed long before the current drug licensing standards were implemented. And both have side effect profiles and toxicities that rival some prescription drugs. But they’re hardly alone in the over-the-counter (OTC) marketplace, which is a collection of drug products with varying levels of effectiveness and safety. When it comes to decisions about access, science informs, but does not determine, your ability to buy a drug without a prescription.

FACTORS INFLUENCING ACCESS

In the United States, as in most other countries, drug regulation has evolved over time. Oversight started in 1906, with standards set for strength and purity. Safety standards were introduced in 1938, but existing drugs, which were generally recognized as safe, were exempted from this requirement. It was recognized that some drugs required specific expertise to use, and the concept of prescription-restricted drugs was introduced at that time. Safety and efficacy standards didn’t arrive until 1962, following the thalidomide tragedy, and again, drugs that were generally recognized as safe and effective were exempted from these new requirements. The U.S. regulatory framework is largely unchanged since that time. Despite retroactive evaluations of efficacy that have been applied since the 1960’s to evaluate older drugs, the reality is that older drugs with a long history of use may not be supported by the robust clinical data that would be demanded for newly marketed drugs.

Today, regulators like the FDA determine a drug’s prescription status. Prescription-only drugs require physician diagnosis, and are for conditions that cannot be self-diagnosed. These drugs may have the potential to produce dependency, have significant drug interactions, or have the potential to cause resistant organisms to develop. For a drug to be considered for OTC status, the FDA states that consumers need to be able to self-diagnose, self-treat, and self-manage the condition in question. OTC products are expected to offer a wider margin of safety over prescription drugs, in the event that they are used inappropriately.

Some countries have a sizable “behind the counter” (BTC) category, for drugs which can be purchased without a prescription, but require a pharmacist’s authorization for sale. BTC drugs may have a dependency potential, or a complicated dosing schedule. Or, the drug may have the characteristics of a prescription drug, but the need for emergency access outweighs prescription controls, such as insulin, nitroglycerin, or Epi-pens. Proponents of BTC argue it offers greater consumer access to drugs that do not require physician consultation, but benefit from pharmacist consultation. Detractors cite the lack of physician oversight, or possible attempts by manufacturers to circumvent more strict prescription drug regulatory and marketing requirements. In some countries, even cholesterol-lowering medications like simvastatin (Zocor) are BTC, clearly pushing the limits on what can reasonably be regarded as self-managed conditions. Drugs can move both directions: In the United States, emergency contraception (Plan B) recently moved BTC for women 18 years of age and older. Pseudoephedrine (Sudafed) was an OTC drug for years until it moved BTC in many countries: not because of safety reasons, but because it’s a key ingredient in manufacturing methamphetamine.

Where the prescription/non-prescription line gets fascinating (to pharmacists, anyway) is when you start comparing between countries. Pharmacy “tourists” engage in a kind of drug arbitrage, stocking up on products they can’t get back home. Canadian visitors to the United States load up on omeprazole (Prilosec/Losec) for stomach problems, Neosporin antibiotic eye drops, 1% hydrocortisone cream, Primatene Mist, and until recently, naproxen (Aleve). American visitors to Canada are renowned for buying large supplies of 222’s (codeine, aspirin, and caffeine), Tylenol #1 (codeine, acetaminophen, and caffeine) and until recently, antihistamines like Reactine and Claritin. Fluconazole tablets (for yeast infections) are OTC in Canada, but prescription in the USA. It’s clear, even comparing between two countries with similar regulatory frameworks, like Canada and the USA, that there are different factors under consideration.

UNDERSTANDING THE VARIATION

Beyond the regulations themselves, how evidence is interpreted seems to play a large factor in influencing decisions about prescription status. Consider cough and cold products in children: A handful of ingredients have been used for decades, and were approved long before current standards were in place. Clinical data supporting pediatric use is either of poor methodologic quality, or lacking altogether. Over the past few years, reports of (sometimes fatal) side effects in children prompted several countries to review this group of products:

• An FDA advisory panel concluded that cough and cold products in children were ineffective and potentially hazardous. The panel recommended that they should be relabelled to indicate “do not use” in children under the age of six. Following this announcement, product manufacturers voluntarily relabelled their products to state “do not use” in children under the age of four.
• Around the same time, Health Canada announced that cough and cold products would be relabelled to caution against use in children under the age of six. Products developed just for this age group will be no longer be sold. This extends an earlier decision to remove from the market any products intended for children under the age of two.
• In Australia, cough and cold products are now labelled “do not use” for those under the age of 2, but remain available by prescription. They continue to be marketed and sold with labelling for children aged 2 – 12.
• In the United Kingdom, products for children under the age of six were withdrawn. Medication for children aged 6 – 12 will continue to be available, with new warnings on the label.

Four regulators. Same data. Four different decisions. Each regulator had to weigh issues such as the mild and self-limiting nature of the illness, the consequences of rare but sometimes serious side effects, the perceived effectiveness of restrictions/relabelling, and the general philosophy about minimum safety standards for licensed drug products.

BALANCING RISK AND BENEFIT

Prescription or OTC, no drug is absolutely safe under all circumstances. In order to have a meaningful therapeutic effect, any drug can be expected to cause some sort of side effects. And all have a toxicity profile that must be evaluated, and weighed against the benefit that is expected. Old drugs have a long history of use, which helps us understand their side effect profile, as well as the prevalence of any rare adverse effects. But the trade-off can be that these drugs may never have been adequately assessed for efficacy, particularly for the way they are being used. It’s one reason why different regulators routinely make different decisions on prescription / non-prescription status: Balancing access with safety, and the implications of possible widespread use of a drug, with sometimes very limited clinical data.  Science informs this decision, but it’s one factor among many that are considered. Decisions are made that reflect this balance.

What does this mean for science-based medicine advocates? Understanding the factors that influence regulatory decisions force us to stay vigilant, and bring the evidence to bear even on seemingly straightforward health interventions. A non-prescription drug isn’t necessarily effective, or safer than prescription alternatives. If data emerges to suggest a drug causes more harm than good, then we should stop using it. Where the evidence suggests that drugs can be safely and effectively used without the need for physician intervention, we should support their move to OTC status.

It’s not a perfect process, as the cases show. Regulatory systems consider a number of issues when evaluating drugs, of which the underlying science is just one factor. There is a considerable grey area, and it reinforces the importance of considering OTC drugs just as we do for other health interventions: evaluating risk and benefit, and ensuring there’s evidence to support the decisions we make.

Mark Crislip is always a hard act to follow, particularly when he’s firing on all cylinders, as he was last Friday. Although I can often match him (and occasionally even surpass him) for snark, this time around I’m going to remain mostly serious because that’s what the subject matter requires. I’ve said it before and I’ll say it again: I’m a bit of an odd bird in the world of cancer in that I’m both a surgeon and I run a lab. Sadly, there just aren’t very many surgeons doing basic and translational research these days, thanks to declining NIH funding, increasing clinical burden necessitated by declining reimbursements, and the increasing complexity of laboratory-based research. That’s not to say that there aren’t some surgeons out there doing excellent laboratory research, but sometimes I feel as though I’m part of an endangered species, particularly years like this when grants are running out and I need to renew my funding or secure new funding, the consequence of failure being the dissolution of my laboratory. It’s a tough world out there in biomedical research.

As tough as biomedical research is in cancer, to my mind far tougher is research trying to tease out the relationship between environmental exposures and cancer risk. If you want complicated, that’s complicated. For one thing, obtaining epidemiological data is incredibly labor- and cost-intensive, and rarely are the data clear cut. There’s always ambiguity, not to mention numerous confounding factors that conspire to exaggerate on the one hand or hide on the other hand correlations between environmental exposures and cancer. As a result, studies are often conflicting, and making sense of the morass of often contradictory studies can tax even the most skillful scientists and epidemiologists. Communicating the science and epidemiology linking environment and cancer to the public is even harder. What the lay person often sees is that one day a study is in the news telling him that X causes cancer and then a month later another study says that X doesn’t cause cancer. Is it any wonder that people are often confused over what is and is not dangerous? Add to this a distinct inability on the part of most people, even highly educated people, to weigh small risks against one another (an inability that has led to phenomena such as the anti-vaccine movement), and the task of trying to decide what is dangerous, what is not, how policy is formulated based on this science, and how to communicate the science and the policy derived from it to the public is truly Herculean.

The President’s Cancer Panel (PCP) marched straight into this fray last week by issuing its 2008-2009 Annual Report entitled Reducing Environmental Cancer Risk, What We Can Do Now. The Panel on Cancer was mandated under the National Cancer Act of 1971, the legislation passed as a result of President Richard Nixon’s declaration of “war on cancer,” and its function is to “monitor the development and execution of the activities of the National Cancer Program, and shall report directly to the President.” Previous reports have addressed subjects such as Promoting Healthy Lifestyles (2006-2007); Translating Research Into Cancer Care: Delivering on the Promise (2004-2005); Living Beyond Cancer: Finding a New Balance (2003-2004); and The Meaning of Race in Science–Considerations for Cancer Research (1997). Not surprisingly, this year’s report is more contentious than the average President’s Cancer Panel Report because few areas of cancer research are as controversial or impact as directly on public policy as the assessment of environmental risks of cancer and what to do about those risks.

The PCP report is very long (over 200 pages), although there is a lot of white space on each page, but for those of you who don’t feel inclined to read the whole thing, the executive summary does a good job of boiling down the vastness of the report into a more digestible chunk. It begins, as all such reports do, by pointing out the enormity of the cancer problem in the U.S.:

Despite overall decreases in incidence and mortality, cancer continues to shatter and steal the lives of Americans. Approximately 41 percent of Americans will be diagnosed with cancer at some point in their lives, and about 21 percent will die from cancer. The incidence of some cancers, including some most common among children, is increasing for unexplained reasons.

Public and governmental awareness of environmental influences on cancer risk and other health issues has increased substantially in recent years as scientific and health care communities, policy makers, and individuals strive to understand and ameliorate the causes and toll of human disease. A growing body of research documents myriad established and suspected environmental factors linked to genetic, immune, and endocrine dysfunction that can lead to cancer and other diseases.

Between September 2008 and January 2009, the President’s Cancer Panel (the Panel) convened four meetings to assess the state of environmental cancer research, policy, and programs addressing known and potential effects of environmental exposures on cancer. The Panel received testimony from 45 invited experts from academia, government, industry, the environmental and cancer advocacy communities, and the public.

In order to address the question of environmental influences on cancer, the Panel decided to address the following areas:

1. Exposure to Contaminants from Industrial and Manufacturing Sources. These include a wide variety of manufactured chemicals and industrial by products used in the manufacture of mass-produced products. The report notes that numerous chemicals used in manufacturing remain on products as residues or are integral parts of the products themselves. It is also noted that new chemicals are being created continually.
2. Exposure to Contaminants from Agricultural Sources. There are numerous chemical exposures due to chemicals used in agriculture, particularly pesticides, solvents, and fillers. Some of these leech into the soil and water and produce exposure this way.
3. Environmental Exposures Related to Modern Lifestyles. These exposures include pollution from vehicles, chemicals used in pest control, and exposure to radio waves and electromagnetic fields from cell phone radiation and electrical power lines, respectively.
4. Exposure to Hazards from Medical Sources. This source consists primarily of radiation from medical tests and the potential of contamination of the environment from discarded pharmaceuticals.
5. Exposure to Contaminants and Other Hazards from Military Sources. There still remain a lot of areas around military bases. Nearly 900 Superfund sites are abandoned military facilities or facilities that produced materials for military use.
6. Exposure to Environmental Hazards from Natural Sources. This class of exposure includes naturally occurring carcinogens such as radon, uranium, and arsenic.

Overall, the report is a comprehensive look at environmental exposures that could potentially contribute to various cancers and that we can do something about. In all my years in cancer research, I can’t recall ever seeing its like coming from such a mainstream source. The panel proposes several suggested approaches to this problem, including:

1. The adoption of a new “precautionary, prevention-oriented approach” to replace our “current reactionary approaches in which human harm must be proven before action is taken to reduce or eliminate exposure.” As a part of this approach, it is recommended that the burden of proof of safety should be shifted to the manufacturer, rather than the current burden of proof being upon the government to prove harm.
2. A thorough new assessment of workplace and other exposures to quantify risk.
3. A more coordinated system for promulgating environmental contaminant policy and regulations driven by science and free of political and industry influence.
4. Epidemiological and hazard assessment research in areas where the evidence is unclear.
5. New research tools and endpoints to assess environmental exposure and risk, including high throughput models to assess multiple exposures simultaneously, methods for long term monitoring and quantification of electromagnetic energy sources, such as power lines and cell phones.
6. Better policies regarding cancer risk due to radon.
7. Actions to minimize exposure to medical radiation sources.
8. Addressing the unequal burden to known and suspected carcinogens.
9. Encouraging physicians to take better health histories of environmental exposures.
10. “Green chemistry” initiatives.
11. Measures to increase public awareness of risk due to environmental exposures.

As you can see, if the recommendations, some of the details of which are fleshed out (mostly) in the 200 page report, if adopted would require enormous policy changes. Of course, one thing that must be remembered about reports like this is that they are every bit as much political documents as they are scientific and medical documents. After all, they point out problems that very well could require new laws and/or new regulations in order to address. This report definitely falls into this category in a big way because, if adopted, its recommendations would demand action by the government. Indeed, the report itself blames weak laws, lax enforcement, and overlapping and conflicting regulatory authority, but, more strongly, it blames the attitude that industrial chemicals are safe unless strong evidence that they are not safe emerges.

But how strong is the science?

From my perspective, the report is a mixed bag, a mixture of the (mostly) good, a (little) bad, and (at least one) ugly thing. It’s also rather annoying that, of the over 400 references, most of them appear to be government reports and review articles, with very little primary literature cited. First the good, though. The report emphasizes quite strongly that what we know about the environmental contribution to cancer has lagged far behind our knowledge of other aspects of cancer. More importantly, one aspect of the environmental contribution to cancer that we often don’t consider strongly enough is that children tend to be more susceptible to environmental insults of many kinds, particularly carcinogenic insults:

An analysis by the National Academy of Sciences found that children are particularly vulnerable to environmental contaminants for several reasons. Due to their smaller size, children’s exposures to toxics are disproportionately large compared with adults. Because their metabolic pathways are immature (particularly during fetal development and in the first months after birth), they are slower to metabolize, detoxify, and excrete many environmental chemicals. As a result, toxins remain active in their bodies for a longer period of time than would be the case in adults. In addition, children have lower levels of some chemical-binding proteins, allowing more of a toxic agent to reach various organs, and their blood-brain barrier is more porous than that of adults, allowing greater chemical exposures to the developing brain. Children’s bodies also are less able to repair damage due to toxic exposures, and the complex processes that take place during the rapid growth and development of children’s nervous, respiratory, immune, reproductive, and other organ systems are easily disrupted.

Children have many more years of life ahead of them than do adults—more time in which to be exposed to environmental toxics and time to develop diseases (including cancer) with long latency periods initiated by early exposures.

Moreover, at the same time that mortality rates for childhood cancers have been plummeting dramatically, the incidence of childhood cancers has been steadily climbing, as shown by this graph “borrowed” from the report:

The reason for this increase is not known, but genetics is an unlikely cause for such a rapid increase. In addition, it is unlikely that better diagnosis due to the introduction of MRI and better CT scanning is likely to be the cause, because the increase is too steady. That leaves environmental factors as one suspect for a major cause. Certainly, this is worth examining, as it may provide the “greatest bang for the buck.” Such studies could even benefit adults in terms of cancer risk. For example, lately, our cancer institute has become very interested in environmental contributors to breast cancer. One thing that has become clear is that such exposures may have their greatest effect in childhood or, in particular, during puberty, which is when the mammary gland undergoes its most rapid growth and development. Indeed, although this increases susceptibility to carcinogens in children has long been appreciated, but the characterization of these differences, again, has lagged behind other areas of cancer research. This is especially relevant to the section on the risk of medical radiation, with recent studies suggesting the possibility of tens of thousands of excess cancers in the U.S. due to medical radiation from the increasingly common use of CT scans and studies suggesting that radiation from mammography may contribute to a small number of breast cancers.

Another good part of the report is its emphasis on the deficiencies in our current technology and tools for assessing the carcinogenic potential of various chemicals. Related to the report’s emphasis on how little we know about carcinogenesis in children, the report criticizes current animal models because they fail to capture the impacts of early exposures and miss the late effects of such exposures. Also problematic is that most animal studies use long-term, high-dose exposures that may have little relation to humans. Consequently, the report urges the development of alternatives to animal testing involving testing in human cells in vitro. I’m rather skeptical that this recommendation will produce much benefit very fast. After all, one reason we use animals is because, as imperfect as animal carcinogenesis studies are, the correlation between cell culture studies is even more unreliable than that of animal studies.

One recommendation of the report that intrigued me was its assessment of how science has generally focused on one compound at a time without considering how they may interact. This reminds me of how in the past we concentrated on one gene at a time as a causative agent for cancer (such as oncogenes); yet over the past ten years it has become increasingly clear that cancer is often driven by many genes, each of which individually plays a relatively small role. The Panel thus recommends the development of high throughput screens that can examine many chemicals at once and test for interactions, a recommendation that struck me as worthwhile, although I am having trouble envisioning what such a test would look like or how it would be validated. The problem, of course, is that, as more chemicals are tested, the possible combinations skyrocket exponentially.

One major part of the report deals with one specific environmental exposure, the thousand pound gorilla these days, namely BPA, which was discussed in the context of the report’s increasing emphasis on the precautionary principle. This part of the report, to me, was a little bit dicey in that the precautionary principle is very difficult to apply. I’ve discussed this matter before in the context of how preemptively removing mercury from vaccines helped fuel an anti-vaccine panic over the mercury in the thimerosal preservative that used to be in vaccines. The question of how much evidence is necessary to justify banning a compound doesn’t go away, and it still remains a profoundly political question. The report basically glosses over the question of where one should draw the line in implementing the principle, other than suggesting shifting it to more caution. It also dances around the question of how we would pay for this, given that the implementation of the recommendations in this report would require massive increases in the budgets of the relevant agencies — particularly since the report itself documents just how short-staffed and under-funded many of these agencies are.

One glaringly dubious part of the report compared to the rest is how it deals with the issue of cell phones and cancer. After emphasizing that there is no good evidence to support a link between cell phones and cancer and pointing out that the epidemiological evidence is in essence negative, the report proceeds as though a link between cell phone use and brain or head and neck tumors were biologically plausible. As I’ve described before, it’s not. Indeed, from a biological standpoint, a strong link between cell phone use and brain cancer (or any other cancer) is not very plausible at all; in fact, it’s highly implausible. Cell phones do not emit ionizing radiation; they emit electromagnetic radiation in the microwave spectrum whose energy is far too low to cause the DNA damage that leads to mutations that lead to cancer. While it is possible that perhaps heating effects might contribute somehow to cancer, most cell phones, at least ones manufactured in the last decade or so, are low power radio transmitters. It is also necessary to acknowledge the possibility that there might be an as yet undiscovered biological mechanism by which low power radio waves can cause cancer, perhaps epigenetic or other, but the evidence there is very weak to nonexistent as well. Basically, based on what we know about carcinogenesis, a postulated link between cell phones and cancer is highly implausible. It’s not homeopathy-level implausible, but it’s pretty implausible nonetheless. Consequently, in the absence of better basic science, I have a hard time managing to muster any enthusiasm about recommending more studies than the ones that are already going on.

That ugly bit aside, though, the President’s Cancer Panel report is in general cautious and makes sensible policy recommendations. It also makes a number of (mostly) sensible recommendations for individual citizens. In general, it is cautious and highlights a neglected aspect of cancer research.

That must be why the pro-industry group American Council on Science and Health (ACSH) is on the counterattack, for example:

Elizabeth M. Whelan, president of the American Council on Science and Health, whose views often coincide with industry’s, noted that despite the growing exposure to chemicals in the environment, “cancer death rates are going down. The so-called environmental trace levels of chemicals play no role whatsoever in the etiology of cancer.”

And:

“This so-called Presidential Cancer Panel, which consists of two physicians, has obviously been politically pressured by the activists running the EPA,” says ACSH’s Dr. Gilbert Ross. “When they mention babies being ‘pre-polluted’ and the alleged dangers of all of these chemicals, they not only sign their name to activist screeds, they neglect to mention that the dose makes the poison, and that finding traces of chemicals at levels of parts-per-billion does not imply a health hazard. And of course they do not address the potential health hazards of banning important chemicals from consumer products.”

Of course, the obvious retort to that is that the presence of chemicals at levels of parts-per-billion doesn’t imply that there’s isn’t problem, either, but that’s apparently what ACSH wants you to believe. There may be a problem; there may not. We’ll never know if we don’t study the issue. It is probably true that most trace contaminants are not health hazards, it’s also very likely true that some of them are, and if we don’t study the issue we will never know. But that’s ACSH’s M.O.: deny there is a problem; deny even the possibility that there might be a problem; criticize the tools used to study a problem even if they are the best we have, however imperfect. Sometimes ACSH even takes it to ridiculous extremes. In other words, other than tobacco, when it comes to the assessment of health risks to listen to ACSH is in essence to hear industry’s viewpoint, as Jon Stewart demonstrated so brilliantly last year. Any organization that can claim with a straight face that encouraging healthy eating is “elitist” is not one that I can take seriously.

A more reasonable criticism comes from the American Cancer Society’s Michael J. Thun, MD:

Issues highlighted in both reports include the accumulation of certain synthetic chemicals in humans and in the food chain; the large number of industrial chemicals that have not been adequately tested; the potentially greater susceptibility of children; the possibility that some chemicals or combinations of chemicals may have effects at low doses; and the potential risks from widely used medical imaging procedures that involve ionizing radiation.

Unfortunately, the perspective of the report is unbalanced by its implication that pollution is the major cause of cancer, and by its dismissal of cancer prevention efforts aimed at the major known causes of cancer (tobacco, obesity, alcohol, infections, hormones, sunlight) as “focused narrowly.”

This seems to be missing the point by more than a bit. The very point of the report was to focus on an aspect of cancer prevention that the Panel considered to have been historically underrepresented. This year, the President’s Cancer Panel report was designed to focus on one aspect of cancer, namely environmental influences on cancer. As such, of course it emphasized — shockingly — environmental influences on cancer. It’s also just plain wrong that the report “dismisses” cancer prevention efforts aimed at the stronger known exposures and risk factors for cancer; rather, it argues that we should be doing more to ameliorate cancer risk from environmental exposures, be it to chemicals or the excessive use of medical radiation in imaging tests.

Basically, I found the ACS’s objections to be rather puzzling, given that just last fall the ACS published a position paper, many parts of which sound eerily similar to the President’s Cancer Panel report. For example, these are the things that the ACS recommends:

The position statement on cancer prevention also says:

• New strategies for toxicity testing, including the assessment of carcinogenicity, should be implemented that will more effectively and efficiently screen the large number of chemicals to which people are exposed. This very same recommendation is in the President’s Cancer Panel report.
• Occupational and community exposures should meet regulatory standards, and research to identify and reduce carcinogenic hazards should be supported. Ditto.
• The agencies that set and enforce environmental standards need to be appropriately funded and science-based to keep pace with scientific developments and to update their standards accordingly. This is more or less the same as what the President’s Cancer Panel recommends.
• Although certain exposures are unavoidable, exposure to carcinogens should be minimized or eliminated whenever feasible. A little different emphasis, but basically the same idea as embodied in the President’s Cancer Panel report.
• The public should be provided with information so that they can make informed choices. Absolutely the same as the President’s Cancer Panel report.
• Communications should acknowledge and not trivialize public concerns, but at the same time should not exaggerate the potential magnitude or level of certainty of the potential risk.

The last point seems to be the only point where the ACS and the President’s Cancer Panel differ significantly, and I will admit that the President’s Cancer Panel report is a bit too certain in its tone when it comes to several issues. And, straight from the article:

The exposure levels to the general public are typically orders of magnitude lower than those experienced historically in occupational or other settings in which cancer risks have been demonstrated. The resulting cancer risks are generally so low that they cannot be measured directly. Nevertheless, there is reason to be concerned about low-level exposures to carcinogenic pollutants because of the multiplicity of substances, the involuntary nature of many exposures, and the potential that even low-level exposures contribute to the cancer burden when large numbers of people are exposed. Concerns about the toxic and carcinogenic potential of these exposures are amplified by broader public concerns regarding the effectiveness of hazard identification and the regulation of potentially toxic exposures in the United States and other economically developed countries, as well as high levels of exposures to known carcinogens that still occur in many developing countries.

All of this is very similar to what is in the President’s Cancer Panel report, the main difference being more of emphasis than anything else and a disagreement over whether environmental contributions to cancer other than the strong, well-characterized ones (like smoking) are underestimated or not. At the risk of falling prey to the fallacy of the Golden Mean, I rather suspect that the real risk is somewhere in between the position of the ACS and that of the President’s Cancer Council. The reason that I don’t think the Golden Mean fallacy will be a big deal here is because the positions of the two are actually pretty close, despite Dr. Thun’s objections. When the ACSH points to the ACS as “harshly criticizing” the report, even going so far as to entitle one post Praise be to Thun, it’s clearly exaggerating the extent of disagreement for its own purposes.

The President’s Cancer Panel report represents a document that is at the same time scientific, medical, and also highly political, and that needs to be remembered. It has also been heartening to epidemiologists and public health officials, some of whom have criticized the National Cancer Institute system for publicizing avoidable causes of cancer other than smoking to be “virtually non-existent.” This report, as flawed as parts of it are, represents a refreshing first step towards addressing that shortcoming. My only fear is that, if the results are not communicated well, we could have a series of environmental cancer scares on the basis of very little evidence, given the uncertainty inherent in many of these studies. However, if this is handled well, the result could be science-based health policies that minimize public exposure to known carcinogens and give people the information necessary to allow them to act for their own benefit.

This is not an easy blog to write.  Doctors Novella and Gorski want the entries to be formal, academic, referenced, with a minimum of snark.

For the most part I comply. But sometimes. Sometimes. It is hard, so hard,  not to spiral into sarcastic diatribes over the writings that pass for information on the interwebs. How should one respond to profound ignorance and misinformation?  I wish, sometimes, that I could be an irascible computer as well.

What brings on this particular bit of angst is a bit of whimsy on the Internet called “9 Questions That Stump Every Pro-Vaccine Advocate and Their Claims.”  by David Mihalovic, ND. Mr. Mihalovic identifies himself as “a naturopathic medical doctor who specializes in vaccine research.” However, just where the research is published is uncertain as his name yields no publications on Pubmed.  BTW. I specialize in  beer research.  Same credentials.

The nine questions show up frequently on the interwebs, similar to questions on what to ask when you want to stump an evolutionist.  Similar to the supposed stumpers for evolution, the vaccine questions are grounded in misinformation, ignorance or laziness.  Let’s go through them one at a time.

1. Could you please provide one double-blind, placebo-controlled study that can prove the safety and effectiveness of vaccines?

One trial? It took me 55 seconds to find  ”Efficacy of 23-valent pneumococcal vaccine in preventing pneumonia and improving survival in nursing home residents: double blind, randomised and placebo controlled trial” and that included time to boot the browser and mis-spell the search terms.  ’Vaccine’, ‘efficacy’,  ’randomized’ and  ’placebo control trial’  results in 416 Pubmed references; add ’safety’ to the search terms, you get 126 returns. 416 is easily more than one.  Of course, to find them you have to look.

Of course, I am a highly educated adult who constantly searches the web for medical information.  For hoots and giggles, I asked my 12 year old son, whose passions are basketball and filming comedy videos, to find me a reference that met the same criteria and I timed him.

Twenty two seconds, not including boot time,  to find “Randomized, Placebo-Controlled Trial of Inactivated Poliovirus Vaccine in Cuba” from the NEJM.  Can anyone beat my son?

12 yo one,  Mihalovic 0.  Served.

As long as we are on the topic, since he evidently place great store in science, could Mihalovic please provide one double-blind, placebo-controlled study that can prove the safety and effectiveness of naturopathy?  I would be happy at this point to know just to know he was able to do a pubmed search correctly just to make me look the fool.

2. Could you please provide scientific evidence on ANY study which can confirm the long-term safety and effectiveness of vaccines?

Long term is vague. What is long term?  Smallpox disappeared in 1977  thanks to the vaccine.  I have not seem a case of smallpox in my medical career, which now on it’s 31st year. No reported long term toxicities of the smallpox vaccine  and the eradication of smallpox appears to me to represent reasonable evidence for long term safety and effectiveness. But it would.

No vaccine has 100%  efficacy, and whether  infected naturally or by  a vaccine, immunity wanes with time.  In  earlier times, people would have their immunity boosted by exposure to disease and maintain their antibody levels.  It is not the initial infection that leads to better immunity from natural infections, as posited by some antivaccine people, but the the fact that people were constantly re-exposed to wild type disease.

It is interesting what is  occurring with shingles.  Everyone used to get chickenpox as a child, and then, as they raised their kids and grand kids, were re-exposed to the virus and boosted their immunity. Currently, due to the chickenpox vaccine and a change in the  way children are raised, older adults are not getting exposed naturally to chickenpox, immunity is waning, and there is an increase in shingles in older adults.  Part of why they need the zoster vaccine.

Clever conspiracy to increase the use of the zoster vaccine, huh?

Unless exposed to new infection, immunity, as measured by antibody levels directed against the infecting agent, can decline over time. That is to be expected.  The nice thing about the immune system, unlike water, is that it remembers the infection. It is primed so that if exposed again at a later date, it can almost instantly produce large amounts of antibody to nip an infection in the bud. So rather than prevent infection, in some people far removed in time from the vaccine, they may instead have a shorter, less severe illness and be infectious for a shorter period of time, thereby decreasing spread.

There is a nice review in the NEJM on duration of immunity (first search in Pubmed using duration of immunity vaccine, results in 17 seconds, including correcting typos.  Seriously, just how hard is it to find this information?  As would be expected, it depends on the disease and the vaccine (live better than killed). They estimated the half-life for the varicella zoster virus immunity at 50 years, 200 years for measles and mumps, and 11 years for tetanus.  If you peruse the references, you can find other studies that show variable but sustained response to vaccines,  for example 90% maintain immunity to smallpox up to 75 years after vaccination.

Long term safety was more difficult, 5 years was the limit of time I could find  for safety studies of  Hepatits B.  Most vaccine toxicities are found in the first week or two after the inoculation and the studies follow most patients for a year.  Probably would not cut it as long term for Mihalovic.

BTW, could you please provide scientific evidence on ANY study which can confirm the long-term safety and effectiveness of naturopathy?

3.  Could you please provide scientific evidence which can prove that disease reduction in any part of the world, at any point in history was attributable to inoculation of populations?

Smallpox? Smallpox? Smallpox? Anyone? Smallpox? Buehler? Buehler?

Again I get back to the whole binary, black and white approach that characterizes many with whom we cross medical swords.  The decrease in infectious diseases has been multifactorial, due to improved nutrition, improved hygienic (lets hear it for the flush toilet) and understanding the epidemiology of diseases.  Knowing how a disease is spread has always been critical in decreasing its spread.  Note that none, none, none of the interventions that have decreased the spread of infections in the last 200 years or so have come from naturopathic tradition.

The teasing out the effects of vaccines on populations is always fraught with potential controversy. There are always multiple confounders.  The best example of the beneficial effects of vaccines was from JAMA.

“Objective  To compare morbidity and mortality before and after widespread implementation of national vaccine recommendations for 13 vaccine-preventable diseases for which recommendations were in place prior to 2005.

Design, Setting, and Participants  For the United States, prevaccine baselines were assessed based on representative historical data from primary sources and were compared to the most recent morbidity (2006) and mortality (2004) data for diphtheria, pertussis, tetanus, poliomyelitis, measles, mumps, rubella (including congenital rubella syndrome), invasive Haemophilus influenzae type b (Hib), acute hepatitis B, hepatitis A, varicella, Streptococcus pneumoniae, and smallpox.

Main Outcome Measures  Number of cases, deaths, and hospitalizations for 13 vaccine-preventable diseases. Estimates of the percent reductions from baseline to recent were made without adjustment for factors that could affect vaccine-preventable disease morbidity, mortality, or reporting.

Results  A greater than 92% decline in cases and a 99% or greater decline in deaths due to diseases prevented by vaccines recommended before 1980 were shown for diphtheria, mumps, pertussis, and tetanus. Endemic transmission of poliovirus and measles and rubella viruses has been eliminated in the United States; smallpox has been eradicated worldwide. Declines were 80% or greater for cases and deaths of most vaccine-preventable diseases targeted since 1980 including hepatitis A, acute hepatitis B, Hib, and varicella. Declines in cases and deaths of invasive S pneumoniae were 34% and 25%, respectively.”

Milhalovic,  could you please provide scientific evidence which can prove that disease reduction in any part of the world, at any point in history was attributable to naturopathy?

4. Could you please explain how the safety and mechanism of vaccines in the human body are scientifically proven if their pharmacokinetics (the study of bodily absorption, distribution, metabolism and excretion of ingredients) are never examined or analyzed in any vaccine study?

There is, superficially, some truth in this statement.  Most pharmacokinetics are done prior to the clinical efficacy trials.  That is why there are phase 1 and phase 2 trials. The assumption being that if you exam influenza vaccine pharmacokinetic studies in one group it can be extrapolated to similar populations.  I think that is reasonable. So no, there are no pharmacokinetic studies in the clinical efficacy trials, those were done prior to the efficacy trials.  But it is not hard to find the phase 1 and 2 trials if you are so moved.

Milhalovic, could you please explain how the safety and mechanism of naturopathic nostrums in the human body are scientifically proven if their pharmacokinetics (the study of bodily absorption, distribution, metabolism and excretion of ingredients) are never examined or analyzed in any naturopathic nostrum study?

Is this getting old?  There is something to be said for repetition.

5. Could you please provide scientific justification as to how injecting a human being with a confirmed neurotoxin is beneficial to human health and prevents disease?

I presume the issue is mercury. Maybe aluminum. The latter is not in most vaccines, although as been discussed at length on this blog, the amount of mercury and aluminum found in vaccines is minimal and, at the dosing and formulation, has never been demonstrated to cause neurotoxicity from vaccines.  Of course, I am old school and think there is a dose response effect of drugs, and that a greater amount leads to a greater response.  Most naturopaths receive extensive training in homeopathy, where the less the amount, the greater the response.  So I would presume arguments based on chemistry would have little meaning to an ND, although I would not want my appletini made by a practitioner of homeopathy.

Of course, it is not the ‘neurotoxin’ that is being used to prevent disease, but the antigens of the potential infection. That is assuming that the author of the nine questions does not consider the antigens to be neurotoxins, and to judge from his understanding of disease later in the post, I am not so certain he warrants the benefit of the doubt.

Could you please provide scientific justification as to how applying naturopathy to a human being is beneficial to human health and prevents disease?

6. Can you provide a risk/benefit profile on how the benefits of injecting a known neurotoxin exceeds its risks to human health for the intended goal of preventing disease?

Since there is no longer mercury in most vaccines, I will assume, for the sake of argument, he is referring to aluminum.  Risk from aluminum in the H. influenza type b vaccine, where aluminium is used as a adjuvant: zero.

The benefit from the vaccine:

“From eight trials, the protective efficacy of the Hib conjugate vaccine was 84% (OR 0.16; 95%CI 0.08-0.30) against invasive Hib disease, 75% (OR 0.25; 95%CI 0.08-0.84) against meningitis, and 69% (OR 0.31; 95%CI 0.10-0.97) against pneumonia. Serious adverse events were rare.”

Seems a good trade off. No risk from aluminum, significant decrease in morbidity and mortality from disease.

7. Could you please provide scientific justification on how bypassing the respiratory tract (or mucous membrane) is advantageous and how directly injecting viruses into the bloodstream enhances immune functioning and prevents future infections?

Well, things really get off the rails here.  Vaccines are not injected into the blood stream, they are infected into the soft tissues.   At a simple level, an infection enters to body, the body makes a variety of antibodies to the constituent parts of the infecting organism and next time the patient is exposed, the pre-existing antibody can, if there is a match with new strain, inactivate the new infection.

It doesn’t matter how the antigen is presented to the immune system, the response is the same. Natural influenza, inhaled influenza vaccine, or injected influenza vaccine, the same antibody will be made to the proteins.

Mihalovic says later

“All promoters of vaccination fail to realize that the respiratory tract of humans (actually all mammals) contains antibodies which initiates natural immune responses within the respiratory tract mucosa. Bypassing this mucosal aspect of the immune system by directly injecting viruses into the bloodstream leads to a corruption in the immune system itself. As a result, the pathogenic viruses or bacteria cannot be eliminated by the immune system and remain in the body, where they will further grow and/or mutate as the individual is exposed to ever more antigens and toxins in the environment which continue to assault the immune system.”

This is what we call in the trade, gibberish. At least it makes no sense to me.  I will leave to the readers to search, Bible Code style, for truthiness in the above selection.

8. Could you please provide scientific justification on how a vaccine would prevent viruses from mutating?

That is actually a very interesting question. It has nothing to do with why we give vaccines and  I fear our intrepid ND does not have a firm grasp on what he is talking about as he says

“Despite the injection of any type of vaccine, viruses continue circulating through the body, mutating and transforming into other organisms. The ability of a vaccine manufacturer to target the exact viral strain without knowing its mutagenic properties is equivalent to shooting a gun at a fixed target that has already been moved from its location. You would be shooting at what was, not what is!”

Mutating and transforming into other organisms. Sigh.  Either the author is a sloppy writer  (sloppy writing (not typos, but logic and word selection) reflects a sloppy mind) or his understanding of microbiology is so profoundly mistaken it boggles the mind that he takes care of patients.  And in Oregon he would allowed by the state to prescribe antibiotics and other pharmaceuticals.

If you have a population of viruses and a specific antibody against the virus, then those naturally occurring mutants that are not recognized by the antibody should have a replication advantage.  It is possible that the vaccine can help select for new strains of an infection, but not new organisms.

Vaccines selecting for new mutants has been looked at for the Hepatitis B vaccine, and found not to be a issue.

In HIV, there is an ongoing interaction between the immune response and the virus, driving mutations that escape the immune system and, in some patients leads to a marked increase in HIV replication and a clinical decline decline. Oh wait, this is a natural infection. That shouldn’t happen.  It is the vaccines that do this.

There is nothing unique about the vaccine response acting as environmental pressure on the evolution of infections; the response from the natural infections should be the same.  I would wonder, since the response to  a natural infection is broader, with antibodies made to numerous parts of the infection, rather than the few key antibodies provided by the response to the vaccine, whether a natural infection would lead to a faster mutation rate.  As a rule in the microbial world, the more intense the stress, the faster and more varied the mutations.  More antibiotics leads to faster development of resistance in E. coli, not its delay.

9. Could you please provide scientific justification as to how a vaccination can target a virus in an infected individual who does not have the exact viral configuration or strain the vaccine was developed for?

Mr. Black and White.  Antibody response is not all or nothing, there is a gradient of response between the developed antibody and the site to which it is directed.  A good example is the H1N1 influenza.  People exposed to the strains from the first half of the century had antibody that was partially protective for the 2009 strain.  The reason?

“The pandemic influenza virus (2009 H1N1) was recently introduced into the human population. The hemagglutinin (HA) gene of 2009 H1N1 is derived from “classical swine H1N1″ virus, which likely shares a common ancestor with the human H1N1 virus that caused the pandemic in 1918, whose descendant viruses are still circulating in the human population with highly altered antigenicity of HA. However, information on the structural basis to compare the HA antigenicity among 2009 H1N1, the 1918 pandemic, and seasonal human H1N1 viruses has been lacking. By homology modeling of the HA structure, here we show that HAs of 2009 H1N1 and the 1918 pandemic virus share a significant number of amino acid residues in known antigenic sites, suggesting the existence of common epitopes for neutralizing antibodies cross-reactive to both HAs. It was noted that the early human H1N1 viruses isolated in the 1930s-1940s still harbored some of the original epitopes that are also found in 2009 H1N1. Interestingly, while 2009 H1N1 HA lacks the multiple N-glycosylations that have been found to be associated with an antigenic change of the human H1N1 virus during the early epidemic of this virus, 2009 H1N1 HA still retains unique three-codon motifs, some of which became N-glycosylation sites via a single nucleotide mutation in the human H1N1 virus. We thus hypothesize that the 2009 H1N1 HA antigenic sites involving the conserved amino acids will soon be targeted by antibody-mediated selection pressure in humans. Indeed, amino acid substitutions predicted here are occurring in the recent 2009 H1N1 variants. The present study suggests that antibodies elicited by natural infection with the 1918 pandemic or its early descendant viruses play a role in specific immunity against 2009 H1N1, and provides an insight into future likely antigenic changes in the evolutionary process of 2009 H1N1 in the human population.”

Oops.  Not simple.

But the result?

“Over 75% of confirmed cases of novel H1N1 occurred in persons < or = 30 years old, with peak incidence in the age range 10-19 years. Less than 3% of cases occurred in persons over 65, with a gradation in incidence between ages 20 and 60 years.The sequence data indicates that novel H1N1 is most similar to H1N1 viruses that circulated before 1943. Novel H1N1 lacks glycosylation sites on the globular head of hemagglutinin (HA1) near antigenic regions, a pattern shared with the 1918 pandemic strain and H1N1 viruses that circulated until the early 1940s. Later H1N1 viruses progressively added new glycosylation sites likely to shield antigenic epitopes, while T-cell epitopes were relatively unchanged.

CONCLUSIONS: In this evolutionary context, Original Antigenic Sin exposure should produce an immune response increasingly mismatched to novel H1N1 in progressively younger persons. We suggest that it is this mismatch that produces both the gradation in susceptibility and the unusual toxicity”

The better the antibdy fit for the epitope (where the antibody binds) the better the effect, but it doesn’t have to be all or nothing. Mihalovic would probably ask, what good is half an eye, why have half a wing, or half a brain?

He finishes,

“I have never encountered one pro-vaccine advocate, whether medically or scientifically qualified, who could answer even 1 let alone all 9 of these questions. One or all of the following will happen when debating any of the above questions:

- They will concede defeat and admit they are stumped.

- They will attempt to discredit unrelated issues that do not pertain to the question.

- They will formulate their response and rebuttal based on historical arguments and scientific studies which have been disproved over and over again. Not one pro-vaccine advocate will ever directly address these questions in an open mainstream venue.”

I am neither stumped not defeated. I know how to search Pubmed for medical information.

My response directed specifically to the questions.

My arguments are based on modern studies that a 12 year old can find in less than a minute, none of which have been disproved once, much less over and over.

SBM is an open mainstream venue.

I do feel like I just had won Jeopardy playing against Prof. R.J. Gumby; where is the honor in that?

And people wonder why I question the wisdom of allowing naturopaths to function as primary care providers.

Science-based medicine is, among other things, a tool.  Science helps us sequester our biases so that we may better understand reality.  Of course, there is no way to avoid being human; our biases and our intuition still betray us, and when they do, we use other tools.  Ethics help us think through situations using an explicitly-stated set of values that most of us agree upon (and in order to get wide agreement, these precepts must be pretty general).

Ethical problems are a normal part of medical practice. In medical school I received a bit of formal didactic education on ethics, and on the floors we often have formal ethical discussions to help understand and resolve conflicts.   But ethics are not a weapon used to obtain a result we want; they are a tool to give a framework for understanding and resolving dilemmas.  Ethical dilemmas can arise out of may types of conflicts, for example when our personal beliefs clash with those of our patients, or when patients’ and families’ desires conflict.  They can also arise when we as physicians are constrained in our actions by outside forces.

For example, if an outside agent, say a government, were to ask us to use our professional relationship with a patient to harm them, but the goal was to achieve a greater good (think Guantanamo), we could look at basic medical ethics principles to help clarify the conflict.  I would object on the basis of many of these shared ethics: it violates patient autonomy, it causes them harm, and fails to benefit them.   My responsibility to avoid harming my patient trumps my government’s desire to obtain information via torture.

Despite our attempts to use ethics as a tool, there are some areas that are so fraught with controversy that we may not always come to a satisfactory resolution.  Should doctors participate in executions? (I say “no” but the question is complex.) What about abortion (which is not, by the way, the topic of this post)?  My own interpretation of medical ethics requires me to support a right to abortion for my patients.  Some physicians find abortion so abhorrent that they cannot support it.  For doctors who cannot—for whatever personal reasons—support a right to an abortion, ethics demand that they serve their patients’ needs above their own.  There is no set of data that says that “abortion is harmful to women”, so doctors who oppose abortion cannot claim that science supports their bias.  But if  a doctor legitimately felt that a particular abortion would bring physical harm to a particular woman, then they must give her the advice they feel is necessary.  Conversely, if a doctor feels that a particular abortion may help a particular patient, they must tell the patient.

All this is by way of introduction to a big dilemma.  Most doctors don’t work in Guantanamo, and most don’t deal with abortion on a daily basis.  But many hospitals in the U.S. have some sort of religious affiliation.  Approximately 20% of U.S. hospital beds are religiously-affiliated.  How does this affect the care given by doctors working with these institutions?

A new study published in the Journal of General Internal Medicine aims to answer that question.  Among primary care physicians (PCPs) polled, about 43% had worked in religion-affiliated institutions.  Nearly 20% of these doctors had encountered conflicts with the institution’s religious-based policies.  Encouragingly, 86% of these doctors indicated they would refer patients to an institution where appropriate treatment was available.  Ten percent indicated that they would offer alternatives available at the religious institution, and about 4% said that they would provide the service in violation of hospital policy. (It wasn’t clear to me from my reading of the study whether this also indicated what doctors actually did, or just what they thought they would do.)

In their analysis, the authors found a number of variables that further illuminate these conflicts.  Older physicians where less likely to report conflict, but it isn’t clear whether this is because they fail to perceive an ethical conflict or they just don’t run into problems.  One of the most interesting findings was that, “[n]either religious affiliation nor physician-institution congruence was significantly associated with having experienced conflict with religiously affiliated institutions.”

From an ethical perspective, these data are mixed.  It is comforting that the polled doctors were more often willing to make decisions based on their patients’ needs rather than institutional policies, but it is disturbing that such significant barriers to care arise from these  policies.  Transparency is an important concept in the ethical delivery of medical care; motivations, limitations, and expectations should be clear.  If, for example, a health care system never allows prescription of birth control, this should be made explicit to all providers and patients, and insurance companies who deal with these institutions should make this clear to their customers to allow for informed decision-making.

On a personal and professional level, I find the intrusion of sectarian values into health care disturbing, especially since most of these institutions take money from federally-funded programs such as Medicare and Medicaid.  At the same time, many of these institutions provide significant amounts of charitable care.  I do not believe, however, that this creates a balance.  Charity is good, but treating human beings with dignity and allowing for the science-based delivery of medical care should be a minimum requirement.

References

Stulberg, D., Lawrence, R., Shattuck, J., & Curlin, F. (2010). Religious Hospitals and Primary Care Physicians: Conflicts over Policies for Patient Care Journal of General Internal Medicine DOI: 10.1007/s11606-010-1329-6

On SBM we have documented the many and various ways that science is abused in the pursuit of health (or making money from those who are pursuing health). One such method is to take a new, but reasonable, scientific hypothesis and run with it, long past the current state of the evidence. We see this with the many bogus stem cell therapy clinics that are popping up in parts of the world with lax regulation.

This type of medical pseudoscience is particularly challenging to deal with, because there is a scientific paper trail that seems to support many of the claims of proponents. The claims themselves may have significant plausibility, and parts of the claims may in fact be true. Efforts to educate the public about such treatments are frustrated by the mainstream media’s lazy tendency to discuss every study as if it were the definitive last word on a topic, and to site individual experts as if they represent the consensus of scientific opinion.

Recent claims made for low dose naltrexone (LDN) fit nicely into this model – a medical intervention with interesting research, but in a preliminary phase that does not justify clinical use. And yet proponents talk about it as if it is a medical revolution.

Background on Naltrexone

Naltrexone is an FDA approved drug that binds to and inhibits opiate receptors – whose primary known function is to bind endogenous opiates (endorphins and enkephalins) and reduce pain. These are the same receptors that morphine, heroine, and other opiate drugs bind to. The primary use of naltrexone is to rapidly reverse opiate toxicity, or in the chronic treatment of opiate addiction.

But biology is always more complex than our initial understanding of any system. Evolution has a tendency to use what is at hand, and so receptors and hormones have been frequently co-opted for other uses over evolutionary history. This is partly why medications often have side effects – the target of the drug is used for more than just the desired effect.

There is also evidence that opiate receptors exist on other cell types, including cells involved in immune function, and activating or inhibiting these receptors may therefore modulate immune function or other biological functions. So far so good – all interesting and fairly standard basic science.

Translational Research

In the case of LDN the major problem comes at the level of translational research – taking what we are learning from basic science and applying it to specific clinical applications. It should be noted that this type of research is very unpredictable. Most of the promising leads provided by basic science do not lead to effective treatments. There are many possible reasons for such failure to translate to clinical outcomes. It is possible that the basic science picture is still significantly incomplete, and the piece or pieces that are missing alter the ultimate clinical effect of the intervention. It is also possible that the basic science is simply wrong in one or more of its conclusions. Further, the basic science may be correct, and the predicted outcome legitimate, but the size of the effect clinically insignificant, and therefore not seen in clinical trials.

Or, the basic science may be looking at markers that are associated with the biological or disease process they are interested in, but are not causally related (just downstream effects), and therefore manipulating the markers has no effect. Or the markers may be very nonspecific and completely incidental. For example, many things will activate the immune system incidentally, resulting in elevated markers for immune activity. But modifying these markers, or even immune activity may do nothing for the underlying disease or process you want to treat.

There are therefore many blind alleys. The basic science should therefore be used cautiously, to point in the direction of potential translational research – but not to justify clinical treatments.

Translational and other clinical research then proceeds to preliminary pilot studies. These types of studies are generally small and either open (not blinded) or with some blinding. They are not large, rigorous, and reliable clinical trials. The purpose of pilot studies is to see if a new treatment or approach is basically safe, and if it has any potential. You want to make sure that patients do not do clearly worse on the treatment. The point of preliminary research is to justify larger clinical trials – not to support clinical claims.

I have discussed previously the work of John Ioannidis that indicates that most published research is wrong. Don’t take this the wrong way – on scientific questions the research eventually works itself out. But when you take any question that has been fairly definitively answers, and then look back through the literature, many if not most of the preliminary studies published on the question turn out to have been wrong in retrospect. The take home lesson for this is that, when you are at the pilot study stage most positive studies will not pan out when more rigorous studies are done.

This should not be surprising. There are multiple factors that are known to bias small or poorly controlled studies toward the positive – placebo effects, experimenter bias, and publication bias just being the most obvious.

If you read the conclusions to even very positive pilot studies you will find, “This study indicates that treatment X is well-tolerated by patients with disease Y,” or “This study indicates that larger clinical studies are warranted.” When researchers have to couch their conclusions in terms that will get past peer-review, that is all they can say. Problems arise, however, when proponents (whether or not they are the researchers) begin to make clinical claims that go beyond such caution.

Low-Dose Naltrexone

So what is the current state of the science of LDN? At this point the basic science shows that opiate receptors, as I indicated, do more than modulate pain. This means they are a potential target for the development of new drugs, or new applications of existing drugs. While naltrexone is an antagonist – it inhibits opiate receptors – LDN causes a compensatory upregulation of native endorphins and enkephalins, which last beyond the effects of the naltrexone itself. This means, paradoxically, that a daily dose of LDN can be used to chronically increase endorphin and enkephalin levels.

This is all perfectly reasonable, but still a bit preliminary, basic science. It indicates the potential for translational research – nothing more.

What about the clinical evidence? A search of PubMed for “low-dose naltrexone” reveals only pilot and preliminary studies. The quick bottom line is that there does not appear to be a single medical application of LDN (outside of addiction) that is supported by a class I clinical trial, let alone a consensus of rigorous studies. What we do see is a smattering of pilot studies for a few diseases.

One study on fibromyaligia found symptomatic relief and reduced pain and tenderness. Beyond being preliminary, such effects could simply be due to increased endorphins (natural pain reducers), without having to invoke any other mechanism.There are also a few studies looking at Crohn’s disease and experimental allergic encephalitis (EAE – a rat model of multiple sclerosis) with some  positive effects. The EAE study adds the further element of extrapolating from an animal model to a human disease.

There is also a pilot study of LDN in autism. While one outcome measure was positive, the rest were negative – which to me is a negative study.  At the very least, LDN looks less promising for autism than for either painful or autoimmune diseases, which does make sense given that autism is a very different and complex disorder.

So far this would all be just an obscure corner of medical research, hardly worth the public’s attention and of use only to medical researchers looking for promising leads to follow up. But here is where the pseudoscience comes in – some advocates are promoting LDN as a breakthrough medical treatment for a long list of diseases and disorder, going well beyond the research.

The website, lowdosenaltrexone.org, embellishes the preliminary research and presents LDN as an effective treatment. They list that it is effective for:

Cancers:

* Bladder Cancer
* Breast Cancer
* Carcinoid
* Colon & Rectal Cancer
* Glioblastoma
* Liver Cancer
* Lung Cancer (Non-Small Cell)
* Lymphocytic Leukemia (chronic)
* Lymphoma (Hodgkin’s and Non-Hodgkin’s)
* Malignant Melanoma
* Multiple Myeloma
* Neuroblastoma
* Ovarian Cancer
* Pancreatic Cancer
* Prostate Cancer (untreated)
* Renal Cell Carcinoma
* Throat Cancer
* Uterine Cancer

Other Diseases:

* ALS (Lou Gehrig’s Disease)
* Alzheimer’s Disease
* Ankylosing Spondylitis
* Autism Spectrum Disorders
* Behcet’s Disease
* Celiac Disease
* Chronic Fatigue Syndrome
* CREST syndrome
* Crohn’s Disease
* Emphysema (COPD)
* Endometriosis
* Fibromyalgia
* HIV/AIDS
* Irritable Bowel Syndrome (IBS)
* Multiple Sclerosis (MS)
* Parkinson’s Disease
* Pemphigoid
* Primary Lateral Sclerosis (PLS)
* Psoriasis
* Rheumatoid Arthritis
* Sarcoidosis
* Scleroderma
* Stiff Person Syndrome (SPS)
* Systemic Lupus (SLE)
* Transverse Myelitis
* Ulcerative Colitis
* Wegener’s Granulomatosis

Right there we have a huge red flag – a treatment that works for a long list of diseases with different etiologies. Many of the diseases on the list are auto-immune, and therefore an immunosuppresant could theoretically be applied to many auto-immune diseases. But many of the diseases on the list are not auto-immune.

Treating a long list of cancers is another red flag, as well as HIV/AIDS. The justification for this is that LDS “boosts the immune system,” this phrase alone also being another indication of a dubious treatment. Scientists do not talk of “boosting” the immune system because this concept is too vague to be of any use. The immune system in healthy individuals is probably already operating within optimal parameters, especially since immune activity is a trade off between fighting off invaders while not causing too much damage to the host. Increasing immune activity, therefore, does not always equal improving immune function. In individuals who have a weakened immune system because of chronic disease, poor nutrition, or toxicity their immune systems can be restored to more normal function with treatment – but these are often specific treatments that address an underlying cause.

Further, there is an inherent contradiction in simultaneously treating diseases that are auto-immune (the immune system attacking the host), and immunodeficiency diseases (like AIDS) and claiming to treat cancer by “boosting” immune activity. Increasing immune activity actually worsens auto-immune diseases, and suppressing the immune system would worsen AIDS. This is a difficult contradiction to resolve.

The end result is just another bogus treatment with claims that are literally too good to be true, based upon pre-clinical or preliminary evidence only. Proponents have turned into proselytizers – saying on their website:”

If you or someone you know has connections in the media, the medical community, or to those in developing countries involved in AIDS policy or treatment, please let them know about LDN.

Truly promising and science-based treatments do not need an organization to promote them. The science will speak for itself.

Conclusion

The opiate system and drugs to manipulate it are standard biomedicine, and we may see an expansion of the indications for naltrexone as the clinical research progresses. I would also not be surprised at all if this line of research does not pan out – we simply cannot tell at this stage.

Meanwhile, the LDN community are turning a promising if preliminary treatment into essentially what is snake oil by promoting it for an implausibly long and contradictory list of indications. They are making the classic mistake of extrapolating prematurely from preliminary evidence, and relying heavily on anecdotes. Anecdotes are just another form of preliminary evidence (a particularly weak form at that)  that should only be used to indicate promising new research, but not as a basis for clinical claims.

Ironically, LDN promoters may in fact harm research into LDN by giving it a bad name. Researchers may be reluctant to hitch their careers, or funding agencies commit resources, to a treatment that has a dubious reputation. If the research is promising it will still get done, but if anything it is likely to be slowed by the efforts of the LDN promoters.

This is just one of the many ways in which pseudoscience poisons the system.

Last week I wrote about the CME presentations at an obesity course put on by the American Society of Bariatric Physicians. I saved the most controversial one for last. Dr. Kendall Gerdes is a former president of the American Academy of Environmental Medicine, which I have previously written about. The AAEM is not recognized by the American Board of Medical Specialties and is categorized by Quackwatch as a questionable organization. Dr. Gerdes spoke on food allergies and food addiction.

I wasn’t convinced: I thought much of what he said was questionable. I thought, as a challenge for our readers, it might be an interesting exercise to present his information without comment and let readers look for flaws and form their own opinions. At the end, I’ll offer some suggestions of things to think about.

He described the concept of food addiction as a powerful tool to free patients from compulsive eating. Patients may “have the experience of” being addicted to foods or have symptoms of hunger and of just not feeling well. Specific symptoms of food addiction include fatigue, fibromyalgia, GI symptoms, cardiac arrhythmias, asthma, rhinitis, arthritis and seizures. There is no “gold standard” way to diagnose food allergies. He relies mainly on avoidance and challenge.

 Heroin Addiction: A Model for Foods

• As long as the junkie gets the “right dose” at the “right time,” he has no symptoms.
• If too small a dose, or too long an interval, will get withdrawal symptoms.
• Over time, the interval shortens and the needed dose increases.
• If the junkie is having withdrawal symptoms, the “right” dose gives immediate relief.
• After heroin is out of the system, a previously tolerated dose will now cause symptoms.
• Symptoms for food addicted patients follow the same pattern. The addictive food seems “good for me” and makes them feel better.

He says that research shows that partial digestion products of milk, wheat, soy and other proteins bind to brain endorphin receptors.

Patient Presentation

• Trouble with weight.
• Possibly otherwise no complaints.
• Subtle symptoms may be multiple.
• Key feature is variability (random or same time every day)
• Will not know they are addicted.
• Symptoms come when they have not had the food.
• “Favorite” food seems to relieve symptoms

Foods to Suspect

• “Recent” foods (since agriculture) like grains and milk products
• Foods heavily used in our society (coffee, chocolate, soy)
• Foods where patient had allergy as a child that was “outgrown.”
• Examine diet diary looking for heavy reliance on a few foods used 2-3 times a day.
• Watch for multiple forms (milk, cheese, yogurt, ice cream)
• Foods related to known food allergen
• Foods family members don’t tolerate.

Elimination and Challenge

• Avoid all suspect foods for 7-10 days
• If all addictive foods are removed, patient feels better
• Watch for withdrawal symptoms
• If no withdrawal symptoms and/or patient not better
• Check for adherence to elimination diet
• Check what foods were used to replace suspect foods
• Challenge after 7-30 days avoidance
• If a challenge makes symptoms recur, patient is easily convinced
• Easily missed food reactions:
  • “I really feel wonderful” from initial stimulation, followed hours later by “downer.”
  • “Gee, I’m thirsty” – reactions dump fluid into tissues
  • “Same old, same old” – symptoms are so familiar, patient doesn’t recognize that they * came after a time of no or low symptoms
• List all symptoms, even if you don’t think they’re due to the food challenge

He offers elaborate rules for grading severity of reactions and deciding how soon to re-challenge.

Avoiding the “Next” Addiction

• Remember patient has an addictive pattern
• Limit members of the same food family
• Avoid daily use of any food
• Watch out for foods patient “loves”
• Develop a list of food options such as quinoa, amaranth, parsnips, jicama, lichi nuts, cuttlefish, taro, nuts like pine, filberts, macadamia, etc.

Candida

There were a number of slides in the syllabus that the speaker didn’t get to. They indicated that he believes in “the yeast connection.” Lab tests are unreliable, so he makes the diagnosis with a clinical trial of a low-yeast, no sugar diet followed by challenges with foods that he thinks promote yeast growth in the body (milk, wheat, beer, mushrooms, fruit, sugar, etc.) He treats “yeast overgrowth” symptoms with elaborate and very restrictive “low-yeast” diet rules and anti-yeast medications like Nystatin and Amphotericin.

Try It, You’ll Like It

In a private conversation before his talk, Dr. Gerdes told me how he spends an hour with each patient and feels that the benefits justify the extra money he has to charge them. He mentioned one patient who was very grateful and insisted he had helped her when he hadn’t really done anything but listen to her. In his talk, he advised audience members to do their own elimination diet. If you have a positive reaction, you will be better able to see addictions in patients as well as ridding yourself of bothersome symptoms.

Instead of a Conclusion, Food for Thought

I invite readers to examine this material and form their own conclusions. Consider psychological factors, placebo/nocebo responses, confirmation bias, possible confounding factors, the meaning of “allergy” and “addiction,” what we know about physiology, the lack of blinding in elimination/challenge trials, the unreliability of “in my experience” recommendations, and the possibility that inadvertent collusion between patient and doctor might lead to deceptive conclusions. Can you spot any logical fallacies? Is the food addiction hypothesis a falsifiable one? How could it be properly tested? I look forward to an interesting discussion in the comments.

In a paper published in 2008, two academic chiropractors offered this observation: “The health claims made by chiropractors with respect to the application of manipulation as a health care intervention for pediatric health conditions continue to be supported by only low levels of scientific evidence. Chiropractors continue to treat a wide variety of pediatric health conditions.”¹

Despite lack of support by the medical and scientific community, chiropractic treatment of children is growing in popularity, and more chiropractors are specializing in “chiropractic pediatrics.”

The International Chiropractic Association offers a post-graduate “Diplomate in Clinical Chiropractic Pediatrics” (DICCP) and publishes a “peer reviewed” Journal of Clinical Chiropractic Pediatrics. The diplomate syllabus is a 30-module, 360+ hours classroom course during weekends over a three-year period. There is no hospital training and no contact with diseased or injured children — only a “mandatory observational/training weekend at a chiropractic center for special needs children under multi-disciplinary care.”² A post-graduate certification in chiropractic pediatrics (CICCP) can be earned after 180 hours of classroom instruction.

In a June 2008 joint press release, the American Chiropractic Association’s (ACA) Council on Chiropractic Pediatrics and the Council on Chiropractic Pediatrics of the International Chiropractors Association (ICA) announced that the ICA’s Diplomate in Clinical Chiropractic Pediatrics (DICCP) is now recognized by the ACA and its council as the official credential for specialization in chiropractic pediatrics.³

Noting increasing public support for chiropractic treatment of children, a January 2009 press release from the American Chiropractic Association made this announcement: “Survey data indicates that the percentage of chiropractic patients under 17 years of age has increased at least 8.5 percent since 1991.…Studies are beginning to show that chiropractic can help children not only with typical back and neck pain complaints, but also with issues as varied as asthma, chronic ear infections, nursing difficulties, colic and bedwetting.”⁴

A trend toward greater utilization of chiropractic by children has not gone unnoticed by the medical profession. An article in the January 2007 issue of Pediatrics (the official journal of the American Academy of Pediatrics) described chiropractic as the most common complementary and alternative medicine practice used by children, who made an estimated 30 million visits to US chiropractors in 1997.⁵ In 1998, children and adolescents constituted 11% of patient visits to chiropractors.⁶

Promoting a broad scope of practice for pediatric chiropractors, the ICA Council on Chiropractic Pediatrics offers links to abstracts from chiropractic journals that support chiropractic treatment for a great variety of a childhood ailments.⁷ Chiropractors commonly claim to have an effective treatment for otitis media, asthma, allergies, infantile colic, and enuresis. While many of the pediatric conditions treated by chiropractors are self limiting, treatment is offered for such serious conditions as cerebral palsy, epilepsy, myasthenia gravis, ADHD, and Tourette syndrome. For the most part, treatment for all these conditions is based upon detection and correction of “vertebral subluxations.” An article titled “The Child Patient: A Matrix for Chiropractic Care” in a 2005 edition of the Journal of Clinical Chiropractic Pediatrics, for example, stated: “Any alteration in form or function in the child may signal the presence of subluxation, and the subluxation may in turn alter the physiology of the child.”⁸ For wellness and prevention reasons, parents are advised that children should visit a chiropractor 6 to12 times a year to be checked for subluxations.⁸

A 2009 survey of chiropractors and parents of chiropractic pediatric patients, conducted by the International Chiropractic Pediatric Association, revealed that “The indicated primary reason for chiropractic care of children was ‘wellness care’.”⁹ Such care would require manipulating the spines of healthy children for “subluxation correction.”

There is no credible evidence to support the contention that “subluxation correction” will restore or maintain health or that such subluxations even exist.^10,11,12 There are hundreds of subluxation-based studies published in chiropractic journals supporting chiropractic treatment for children but only a few studies disputing such treatment. I suspect that most medical researchers feel that claims based on the chiropractic vertebral subluxation theory are too implausible to warrant investigation. But such claims should not go unchallenged, especially when they involve treatment of children.

Evidence Fails to Support Chiropractic Treatment of Childhood Ailments

To date, legitimate properly-controlled studies have failed to support the claims of chiropractors who treat children for organic ailments. In the case of asthma, for example, a randomized, controlled trial of chiropractic spinal manipulation for children with mild or moderate asthma, published in a 1998 issue of The New England Journal of Medicine, revealed that “the addition of chiropractic spinal manipulation to usual medical care provided no benefit.”¹³ A randomized, controlled trial of infantile colic treated with chiropractic spinal manipulation, published in a 2001 issue of Archives of Diseases in Childhood, concluded that “Chiropractic spinal manipulation is no more effective than placebo in the treatment of infantile colic.”¹⁴ A recent systematic review of randomized clinical trials offered this conclusion: “There is no good evidence to show that spinal manipulation is effective for infant colic.”¹⁵

It has been suggested that use of osteopathic manipulative techniques as an adjuvant therapy in routine pediatric care of recurrent acute otitis media might have potential benefit by affecting the patency of the auditory tube.¹⁶ Chiropractors who manipulate a child’s neck in a misguided attempt to correct “subluxations” might provide some symptomatic relief for secretory otitis media by inadvertently stretching the Eustachian tube, facilitating drainage of fluids from the middle ear. But the risk of such treatment outweighs any possible benefit. (Although otitis media is normally self limiting, it should be kept under observation by a pediatrician who can prescribe antibiotics, if needed, when there is acute otitis media with bacterial infection. Otitis media commonly occurs in children under 3 years of age. As the child grows older, changes in the length and angle of the Eustachian tube reduce chances of bacteria or virus traveling from the throat to the middle ear.)

Considering the implausibility of the chiropractic vertebral subluxation theory and the training chiropractors receive, there is good reason to question the ability of chiropractors to diagnose and treat childhood ailments. A correct diagnosis notwithstanding, there is no evidence to support the belief that manipulating the spine of a child to correct “vertebral subluxations” would be appropriate treatment for anything. A 1993 risk/benefit analysis of spinal manipulative therapy for relief of lumbar or cervical pain, published in Online Neurosurgery, advised neurosurgeons that “Potential complications and unknown benefits indicate that SMT [spinal manipulative therapy] should not be used in the pediatric population.”¹⁷

Because of the damage that manipulation might do to cartilaginous growth centers, there is no known justification for using spinal manipulation on an infant or a pre-adolescent child. Yet, some chiropractors recommend that the spine of a newborn baby be adjusted at birth to correct “subluxations.” According to the ICA (International Chiropractic Association) Council on Chiropractic Pediatrics, “Chiropractic care can never start too early.”¹⁸

Generally, pediatricians think of a child as being under 18 years of age — before vertebral end plate growth is completed. In a child under the age of 8 to 10 years, the cartilaginous growth centers are too immature and too vulnerable to injury to be subjected to spinal manipulation. There is some speculation that injury to growth plates might result in spinal deformity (such as scoliosis or Scheuermann’s kyphosis) as growth progresses.¹⁹ Such injury may not be detectable. “The incidence of subtle growth plate fractures following high-velocity [manipulation] techniques in children is surely under-appreciated because of the occult nature of these injuries.”¹⁹

Under normal circumstances, it seems unlikely that the cartilaginous, flexible spine of a healthy child would be as easily injured as an adult spine that has been weakened by degenerative changes. Referred pain caused by organic disease is not commonly experienced by children. When back pain in a child does occur, it is potentially more serious than back pain in an adult and should always be brought to the attention of a board-certified pediatrician.

Spinal manipulation has the potential to injure the spine of a child. A systematic review of 13 studies published up to June 2004 uncovered 14 significant manipulation-related injuries in children up to18 years of age, 9 of which were serious (e.g., subarachnoidal hemorrhage, paraplegia) and 2 of which were fatal (one child died from a brain hemorrhage and another from dislocation of the atlas following neck manipulation). Ten of the injuries were attributed to manipulation done by chiropractors, 1 to manipulation by a physiotherapist, and 1 to manipulation by a medical doctor; 2 injuries were caused by unspecified providers of manipulation. In 20 cases of harm caused by delayed diagnosis as a result of using manipulation, 7 involved a delayed diagnosis of cancer; 2 children died because of delayed treatment for meningitis.⁵ The incidence of spinal injuries in children is reported to be 2 to 5% of all spine injuries.²¹

Dubious Methods Used to “Detect and Correct” Pediatric “Subluxations”

High velocity, low amplitude thrusting, commonly used by chiropractors, is usually the type of manipulation that injures a child’s spine. Most chiropractors who manipulate an infant’s spine may simply use light thumb pressure to “adjust” an allegedly misaligned vertebra, thus reducing possibility of injury. Gentle touch may have a calming affect on an infant. But any manipulative technique applied to the neck of an infant is unnecessary and potentially dangerous. Some chiropractors may use a spring-loaded stylus or an electrically-powered mallet in an attempt to tap vertebrae into alignment. Chiropractors who adjust newborn babies to correct “subluxations” may concentrate on the upper cervical (neck) area of the spine. The upper neck is more likely to be injured by delivery during birth and is most vulnerable to injury caused by manipulation. Pediatricians have observed that “The most common traumatically injured region of the immature spine is the first and second cervical vertebrae.”¹⁹

There is no credible evidence that chiropractors are able to find “subluxations” in the spine of an infant. It seems unlikely that a chiropractor could detect vertebral misalignment by palpating the flexible, cartilaginous spine of an infant through a thick layer of baby fat. I have always suspected that chiropractors who say they can use their fingertips to feel subluxations in a baby’s spine are either deceiving themselves or misinterpreting what they are feeling.

Some chiropractors use surface electromyography, thermography, leg-length checks, or some other questionable device or approach to locate subluxations. It goes without saying that chiropractors should not expose a child to unnecessary radiation by x-raying his or her spine in a search for elusive or nonexistent “subluxations.” In Canada, the Alberta Society of Radiology has recommended that radiologists refuse requests from chiropractors who ask for diagnostic imaging of any type involving children aged 18 years or younger.²¹

Of all the claims made by chiropractors, I regard the claims made by those who treat children to be the most problematic. I have always advised against manipulating the spine of a small child or a newborn baby for any reason. Manipulation of the spine of an adolescent child under the age of 18, no matter who does it, should be done in concert with an evaluation and a diagnosis provided by an orthopedist, preferably a pediatric orthopedic specialist. Caring for children is very different from caring for adults and requires a special expertise. Board-certified medical and osteopathic pediatricians are best qualified to provide or recommend appropriate care based on a correct diagnosis.

Drawing the Line on Chiropractic Treatment of Children

Although spinal manipulation is often recommended as a treatment for back pain, this recommendation does not often apply to children. When the U.S. Department of Health and Human Services published a Clinical Practice Guideline suggesting that spinal manipulation can be helpful for patients with acute low-back problems without radiculopathy (sciatic pain) when used within the first month of symptoms, the report included this statement: “The recommendations included in the guideline may not apply to persons younger than 18 years since diagnostic and treatment considerations for this group are often different than for adults.”²² An adolescent child might benefit from appropriate manipulation designed to relieve symptoms caused by uncomplicated, mechanical-type back problems. But use of chiropractic “spinal adjustments” for “subluxation correction” may delay appropriate treatment based on a correct diagnosis — and the younger the child the greater the chances of misdiagnosis or injury.

Some chiropractors believe that adjusting a child’s spine will stimulate the immune system and help prevent infection. On September 8, 2009, for example, the Journal of Pediatric, Maternal and Family Health — Chiropractic issued a press release titled “Chiropractic Part of Swine Flu Prevention Program in Children.” The editor of the journal recommended that all children should be checked for vertebral subluxations before and during the flu season. “Since the nervous system has a direct effect on the immune system and because the spine houses and protects so much of the nerve system it is important to have your child’s spine checked for any interference.”²³

Such alarming and unscientific views find support in the basic definition of chiropractic and in official chiropractic publications. The National Board of Chiropractic Examiners (NBCE), for example, advises that “Psychoneuroimmunology has revealed an interrelationship between the central nervous system and immunity (consistent with chiropractic philosophy)….By manually manipulating vertebrae into their normal physiological relationship, chiropractic practitioners relieve interference with the nervous system along with accompanying symptoms.” Regarding treatment of children, the NBCE advises that “Chiropractic management of childhood disorders primarily consists of adjusting concomitant spinal subluxations and providing specific nutritional advice and/or support and other palliative measures.”²⁴

All things considered, it is an understatement to say that “Pediatric chiropractic care is often inconsistent with recommended medical guidelines.”⁶ Recommendation of any complementary alternative medicine therapy that has a risk/benefit ratio that is not acceptable and is not supported in medical literature may make a referring physician liable for negligence if the referral causes harm by delaying necessary conventional treatment.²⁵

I don’t know of any reason to believe that it might be necessary to refer a child to a pediatric chiropractor or to use spinal manipulation on a child prior to onset of adolescence. “Wellness care” in the form of “subluxation correction” is unnecessary and scientifically indefensible, and it places children at risk. 

References

1. Gotlib A, Rupert R. Chiropractic manipulation in pediatric health conditions — an updated systematic review. Chiropractic & Osteopathy. 2008;16:11 http://www.chiroandosteo.com/16/1/11 Accessed April 17, 2010.
2. ICA Council. Diplomate in Chiropractic Pediatrics. http://www.icapediatrics.com/members-postgrad.php Accessed April 10, 2010.
3. ACA Council on Chiropractic Pediatrics. Pediatric diplomate certification recognized by both ICA and ACA. 2007. http://www.acapedscouncil.org/pressrelease.html Accessed April 10, 2010.
4. ACA. Increasing numbers of children receive pediatric chiropractic care. January, 2009. http://www.acatoday.org/press_css.cfm?CID=3247 Accessed April 10, 2010.
5. Vohra S, et al. Adverse events associated with pediatric spinal manipulation: A systematic review. Pediatrics.2007; 119(1):e275-e283.
6. Lee A, Li D, Kemper K. Chiropractic care for children. Archives of Pediatrics and Adolescent Medicine. 2000; 154:401-407.
7. ICA Pediatrics. Journal Abstracts. http://www.icapediatrics.com/reference-journals.php Accessed April 10, 2010.
8. Fallon J. The child patient: A matrix for chiropractic care. Journal of Clinical Chiropractic Pediatrics (Supplement). 2005; 6(3).
9. Alcantara J, Ohm J, Kunz D. The safety and effectiveness of pediatric chiropractic: A survey of chiropractors and parents in a practice-based research network. Explore: The Journal of Science and Healing.2009; 5(5):290-295.
10. College of Physicians and Surgeons of the Province of Quebec. A scientific brief against chiropractic. New Physician.1996. http://www.chirobase.org/05RB/CPSQ/00.html Accessed April 10, 2010.
11. Mirtz TA, Morgan L, Wyatt LH, Greene L. An epidemiological examination of the subluxation construct using Hill’s criteria of causation. Chiropractic & Osteopathy. 2009; 17:13. http://www.chiroandosteo.com/content/17/1/13 Accessed April 10, 2010.
12. Nelson C. The subluxation question. Journal of Chiropractic Humanities. 1997; 7(1):46-55.
13. Balon J, et al. A comparison of active and simulated chiropractic manipulation as adjunctive treatment for childhood asthma. The New England Journal of Medicine.1998; 339(15):1013-1020.
14. Olafdottir E, et al. Randomised controlled trial of infantile colic treated with chiropractic spinal manipulation. Archives of Disease in Childhood. 2001; 84(2):138-141.
15. Ernst E. Chiropractic spinal manipulation for infant colic: A systematic review of randomized clinical trials. International Journal of Clinical Practice. September, 2009; 63(9):1351-1353.
16. Mills V, et al. The use of osteopathic manipulative treatment as adjuvant therapy in children with recurrent acute otitis media. Archives of Pediatrics and Adolescent Medicine.2003; 157(9):861-866.
17. Powell FC, et al. A risk/benefit analysis of spinal manipulation therapy for relief of lumbar or cervical pain. Neurosurgery Online.1993; 33(1):73.
18. ICA Home. Council on Chiropractic Pediatrics. http://www.icapediatrics.com Accessed April 10, 2010.
19. O’Neal ML. The pediatric spine: Anatomical and Dynamic considerations preceding manipulation. Comprehensive Therapy.2003; 29(2):124-129.
20. Hayes J, Arriola T. Pediatric spinal injuries. Pediatric Nursing. 2005; 31(6):464-467.
21. Editorial. Alberta radiologists target chiropractors. Canadian Medical Association Journal. 1998; 159(10):1237.
22. Bigos SJ, et al. Acute Low Back Problems in Adults.1994; Rockville, Maryland: U.S. Department of Health and Human Services. AHCPR Publication No. 95-0642.
23. McCoy M. Chiropractic part of swine flu prevention program in children. McCoy Press Research Update. September 8, 2009. http://researchupdate.mccoypress.net/2009/09/08/chiropractic-part-of-swine-flu-prevention-program-in-children.aspx Accessed April 10, 2010.
24. Christensen M, et al. Job Analysis of Chiropractic.2005. Greeley, CO; National Board of Chiropractic Examiners.
25. Cohen MH, Kemper KJ. Complementary therapies in pediatrics: A legal perspective. Pediatrics. 2005; 115(3):774-780.

There is a trend in the media when presenting a contentious topic to provide balance.  For topics not founded upon objective facts this serves the media well; provide both sides of the argument, and let the viewer decide.  The problem is that not every issue is evenly balanced, particularly in science.  Covering the discovery of a new extra-solar planet by giving equal airtime to astronomers and astrologers, for example, would be the height of absurdity, yet this is precisely how the media approaches scientific topics with frightening regularity.  You need look no further than the coverage of evolution, or 2012, or global climate change (that list should derail the comments nicely) for excellent examples of the same type of false balance in mainstream media outlets.

It was with trepidation, then, that I waited to see how PBS’s Frontline handled the topic of vaccination.  I was pleasantly surprised.  “The Vaccine War” introduced the most common concerns expressed about vaccination, and then presented the evidence addressing each concern in turn clearly and concisely.  It gave airtime to some rather prominent anti-vaccine personalities, but the bulk of the program was dedicated to the data, the science, the evidence, and where answers are available it did not hesitate to present them baldly and clearly. “The Vaccine War” was not a comprehensive review of every perspective, every theory, every vaccine and study, but it did provide a fair discussion balanced by the science.

My first clue that Frontline had acquitted itself well was when Dr. Jay Gordon, pediatrician to Jenny McCarthy’s son, tweeted his opinion of the show:

PBS show about vaccines. Don’t bother to watch it.”

Dr. Gordon wasted no time venting his outrage at the show’s message, its tone, and the fact that he was cut from the program at The Huffington Post.  I encourage you to read the original at The Huffington Post, and to post your own comments.  I will discuss his points here in detail, providing the periodic reality check.

Dear Kate,

The Frontline show was disgraceful. You didn’t even have the courtesy to put my interview or any part of the two hours we spent taping on your web site.

Dr. Gordon was interviewed, and his contribution was not felt to provide value to the  program.  He was cut.  That is the prerogative of the producers, and they are under no obligation to include Dr. Gordon just because he was interviewed.  If he is unhappy with his treatment, he is more than welcome to decline the next interview.  In fact, I think that would be an excellent idea.

You created a pseudo-documentary with a preconceived set of conclusions: “Irresponsible moms against science” was an easy takeaway from the show.”

Dr. Gordon needs to review the definitions of “pseudo” and “documentary.”  Is a WWII program on the History channel a pseudo-documentary because it covers the war from the Allied perspective?  Of course not, it provides facts within a context, a narrative; this is essential in a documentary, and it is precisely what the producers of this program have done.  That the producers decided to provide a story based upon facts and science determined the conclusions they presented.

Did you happen to notice that Vanessa, the child critically ill with pertussis, was not intubated nor on a respirator in the ER? She had nasal “prongs” delivering oxygen. I’m sorry for her parents anxiety and very happy that she was cured of pertussis. But to use anecdotal reports like this as science is irresponsible and merely served the needs of the doctor you wanted to feature.”

This objection by Dr Gordon is petty, appalling, and hypocritical.  So what if she wasn’t intubated?  This is a suffering infant who is critically ill and will remain so for weeks.  Is her suffering not worth preventing just because she didn’t die?  Is that how low Dr. Gordon sets his threshold for a child warranting medical care?  This is appallingly callous.

The segment that portrayed vaccine preventable diseases, including the segment with pertussis, was explicitly stated by the program to demonstrate what these diseases look like to a population that, on the whole, has never seen them.  How else would Dr. Gordon propose to provide this information to the public?  This is an entirely appropriate use of an anecdote, as an example of the evidence, rather than as the evidence itself.

Furthermore, by Dr. Gordon’s own admission, the producers did not provide the worst-case scenarios of each of these diseases, all of which can be fatal, though they could easily have done so if their goal was purely emotional manipulation, rather than education of legitimate risks of these diseases.

No one pursued Dr. Offit’s response about becoming rich from the vaccine he invented. He was allowed to slide right by that question without any follow up. Dr. Paul Offit did not go into vaccine research to get rich. He is a scientist motivated by his desire to help children. But his profiting tens of millions of dollars from the creation of this vaccine and the pursuit of sales of this and other vaccines is definitely not what he says it is. His many millions “don’t matter” he says. And you let it go.”

I am glad to read Dr Gordon acknowledge that Dr Offit’s motivation to research and produce vaccines was not financial.  He is a professional who produced an excellent and badly needed vaccine to prevent a nasty disease.  Excellence in our society is usually rewarded with financial compensation.  So what?  The research that lead to Offit’s rotavirus vaccine, the data supporting its safety and efficacy before licensure, and the volume of post-licensure safety and efficacy data replicated by other researchers stands on its own whether Dr Offit is penniless or a billionaire.

Jenny McCarthy resumed being a “former Playboy” person and was not acknowledged as a successful author, actress and mother exploring every possible avenue to treating her own son and the children of tens of thousands of other families.”

Frontline is not obliged to present a full CV on each person appearing in its program, and Ms. McCarthy’s role as a former Playmate is both factual and the original source of her fame.  Dr. Gordon’s perspective heavily biases his description of her as a “mother exploring every possible avenue to treating her own son and the children of tens of thousands of other families”.  She could just as easily (and perhaps more accurately) be described as a mother who, in pursuing her own ill-founded beliefs, has undermined the care of her child, placed him at higher risk of preventable disease, subjected him to worthless therapies while ignoring known serious risks, used her celebrity to disseminate misinformation and fear to the public while simultaneously diverting research time, energy and funds away from fruitful avenues of study, and delaying the time when the tens of thousands of families can better understand autism and be provided with more viable therapies.  Oh, and Frontline could have mentioned her foray into the embarrassing “Indigo Child” nonsense.  Perhaps describing her as a “former Playboy” isn’t so bad.

I trusted you by giving you two or three hours of my time for an interview and multiple background discussions. I expressed my heartfelt reservations about both vaccines and the polarizing of this issue into “pro-vaccine” and “anti-vaccine” camps. I told you that there was at least a third “camp.” There are many doctors and even more parents who would like a more judicious approach to immunization. Give vaccines later, slower and with an individualized approach as we do in every other area of medicine.”

This is a straw man.  No one, even the most staunch vaccine advocates, advocate the identical vaccination regimen for every child.  There are uncommon but clear reasons to deviate from the vaccination schedule due to a child’s individual medical history.  However, these are based upon evidence, not the arbitrary judgment of individual physicians.

What evidence does Dr. Gordon provide that later, slower, individualized vaccination schedules do anything but reduce the herd immunity of a community, increase the number of doctor visits, decrease the likelihood that a child will be fully immunized, or increase the time for which a child is unprotected?  No such evidence exists, so one must wonder on what he has based this recommendation.

The “individualized approach” to medicine warrants a series of posts all to its own. Suffice to say that while there are uncommon times when a patient’s care must deviate from the usual approach, standardization of care is one of the most effective ways of improving patient outcomes, and is one of the pillars of evidence-based (and science-based) medicine.  “Every other area of medicine” is making its best advances through the standardization of medical care, not capricious, evidence-free judgment calls of individual physicians.

What did you create instead?

“The Vaccine War.”

A war. Not a discussion or a disagreement over facts and opinions, but a war. This show was unintelligent, dangerous and completely lacking in the balance that you promised me — and your viewers — when you produced and advertised this piece of biased unscientific journalism. “Tabloid journalism” I believe is the epithet often used. Even a good tabloid journalist could see through the screed you’ve presented.”

And I believe this is one of the better examples of “projection” that I’ve come across.  I touched on the idea of “balance” in journalism at the beginning, and will not rehash it here.

You interviewed me, you spent hours with Dr. Robert Sears of the deservedly-illustrious Sears family and you spoke to other doctors who support parents in their desire to find out what went wrong and why it’s going wrong and what we might do to prevent this true epidemic.”

Dr. Gordon sets up a false-dichotomy here.  He pretends that only physicians who believe vaccines cause autism support parents of autistic children, or want to find the root cause of autism, or to find viable treatments or ways to prevent it.  This is absurd.

How deserving Dr. Sears is of his popularity we have addressed on SBM in the past, and can be found here.

Not a measles epidemic, not whooping cough. Autism. An epidemic caused by environmental triggers acting on genetic predisposition. The science is there and the evidence of harm is there.”

Autism diagnoses are higher than they have been in the past, and they are unsettlingly common, warranting a large-scale research, therapeutic, and support system that is currently lacking.  This is due in large part to increased awareness and broadened definitions of what places someone on the autism spectrum, though the possibility of a smaller scale true increase in the incidence of autism has not yet been confirmed or ruled out.  To label this as a “true epidemic” is inaccurate on several fronts.

Dr. Gordon is correct that autism has an indisputable genetic predisposition.  However, to what degree environmental triggers play a role, and which triggers these may be have not been established.  The science is there, but it does not come remotely close to supporting Dr. Gordon’s statement.

Most importantly, the evidence of harm, of vaccines causing autism, is not only not there, but overwhelmingly demonstrates no evidence of correlation between vaccines and autism.

Proof will come over the next decade.”

Oh, so Dr. Gordon doesn’t have proof now.  Thank you for clarifying.

The National Children’s Study will, perhaps by accident, become a prospective look at many children with and without vaccines. But we don’t have time to wait for the results of this twenty-one year research study:”

“We don’t have time to wait” The same can be said of every single medical condition suffered by a human being.  This doesn’t minimize their suffering, it drives home the point that we must perform the highest quality science possible and reject hypotheses that have been found to be without merit.  The proposed vaccine/autism link is one such hypothesis.

We know that certain pesticides cause cancer and we know that flame retardants in children’s pajamas are dangerous. We are cleaning up our air and water slowly and parents know which paint to buy and which to leave on the shelves when they paint their babies’ bedrooms.”

Where such statements are true they were found and confirmed by scientific inquiry, and when they are false they are refuted by the same method.  Belief and opinions are irrelevant when objective data is available, and the above paragraph is an irrelevant distraction to the topic of Dr. Gordon’s letter.

The information parents and doctors don’t have is contained in the huge question mark about the number of vaccines, the way we vaccinate and the dramatic increase in autism, ADD/ADHD, childhood depression and more. We pretend to have proof of harm or proof of no harm when what we really have is a large series of very important unanswered questions.”

That we don’t have the answers to everything does not mean that we don’t have the answers to anything, nor does it give us license to ignore the evidence we do have.

In cased you were wondering, as I practice pediatrics every day of my career, I base nothing I do on Dr. Wakefield’s research or on Jenny McCarthy’s opinions. I respect what they both have done and respectfully disagree with them at times. I don’t think that Dr. Wakefield’s study proved anything except that we need to look harder at his hypothesis.”

Case in point.  We have looked harder at Dr. Wakefield’s hypothesis, and it has failed catastrophically.  With no evidence in its favor and much against, Dr. Gordon has yet to reject Dr Wakefield’s hypothesis.

Of equal interest, is Dr. Gordon willing to acknowledge that the original paper Dr Wakefield published in The Lancet is at best a scientific embarrassment?

I don’t think that Jenny McCarthy has all the answers to treating or preventing autism but there are tens of thousands of parents who have long needed her strong high-profile voice to draw attention to their families’ needs: Most families with autism get inadequate reimbursement for their huge annual expenses and very little respect from the insurance industry, the government or the medical community. Jenny has demanded that a brighter light be shone on their circumstances, their frustration and their needs.”

I actually agree with Dr. Gordon here.  Autism is indeed a widespread problem badly in need of high-quality research, and families are in dire need of support.  It is unfortunate that the advocate they have found was so badly misguided by her pediatrician.  Dr Gordon was in the position to guide her, to educate her, connected her with experts in childhood development and autism and enabled her to use her enthusiasm and desire to help her son and the rest of the autistic community.  Unfortunately, Dr Gordon squandered this opportunity, to the detriment of us all.

I base everything I do on my reading of CDC and World Health Organization statistics about disease incidence in the United States and elsewhere.”

Dr. Gordon claims that he bases his decisions on evidence.  Yet he has come to different conclusions from those who generated the evidence, and those who are experts in the field.  Only one group can be right, and neither the evidence nor the odds are in his favor.

I base everything I do on having spent the past thirty years in pediatric practice watching tens of thousands of children get vaccines, not get vaccines and the differences I see.”

Experience has value, but it is little more than a long series of anecdotes, and as such it can also be a trap.  Nearly every modern physician can make a similar statement, as can every homeopath, acupuncturist, phrenologist, faith healer and shaman.  Placing personal experience, no matter how vast, above solid objective data is a hallmark of someone practicing pseudoscience, and it is precisely this sin that Dr. Gordon commits.

Vaccines change children.”

An assertion made without evidence can be rejected with the same.  Dr. Gordon clearly feels he has discovered new information, a previously unidentified pattern, yet he has not even bothered to publish a simple case series to try to convince the medical community of his claim.  Making such a statement without evidence is irresponsible.

Most experts would argue that the changes are unequivocally good. My experience and three decades of observation and study tell me otherwise.”

Again, Dr. Gordon feels his experience trumps evidence.

Vaccines are neither all good–as this biased, miserable PBS treacle would have you believe–nor all bad as the strident anti-vaccine camp argues.”

This is another straw-man by Dr. Gordon.  The program clearly acknowledges the presence of adverse events from vaccines, including extremely serious ones.  No one, including the producers of “The Vaccine War,” claim that vaccines are “all good.”  But the benefits do clearly outweigh the risks.

You say the decisions to edit 100% of my interview from your show (and omit my comments from your website) “were purely based on what’s best for the show, not personal or political, and the others who didn’t make it came from both sides of the vaccine debate.” You are not telling the truth. You had a point to prove and removed material from your show which made the narrative balanced. “Distraught, confused moms against important, well-spoken calm doctors” was your narrative with a deep sure voice to, literally, narrate the entire artifice.

You should be ashamed of yourself, Kate. You knew what you put on the air was slanted and you cheated the viewers out of an opportunity for education and information. You cheated me out of hours of time, betrayed my trust and then you wasted an hour of PBS airtime. Shame on you.”

As Dr. Gordon draws his rant to a close, he returns to telling a PBS producer how to do her job.  He does not, however, at any time provide any evidence to contradict a single pertinent point or piece of evidence made in the entire hour of “The Vaccine War.”

The way vaccines are manufactured and administered right now in 2010 makes vaccines and their ingredients part of the group of toxins which have led to a huge increase in childhood diseases including autism. Your show made parents’ decisions harder and did nothing except regurgitate old news.

Parents and children deserve far better from PBS.”

How can Dr. Gordon write the preceding paragraph and then claim to be anything other than anti-vaccine? PBS is not the one to be ashamed; our children deserve better stewardship than that of Dr. Jay Gordon.

Those with an anti-vaccine ideology come from various starting points. There are those who just hate vaccines – because they don’t trust the system, they don’t like the idea of injecting something into their children, or they blame vaccines for their child’s illness or disorder. There is also the “mercury militia” – those who blame environmental mercury for all ills, and whose attention was drawn to vaccines through the mercury-based thimerosal connection. I wrote recently about another group – radical environmentalists who see vaccines and just another environmental exposure the government is trying to cover up.

There is another group that has been around for a while but about which I have not written before – some elements of the right-to-life group. What is their connection to vaccines? – the false belief that vaccines contain cells from aborted fetuses. Recently Lifenews published an article with the following headline: Study Suggests Link Between Autism and Use of Cells From Abortions in Vaccines. The study, of course, does nothing of the sort.

The EPA Study

LifeNews editor, Steven Ertelt, was referring to a recent EPA study published in Environmental Science Technology called Timing of Increased Autistic Disorder Cumulative Incidence. If you read the paper you will find no mention of vaccines, let alone fetal cells in vaccines. The study simply looked at databases of autism diagnosis to see if there was a point at which the increasing cumulative diagnoses was most sharp – any turning points in the data. The point of this exercise is to suggest where to look for a potential environment factor contributing to autism – because that’s what the EPA does, look for environmental exposures that are causing human disease.

They found that in the California, Danish, and worldwide datasets the turning point happened around 1988-1989, while in the Japanese dataset the turning point was spread out more from 1988-1996. Therefore, they conclude, if we want to look for an environmental factor we should look for things whose exposure began around 1988-1989. That is the extent of their conclusion – nothing about vaccines or abortions.

In fact, their study did not even establish that the rising rates of autism are due to any environmental factor. In the discussion they give a nice summary of other documented contributors. These include diagnostic substitution, expanding the diagnostic criteria, younger age at diagnosis, influx of children with the diagnosis to areas with good services, and increased awareness and surveillance. No one of these factors can explain the entire increase, but it is possible that all of them together can, and it is certain that they explain at least part of the rise of autism diagnosis. A real increase cannot be ruled out, but is not necessary to explain the data – and this study does not change that.

The Abortion Link

Ertelt demonstrates the ability of dedicated ideologues to transform a study beyond all recognition. He reports:

The 1988 date is significant because, as pro-life blogger Jill Stanek notes, the Sound Choice Pharmaceutical Institute indicates that’s when the Advisory Committee on Immunization Practices added a second dose of the MMR vaccine, containing fetal cells from aborted babies, to its recommendations.

That’s it – a second dose of MMR vaccine was added. Since the vaccine schedule was being expanded regularly over the last two decades, no matter what date the EPA study found as the turning point for increased diagnosis, a temporal link to some vaccine could have been found. So the fact that this roughly correlates with the addition of a second dose of MMR is meaningless. It is not evidence of a connection. At best this kind of data may suggest a potential link, that would then have to be confirmed by other means – but even that is extremely weak.

Ertelt continues:

“For years the evidence has pointed toward the link between vaccines using DNA from aborted babies and the rise of Autism Disorder rates,” he said. “Parents need and deserve to know the risks associated with vaccinations made from lines derived from the bodies of aborted children.”

“While the pharmaceutical industry ignores the evidence and continues to put our children at risk,” Sound Choice is conducting studies on the impact of residual human fetal DNA in vaccines on the brain development and autism in children, Sedlak continued.

Wait a minute – the headline says (or at least strongly implies) that cells from aborted fetuses are in vaccines, but now they are talking about “lines derived from” cells from aborted fetuses. And then it sounds like they are not talking about cells at all, but just “residual human DNA.” So which is it?

Some vaccines culture the attenuated virus in human diploid cell lines that were derived from aborted fetuses. There are currently two such human cell lines in use: the WI-38 line (Winstar Institute 38), with human diploid lung fibroblasts developed in 1964, and  MRC-5 first cultured in 1970.  So each cell line is over 40 years old. Further, the cells themselves are not part of the vaccine. Viruses are cultured in these cell lines.

It is true that viruses are sloppy in their reproduction – they get their DNA mixed up with other viruses and host DNA. So it is likely that viruses cultured in a human cell line will come away with bits of DNA from that cell line – but so what? There is nothing special or different about this DNA. There is no theoretical reason why it should pose any health risk. This is simple scare-mongering using deception and misinformation.

And that is the point – scaring the public with emotional appeals. A search on this topic reveals dozens of websites and article declaring that there is “aborted fetal tissue” in vaccines – a claim so remote from the tiny sliver of truth on which it is based that it is simply a lie.

I have no issue with those who have a moral objection to anything that derives from abortions, if that is their moral position. I object to distorting the science in order to spread propaganda. If you have to lie to make your point, then your position is severely diminished.

Ertelt further reports

Stanek also commented on the new developments.

“I’ve always read it was mercury in vaccines that was implicated in autism, although many studies state this isn’t true,” she said, noted SCPI debunks the idea.

Interesting – so the pro-life antivaccinationists are at odds with the mercury militia antvaccinationists. They are willing, it seems, to look at the data to debunk the notion that mercury in vaccines is linked to autism, but then happily cite a potential connection to MMR without also noting that the same volume of data also has cleared the MMR vaccine of any connection with autism.

Conclusion

The EPA study is interesting in that it clarifies the timing of the increase in autism diagnoses. It says nothing about the cause of this increase, however, and does not contradict the generally accepted interpretation that artifacts of definition and surveillance are largely, if not completely, responsible for the increase. But ideologues have twisted this study as if it suggests a connection to vaccines, which were not even mentioned in the article and were not part of the research. But not only vaccines – those vaccines that were cultured in cell lines derived over 40 years ago from aborted fetuses.

Further, there is no reason to suspect, either theoretically or empirically, that there is any health risk from using these cell lines in the production of vaccines.

This has not stopped some pro-life antivaccinationists from misrepresenting this study and the background science for their own propaganda purposes. Accurate science should inform moral and ethical discussions, it should not be subverted to an ideological position. One might further consider it immoral to use misinformation to scaremonger about a public health measure, making the position of those pro-life antivaccinationists who engage in such activity even more tenuous.

A few years ago a friend asked me to comment on advice given to her adult daughter by a psychiatrist whom she’d consulted for depression. The psychiatrist had recommended testing samples of saliva and urine for hormone and neurotransmitter levels, the results of which would likely indicate a need for supplements to correct deficiencies or imbalances. According to the psychiatrist, who had an academic appointment at a medical school in New York City, “I have been using these supplements with a great deal of success.” My friend is not medically or scientifically sophisticated, but this made her a little uncomfortable. In that, she was entirely justified.

During our recent panel discussion at the NECSS, a member of the audience identified himself as a clinical pathologist at a major medical center, and wondered what he might do to become involved in the good fight against encroaching pseudoscience in medical schools. Clinical pathology is the medical specialty that concerns itself, in summary, with laboratory tests—their development, their validity, their interpretation, their usefulness and, by implication, their misuse. A topic that we haven’t much featured on SBM (we touched upon it here, here and here, and probably elsewhere) is that of bogus laboratory or other diagnostic tests.

Early in my own education in modern quackery, I found it particularly distasteful not merely that quacks misuse laboratory tests, but that several commercial laboratories market misleading tests. To the untrained eye these laboratories appear to be legitimate, even to the point of their being approved by apparently legitimate certifying bodies. We’ll discuss that below, but first let’s look more closely at the psychiatrist’s recommendations to my friend’s daughter and at other examples of bogus tests.

A Full Service Company

If my friend’s daughter had followed her psychiatrist’s recommendation, she would have sent her saliva and urine samples to a company called NeuroScience, which would have had them tested for certain hormones and neurotransmitters. The psychiatrist would have chosen those tests based on prompting by NeuroScience itself. Here’s what would have happened next:

Based on the laboratory results, NeuroScience, Inc. works with healthcare providers to develop Targeted Amino Acid Therapy (TAAT™) protocols designed to address the spectrum of neurotransmitter and hormone imbalances. Addressing neurotransmitter and hormone imbalances through TAAT™ can lead to significantly improved patient outcomes for a number of today’s most challenging conditions. Why wait? Get Started with NeuroScience, Inc. today.

NeuroScience will even help providers convince insurance companies to pay for the tests. And there’s no extra waiting time, because NeuroScience sells not only the tests, but the remedies. But it sells them exclusively to practitioners, who are then expected to resell them to their patients for a markup (look here for an example of the report that the practitioner will receive). If all goes according to plan, that sweet deal will last quite a while:

It is possible to decrease chances of excitatory overload by introducing inhibitory support for one to two weeks prior to the addition of excitatory support. This 1st phase strengthens just the inhibitory system, allowing it to regain control over the excessive excitatory activity during the night. This often leads to improvements in the quality of sleep in many patients. Excitatory support is then introduced in the second phase to enhance excitatory neurotransmission throughout the day, to increase motivation and reduce fatigue.

The second phase of therapy is structured in a way that mimics the body’s natural circadian rhythms. Excitatory neurotransmitter support, if needed, is typically recommended earlier in the day, when the body requires the energetic and cognitive effects of the excitatory transmitters. Likewise, inhibitory support is typically suggested in the latter half of the day, to calm the body and set the stage for sleep.

Even though specific amino acids can change single neurotransmitter levels rapidly, it is difficult to predict when a patient will experience symptomatic improvement. Many report improvement within the first week, whereas others may require several months of continued therapy to note significant changes. It is our experience that 3-6 months is the average amount of time it takes to optimize neurotransmitters overall.

The transition to the final phase of therapy is recommended when the patient has reached their health goals and their neurotransmitter levels have been optimized, as determined through follow-up lab tests. This phase serves as a maintenance phase, whereby the dosing of products is reduced to the minimum level that maintains the symptom resolution. The unfortunate reality of any approach to neurotransmitter imbalances is that the effects of the intervention may not be maintained with discontinuation. Due to ongoing factors that influence neurotransmitter levels, including stress, diet, and genetics, some individuals will require long-term neurotransmitter support. Hence the focus of the third phase is to maintain optimal neurotransmitter levels long-term to offset factors contributing to their imbalance and in the interest of preventing a recurrence of symptoms. (emphasis added)

Wow! Not only can “addressing neurotransmitter and hormone imbalances through TAAT™ lead to significantly improved patient outcomes,” it can also lead to significantly improved practitioner incomes! What a company! What doc, squeezed by diminishing 3rd-party reimbursements, wouldn’t be tempted to sign up?

There are only a couple of problems. Hormone levels measured in saliva are almost never legitimate. There is no physiologic reason to measure most salivary hormone levels and no generally published ranges of normal levels of hormones measured in saliva. Hormones are typically measured in blood, which makes physiologic sense; some hormones and their metabolites can usefully be measured in urine, but not for the purposes that NeuroScience claims. On the other hand, it is likely easier for NeuroScience to solicit samples when blood-drawing is not involved, and easier for the company to make assertions about “test results” that are unfamiliar to most physicians or labs.

Moreover, even if the test results are technically accurate, I’m aware of no science that links them to non-optimal levels of hormones or neurotransmitters, other than in extreme cases such as pan-hypopituitarism or pheochromocytoma (which are quite different from what NeuroScience is claiming). Nor, even if the tests were entirely legitimate, is there any evidence that the proposed treatments will “optimize” neurotransmitter or hormone levels.

Finally, the conflicts of interest among the seller of the tests, the wholesaler of the supplements, and the retailer of the supplements (i.e., the physician) are obvious.

When Bogus Tests fall into the Wrong Hands

In 2005, an autistic 5 year-old boy died in the office of Dr. Roy Kerry in Butler County, PA, after receiving an intravenous injection of disodium EDTA, the same chelating agent that is being used in the NIH-sponsored Trial to Assess Chelation Therapy (TACT). Kerry, a member of the Mother of all PPOs, the American College for Advancement in Medicine (ACAM), had given this agent to the boy ostensibly to treat “heavy metal toxicity” involving aluminum, mercury, and lead, among other possibilities.

According to the PA medical board’s Factual Allegations, Kerry had used at least two bogus tests to make these purported diagnoses. The nature of the first is unclear, because in the written record Kerry described it only as “testing for the deficiency indicator.” Such vague language suggests not a legitimate blood test but, perhaps, a quack “electrodiagnostic” device such as the “Vegatest” or “Electroacupuncture according to Voll.”

The second bogus test was a “post-provocative urine sample” collected a few hours after the first chelation treatment. This yielded an “elevated” urine lead level, but that is exactly what would be expected for anyone who has just been treated with such a chelating agent, and is thus not indicative of true lead toxicity.

Kerry had also diagnosed the boy with “candidiasis” and “multiple food allergies,” two highly unlikely possibilities that suggest other bogus tests, such as “cytotoxic testing” or the paranormally-based applied kinesiology. He may or may not have used these tests, but such “diagnoses” are common among quacks who preach “detoxification” or who belong to the ACAM.

The Commercial Laboratory Hall of Shame

We are not told the name of the laboratory that Kerry used for the “provocative urine test,” but it was likely Doctor’s Data, Inc. (DDI), a company with a long history of dubious offerings. DDI and another company, Genova Diagnostics (GDX), formerly the Great Smokies Diagnostic Laboratory, sell such bogus tests as hair analysis, urinary amino acids, “intestinal permeability,” “DNA oxidative damage assay,” and various “comprehensive panels” that generate reports explicitly or implicitly calling for “detoxification” schemes, “supplements,” “nutriceuticals,” or “bioidentical hormones,” which participating practitioners are only too happy to provide. Doctor’s Data is proud of its close ties with such PPOs as the ACAM and DAN!, and like GDX is a “supporter” of the ACAM.

Genova also has a cozy relationship with naturopath Michael Murray, a long-time shill for “natural remedies” and co-editor of the Textbook of Natural Medicine, previously discussed here. One of Genova’s former divisions was BodyBalance, which peddles “test kits” directly to consumers ostensibly to measure minerals, hormones, “antioxidant reserves,” and “the body’s natural safeguard for optimal sleep, mood and cell function — melatonin” in saliva, hair, or urine. According to the current BodyBalance website,

BodyBalance is a division of Dr. Murray Natural Living, Inc., that specializes in direct to consumer health screening products. Dr. Murray is one of the world’s leading authorities on natural medicine and the author of over 30 books on natural healing. Dr. Murray and James Kammann, the General Manager of the BodyBalance Division, played key roles in the initial launching of the BodyBalance product line in 1999 when it was launched by Great Smokies Diagnostic Laboratory. BodyBalance was acquired by Dr. Murray Natural Living, Inc. in January 2007.

Our goal at BodyBalance is to help empower consumers to take charge of their health by providing them access to the world’s leading functional medicine laboratory — Genova Diagnostics (see http://www.GDX.net). Established in 1986 as Great Smokies Diagnostic Laboratory, Genova Diagnostics today serves over 8000 primary/specialty physicians and healthcare providers, offering over 125 specialized diagnostic assessments. BodyBalance has the exclusive rights to direct-to-consumer testing with Genova Diagnostics’ innovative tests — a lab that has achieved the highest national and certain state certification standards including CLIA (Clinical Laboratory Improvement Amendments) and the College of American Pathologists.

How is it that commercial laboratories can so easily flout the standards of their field? Don’t the “certifications” just mentioned mean anything? Well, yes and no. The Centers for Medicare & Medicaid Services (CMS) regulates laboratories through the program identified above, the Clinical Laboratory Improvement Amendments (CLIA). There are other certifying bodies and various state requirements. These initiatives have made it more difficult for laboratories to peddle some dubious tests, but clearly there is still ample opportunity for what amounts to diagnostic testing fraud. Doctor’s Data, for example, calls itself

a licensed CLIA laboratory with appropriate state certifications and participates in numerous quality assurance/proficiency testing programs including the College of American Pathology, New York State DOH and Le Centre de Toxicologie du Quebec.

The company offers numerous other “Qualifications,” including “Chinese Certified Hair Standard GBW 09101.” Genova Diagnostics, as previewed above, is just as confident:

a fully accredited medical laboratory, certified in the areas of clinical chemistry, bacteriology, mycology, parasitology, virology, microbiology, non-syphilis serology, general immunology, hematology, toxicology, as well as molecular genetics by six separate health agencies including the Centers for Medicare & Medicaid Services which oversees clinical labs in the United States under the federal Clinical Laboratory Improvement Amendment (CLIA).

NeuroScience also boasts of the legitimacy of its laboratory tests. It outsources these to a convenient “independent” lab, Pharmasan, which seems to be right next door and which shares its founder with NeuroScience:

Gold Standard Laboratory Testing
NeuroScience, Inc. uses an independent, CLIA certified testing lab that is licensed in every state–including New York, which holds the highest level of qualification standards.

Quackwatch: Your Guide to Bogus Diagnostic Tests

You can’t help but have noticed that many of the links in this post are to articles on Quackwatch. That’s because the site is chock full of useful information about bogus tests, far more than can be found elsewhere. There you will find a more comprehensive list of bogus tests than I’ve mentioned here, and a larger list of laboratories peddling them. You’ll also find an article on “Dubious Genetic Testing” co-authored by the Quackwatch founder, Stephen Barrett, and our own Harriet Hall, and an article about bogus “biomedical treatments” for autism showing that—surprise!—Doctor’s Data and Genova Diagnostics are major players there, too.

One place where you will find nothing at all about bogus diagnostic tests is the NCCAM website. This is unfortunate, because the site is widely touted as providing information necessary to “be an informed consumer.”

To the clinical pathologist who asked the question at NECSS, if you’re reading this, and to any others who may be out there: There is a real need for those with expertise in lab tests to get involved in the effort to expose pseudomedicine. This is especially true for any of you who are involved with CLIA. Let’s hear from you!

On Tuesday night PBS FRONTLINE aired an episode about the anti-vaccine movement entitled The Vaccine War (which, by the time you read this, should be available for online viewing in case you missed it). When I first heard that this show was going to air, I was a bit concerned. My concern, of course is what I’m always concerned about when journalists do a story about pseudoscience, be it the anti-vaccine movement, “intelligent design” creationism, various “alternative medicine” modalities, or whatever. We’ve written about such things right here on SBM on more than one occasion, be it Dr. Jay Gordon on The Doctors or Andrew Wakefield being interviewed by Matt Lauer. Although FRONTLINE has done a pretty good, science-based job on controversial topics, I felt some trepidation, particularly after seeing some of the promos for the show, even though it featured Dr. Paul Offit, and other physicians and scientists.

Fortunately, I needn’t have worried. The Vaccine War is not perfect. There are some definite flaws, but by and large it is a rare thing on TV: A science-based discussion of a pseudoscientific movement. True, the opening montage did bring back a bit of that anxiety that this was going to be a “tell both sides” bit of false balance in that it included J.B. Handley blathering and Jenny McCarthy spewing her same false dilemma of measles versus autism. (She’d choose the measles, of course.) I was able to forgive that, because it’s very clear that the producers were just setting up the story. The show then launched straight into a birth and a list of the vaccines that children get, with Melinda Wharton of the CDC and Paul Offit pointing out how much good vaccines do, how we no longer see diseases that once killed thousands or even milions.

Then it was straight to Ashland, OR and the woo, personified by a mother named Jennifer Margulis, a writer for that “natural” repository of woo Mothering Magazine. She wasted no time spewing nonsense about “natural immunity” versus vaccines, claiming that it is better than vaccine-induced immunity. (Yes, it may be more long-lasting, but it comes without the risk of actually getting the diesease.) Dr. Donna Bradshaw-Walters was then introduced, and she described how 28% of Ashland’s children are missing some or all of their vaccines, pointing out that it is only a matter of time before there is an outbreak there. (I wonder how far Ashland is from Portland. Our intrepid fellow SBM blogger Mark Crislip is in the Portland area somewhere.) It was refreshing to note that there are actual pro-vaccine parents in Ashland, one of whom predicted that it would get ugly if there were an outbreak in which vaccinated children started to get sick because of unvaccinated children forming a repository for disease that can spread to vaccinated children whose vaccines didn’t “take,” for whatever reason. The show then described the San Diego measles outbreak and how unvaccinated children are a vector for infection, even to the vaccinated, who are less likely to be infected but not immune, as no vaccine is 100% effective.

Next, there was a segment at Pfizer. This may not have been the best idea strategically, given how it feeds into the distrust of big pharma exhibited by the vaccine fearful, although the scientist interviewed, Dr. Emilio Emini, did a good job of pointing out how vaccines prevent disease. Still, right there, I could envision doubting parents becoming suspicous. Then, of course, there was Dr. Paul Offit, who, although he is the Dark Lord of Vaccination to the antivaccine movement, is nonetheless the one of the most effective provaccine voices. Happily, Offit makes no apologies for having gotten rich from a vaccine. He is enormously proud of it, as he should be. But what he’s proud of is not having gotten rich, but have invented a product that has saved thousands upon thousands of children’s lives. That is truly something to be proud of.

One thing The Vaccine War revealed that I didn’t know was that bioethicist Arthur Caplan had actually contracted polio in his youth. No wonder he is so effective when he argues for vaccines. Equally effective is a scene in which paramedics are being trained, part of their training being to watch videos of children with pertussis and rotavirus. The video of the child with pertussis is horrifying; the suffering of such children is incredible. This class even pointed out that chickenpox can actually be fatal, showing a child with staph sepsis in the pox lesions.

Unfortunately, at this point the aforementioned Margulis demonstrates her extreme ignorance by asking why we are still vaccinating for polio as polio has become more rare. This woman was truly irritating in her arrogance of ignorance. Worse, she kept popping up throughout the show, sadly enough. But that wasn’t enough. There had to be Barbara Loe Fisher, too, spewing her usual anti-vaccine line. Unfortunately, here’s where FRONTLINE fell down on the job. The show actually described BLF not just once, but multiple times, using terms like “vaccine watchdog” or “vaccine safety” advocate, rather than what she is, an anti-vaccine propagandist. Bad FRONTLINE!

Similarly, the interview with Jenny McCarthy was infuriating, as usual. I suppose I should be used to her smug anti-science attitude. Buried in McCarthy’s assault on science and reason, though, there was a rather interesting tidbit. However, you have to go to her complete online interview to find it:

How long after the MMR was that first seizure?

You know, a lot of people think, and probably from me saying in some interviews, that it was after the MMR I noticed changes.

I don’t think it was just the MMR shot that caused any kind of trigger with autism. I think it was a compilation of so many shots to a kid that obviously had some autoimmune disorders. So I would say maybe a couple of months, a month or so after the MMR, I started to notice some physical ailments such as constipation, rashes, eczema. That was like the first little sign. And then the train just kind of descended from there.

This is very different from the stories McCarthy was telling around the time she released her first book, and she even seems to be acknowledging it as she dances around a very simple question. Indeed, I remember McCarthy saying in interview after interview how she saw the “light go out of Evan’s eyes” soon after the shot. That’s why her story resonated with the anti-vaccine movement so strongly, as shown when anti-vaccination activist Ginger Taylor cited what Jenny McCarthy said in her 2007 interview with Oprah:

Jenny says even before Evan received his vaccines, she tried to talk to her pediatrician about it. “Right before his MMR shot, I said to the doctor, “I have a very bad feeling about this shot. This is the autism shot, isn’t it?’ And he said, ‘No, that is ridiculous. It is a mother’s desperate attempt to blame something,’ and he swore at me, and then the nurse gave [Evan] the shot,” she says. “And I remember going, ‘Oh, God, I hope he’s right.’ And soon thereafter-boom-the soul’s gone from his eyes.”

Notice how Jenny appears to have changed her story from its being the MMR to its being a gradual process due to too many vaccines. Truly, her story shifts more than the sands of the Sahara, or the waves of the ocean, or your favorite metaphor for something shifty and lacking substance.

Speaking of shifty and lacking substance, the first Jenny McCarthy segment ran right into an interview with J.B. Handley. There was really nothing new there in that J.B. claims that “tens of thousands” of parents tell him that their children were “never the same” after vaccines, combined with his simplistic mantra: Vaccines cause brain damage and autism is brain injury. Ergo, to him, vaccines cause autism. Of course, it is not really true that autism is “brain injury.” It is a difference in the brain, but there’s no good evidence that autism is primarily due to “brain injury,” although there’s all sorts of quackery out there that purports to treat “vaccine injury” to the brain.

Here’s another point where the FRONTLINE special dropped the ball a bit. The show immediately went into the MMR fear mongering provoked by Andre Wakefield. The problem is that J.B. Handley wasn’t really about MMR, at least not until recently. He was about mercury and thimerosal. Indeed, Generation Rescue until a couple of years ago proclaimed on its website that autism is a “misdiagnosis for mercury poisoning.” (And guess where that mercury exposure came from? That’s right, vaccines.) But the MMR has never had mercury in it, ever. In conflating these issues, FRONTLINE confused two related issues that are not really the same thing, particularly when it started showing a speech by Robert F. Kennedy, Jr. at the Green Our Vaccines rally from two years ago. As someone who knows about the anti-vaccine movement and its history, this was irritating, and it is more than just a nit to pick.

That being said, I do like how, right after a segment in which Jenny McCarthy claims that scientists won’t study whether vaccines cause autism, the show immediately launched into a segment that demonstrated conclusively that that she is either mistaken or lying (take your pick). The issue has been studied extensively in multiple countries, and no link between vaccines and autism has been found. Thus, right after McCarthy made a claim, the claim was demolished totally. Moreover, FRONTLINE did a good job of explaining how correlation does not necessarily mean causation. Just because a diagnosis of autism is made soon after a vaccine does not necessarily mean the vaccine caused autism. It finished this middle part of the documentary by documenting the fall of Andrew Wakefield, in particular pointing out how some of the children in his studies had been referred through lawyers suing vaccine manufacturers.

The beauty of this segment is how FRONTLINE showed that, no matter how much evidence, with J.B. Handley saying, “I don’t give a fuck about what the MMR study said.” (Yes, he did use the F-word, although it was bleeped out and turned to “crap” in the online transcript. Stay classy, J.B.) This was rapidly followed by a demonstration of Barbara Loe Fisher shifting the goalposts asking for more epidemiological studies and basic science studies. It is, as Dr. Offit put it, a classic shifting of goalposts, with Jenny McCarthy blathering about her “mommy warriors” and how “Evan is her science.” In fact, I particularly liked how Dr. Offit explained exactly how the anti-vaccine movement is constantly shifting the goalposts in a way that a lay peson could understand.

Unfortunately, this segment depressed me, because it showed just how much science doesn’t matter in trying to persuade these parents and how the web perpetuates not just the old vaccine myths, but facilitate the spread of new ones. It demonstrates just how much the Internet’s “democratization” of knowledge devalues knowledge, expertise, and science. The forces of pseudoscience proliferate and infiltrate, and, quite frankly, those of us who promote science-based medicine are way behind the eight ball in trying to counter these messages. One thing I had no idea about was just how effective the Desiree Jennings story had influenced high school students not to vaccinate. Roughly half of one class who hadn’t taken the H1N1 vaccine said that the reason they didn’t take the vaccine was because they saw Desiree Jennings on YouTube. This makes me think, more than ever, that blogs such as this one and others are essential in tearing apart such bad information. The result of this information is people like the mothers in Ashland that I discussed last time who ask, “If vaccines work, who am I hurting by not vaccinating?”

The result was shown in the story of a baby who came down with pertussis and almost died. Her situtation was so bad that a chaplain was brought in for possible last rites.

Near the end of the show, there was presented a focus group of people who discussed vaccination. What was interesting is how much vaccination is viewed as a parental choice rather than a societal duty. This in and of itself is not necessarily a bad thing. It’s completely consistent with the psyche many people in the U.S. and the principles of limited goverment and self-reliance. The problem is that this choice is being increasingly undermined by misinformation on the Internet and elsewhere in the media. The message of the anti-vaccine movement that the days of “paternalism” are over echoes very strongly with the whole “health freedom” movement. The problem with this “freedom” is that refusing vaccination endangers more than just the child of the parent making the choice. It endangers other children, vaccinated or unvaccinated. It’s very difficult for anyone to make a well-informed choice when most of the information that pops up when you search the Internet is from the anti-vaccine side.

In the end, I was mostly relieved by The Vaccine War. It was science-based, and it pulled no punches in asserting that there is no good scientific evidence that vaccines cause autism. True, it did confuse the issue of the MMR vaccine and thimerosal-containing vaccines, and that’s more than a minor mistake. It also failed to address the valid reasons why we vaccinated for hepatitis B to neonates. Worse, it was far too kind in its treatment of Barbara Loe Fisher, calling her organization, the National Vaccine Information Center a “vaccine safety” advocacy organization, when it is an anti-vaccine organization, plain and simple. It did a little better with Generation Rescue, showing a bit of the sheer insanity behind the organization and how, no matter how much evidence there is against its position, it never loses sight of its founding principle, namely that it’s absolutely, positively always the vaccines. Always. Those complaints aside, FRONTLINE did a far better job than I expected in deconstructing the anti-vaccine movement. It didn’t compromise on the science, although it may have compromised a bit in how it describes, for example, the NVIC and Generation Rescue.

Will The Vaccine War change minds? Maybe. There’s no way it’s going to change the minds of hard core antivaccinationists of J.B. Handley’s ilk. Almost nothing I can think of can. But it might–just might–reassure parents on the fence that all that horrible stuff they’re hearing on the radio, seeing on TV, and, above all, reading on the Internet about the evils of vaccines are not based in science. That’s actually quite an achievement.

ADDENDUM: There was a segment in which a pro-vaccination parent in Ashland was profiled. In a shot in which she was surfing the ‘net, guess what blog showed up?

Yep:

The American Society of Bariatric Physicians recently invited me to speak at their continuing medical education (CME) conference on obesity in Seattle. They got my name from Stephen Barrett of Quackwatch and asked if I could speak about questionable weight loss treatments like HGH, MIC (methionine, inositol and choline), and the HCG Diet. I seized the opportunity to discuss how to evaluate any medical claim, with examples from alternative medicine as well as from weight loss. My title was “Questionable Evidence for Questionable Treatments.” I talked about some of the things that can go wrong in clinical trials and why simply finding reports of positive randomized controlled trials (RCT) is not enough. I advocated rigorously science-based medicine and recommended the SBM website.

Several people came up afterwards to express their thanks and their agreement, but some of the questions from the audience were rather hostile. One man said he was a military doctor and he was using and teaching acupuncture (which I had criticized as a bad example of “tooth fairy science” in my talk). I asked for his opinion of battlefield acupuncture and he just said “No comment.” A couple of people thought science wasn’t enough and thought it was okay to prescribe questionable treatments when there was no proven effective treatment. I responded that I had no objection as long as the patient was told the facts and not given the false impression that the questionable treatment had been tested and shown to work.

I was glad for the chance to meet some of the ASBP members. I had never met a bariatric physician and was interested to learn about their practices and philosophies. I had never really thought about the fact that most obese patients had associated diseases like hypertension and diabetes, so their overall management could be very complex. I attended the whole obesity course: some of what I heard was educational, some of it was questionable, and some of it was frankly disturbing.

The first speaker was Gary Taubes, author of Good Calories, Bad Calories. I had read his book and agreed with his evaluation of the dietary fat hypothesis, but I was not entirely convinced that he had enough clinically significant evidence to justify replacing it with the carbohydrate hypothesis. In this talk, based on his forthcoming book, he focused on the history of the case against sugar. It was refreshing to hear him say that

Until demonstrated otherwise, high fructose corn syrup is just another form of sugar.

A researcher, John Baxter, MD, discussed new drugs based on thyroid hormone that attempt to separate its beneficial effects on atherosclerosis and obesity from its harmful side effects. Interesting, but still in a very preliminary research stage. He went on to complain about the impediments to approving new drugs. In his opinion, the studies the FDA requires are intended to look for risks rather than benefits. He defended the “file drawer” practice, saying that his group did not publish negative trials that didn’t get the results they wanted (perhaps because the experimental design was flawed), since that would “pollute the literature” (?!).

Dr. Vernon Neppe spoke on nutritional supplementation and biopsychosocial issues. He said that supplements are drugs, they may be dangerous, manufacturing controls are poor, evidence is lacking, pharmacology is complex, interactions are common, there is evidence favoring vitamin D and fish oil supplements but questions remain, and generally food is better than pills. And he addressed the “natural” fallacy by pointing out that snake venom was natural. I was impressed by his common sense and was amazed by his alphabet soup of credentials: I don’t remember ever seeing anyone with more initials after his name. He listed 14 titles: MD, PhD, FRSSAf, DFAPA, DSPE, BN&NP, FRCPC, DABPN, FFPsych, MMed, DPsM, MB, BCh. I only know what the first two mean.

Dr. Kendall Gerdes spoke on food allergy and food addiction, a talk deserving a post just for itself. I’ll cover it next week.

Dr. Robert Lerman recommended omega-3 supplementation for bariatric patients because of its anti-inflammatory, insulin sensitizing, CVD risk-reducing effects and other potential benefits. He made a good theoretical case, but didn’t have any real evidence showing clinical benefit. He cited one study that reported higher maximum weight losses with fish and fish oil supplements than with placebo but did not report the average weight loss or the statistical significance. Without that information, I thought it was too meaningless to bother mentioning.

Dr. Barbara Schneidman reported on hot button issues for state medical boards. Some boards have restricted the use of “weight loss enhancers” to patients with a BMI over 30, and have prohibited using Schedule II drugs for the purposes of weight loss. Audience members thought this was unwise, that doctors should have the freedom to prescribe according to their own clinical judgment.

Jeffrey Bland, PhD spoke on “Beyond the Dogma of the Calorie.” Maybe it’s not that excess calories cause obesity which then causes diabetes, but rather that some underlying mechanism causes both obesity and diabetes. He pointed out that after bariatric surgery the blood glucose and lipid levels fall faster than the weight. He blames an interaction between genetics and the environment that he thinks involves “Larmarckian” inheritance (that’s his synonym for epigenetics). He implicates the gut microbiome as both causing and resulting from obesity. Some of the slides he didn’t get to (but that were included in the syllabus) covered resveratrol and claimed that specific dietary phytochemicals play a role in obesity and metabolic diseases. For what it’s worth, Dr. Bland is featured on Quackwatch. He has been in trouble with the FTC and the FDA for making unsubstantiated claims about supplements sold by his companies. He believes in detoxification and is a notorious promoter of naturopathy.

There were informative talks about managing childhood obesity and about pre- and post-op care for bariatric surgery. A talk on the Mediterranean diet covered a number of evidence-based health benefits, but did not explain why the speaker advocates a “modified” Mediterranean diet supplemented with protein powder, chromium, lipoic acid, and cinnamon.

The ASBP recently issued an official policy statement that HCG does not work for weight loss and that the HCG diet is not recommended. The last speaker on the program challenged the ASBP’s position. He claimed that the “con” studies were flawed, that more studies are needed, and that meanwhile HCG should only be used by physicians with special training and expertise (like him). One of his slides said “It is OK to use a placebo;” he added the caveat “as long as it works.” That statement can be criticized both on the basis of the meaning of the word “placebo” and on the consensus of medical ethicists that using placebos is unethical.

There was a room full of commercial booths. I was amazed at all the innovative ways companies had devised to profit from obesity. Most of them were giving away free samples of foods and supplements. (“You’re too fat, so let us sell you food”?) One product was a calcium citrate/vitamin D supplement disguised as a chocolate candy, with added calories. Is that a good idea? One salesman told me his products were classified as “medical foods” that were covered under a special FDA regulation. The FDA apparently doesn’t agree. They warned Dr. Bland that his similar products did not fit their regulatory definition of medical foods

…because the diseases and conditions described in the product labels do not have distinct nutritional requirements and because the products do not have any unique impact on the dietary management of those diseases and conditions beyond that which could be achieved by modification of the normal diet alone.

More next week.

Last week I participated in a panel discussion at NECSS with John Snyder, Kimball Atwood, and Steve Novella, who reported on the conference last Monday. What I mentioned to some of the attendees is that I had managed to combine NECSS with a yearly ritual that I seldom miss, namely the yearly meeting of the American Association for Cancer Research (AACR) meeting. There are two huge cancer meetings every year, AACR and the annual meeting of the American Society for Clinical Oncology (ASCO). AACR is the meeting dedicated to basic and translational research; ASCO, as the word “clinical” in its name implies, is devoted mainly to clinical research. Personally, being a translational researcher myself and a surgeon, I tend to prefer the AACR meeting over ASCO, not because ASCO isn’t valuable, but mainly because ASCO tends to be devoted mostly to medical oncology and chemotherapy, which are not what I do as a surgeon. Each meeting draws between 10,000 to 15,000 or even more clinicians and researchers dedicated to the eradication of cancer.

Having taken the Acela train from the NECSS meeting in New York straight to Washington, DC for the AACR meeting, I couldn’t help but think a bit about the juxtaposition of our discussion of the infiltration of quackademic medicine into medical academia with the hard core science being discussed at AACR. One session in particular at AACR highlighted what is one of the most significant differences between science-based medicine and the various forms of “alternative” medicine that we discuss here on SBM on such a regular basis. That difference, quite simply put, is the difference between the simple and the complex. “Alternative” medicine supporters often scoff at practitioners of science-based oncology, asking why we don’t have a “cure for cancer” yet, as if cancer were a single disease, or why we haven’t made much more progress since President Richard Nixon declared “war on cancer” back in 1971. One part of the answer is that cancer is incredibly complicated. Not only is it not a single disease, but each variety of cancer is in and of itself incredibly complicated as well. To steal from Douglas Adams, cancer is complicated. You just won’t believe how vastly, hugely, mind-bogglingly complicated it is. I mean, you may think algebra is complicated, but that’s just peanuts to cancer.

On Tuesday morning, I attended a session that hammered home that cancer is complex. The session was called, appropriately enough, The Complexity of Cancer. It was chaired by Dr. Joan S. Brugge, professor of Cell Biology at Harvard Medical School and featured as speakers cancer stem cell expert Dr. Sean J. Morrison of the University of Michigan, as well as two faculty from UCSF, Dr. Lisa M. Coussens and Dr. Allan Balmain. Dr. Brugge spoke about mechanisms that control tumor cell anchorage, as well as the interface between genetics and metabolism in cancer; Dr. Morrison discussed cancer stem cells and how some tumors appear to follow the stem cell model while others didn’t; Dr. Coussens discussed how chronic inflammation can lead to cancer; and Dr. Balmain discussed genetic network analysis as a means of determining the susceptibility to cancer of various cells.

Right from the beginning, Dr. Brugge invoked Nixon’s war on cancer with a particularly appropriate observation, namely that the war has been far more difficult than anyone could possibly have ever envisioned in 1971. Back in 1971, in the wake of the discovery of the first oncogene, src, most scientists studied almost exclusively cancer cells, not appreciating the role of the surrounding matrix of normal cells and connective tissue in both preventing and modulating tumors. It’s true that, even back in 1971, scientists understood that the immune system in controlling cancer, but we lacked the tools to study this system in great detail. Since 1971, the list of discoveries about cancer has been long. Some examples include the discovery of many more oncogenes; tumor suppressor genes; the role of tumor angiogenesis in cancer; cancer stem cells; the rediscovery of the Warburg effect and metabolic derangements in cancer cells; and an enormous number of discoveries in tumor immunology. Each discovery helped us understand better how normal cells become tumors and how tumors grow, invade, and metastasize. But each discovery also led to additional complexities and more questions.

One characteristic that virtually defines a malignant cell in solid organs (as opposed to blood-derived tumors) is its ability to survive when not attached to other cells in its normal surrounding matrix of collagen and other connective tissues. This characteristic of tumor cells has long been recognized, having been first described back in the 1960s. Normal cells, when not attached to the proteins to which they normally cling, rapidly undergo programmed cell death (apoptosis). Apoptosis due to becoming detached is known as anoikis. Dr. Brugge started out discussing her interest in anoikis and understanding how breast epithelial cells survive detachment. Her talk ended up encompassing intracellular signaling pathways, metabolic derangements, and genetics. One observation that is likely underappreciated is that cells that undergo detachment develop metabolic deficiencies that lead to decreased ATP deproduction, decreased cellular energy (real energy, not the fake “energy” — or qi — that alt-med proponents often invoke), and ultimately programmed cell death. One of the more provocative observations is that antioxidants can actually help save these cells by neutralizing reactive oxygen species (ROS) and thereby rescuing fatty acid oxidation. For purposes of this discussion, the details aren’t important (although they are very important for cancer biology). What is important is that antioxidants are not a universal good when it comes to cancer; in the case of the models of breast cancer discussed by Dr. Brugge, antioxidants actually promote the survival of transformed cells because part of the mechanism by which these cells undergo programmed death is through the production of ROS. Does this result mean that antioxidants don’t prevent cancer? Of course not. It does however, when taken in context with other studies, suggest a great deal of complexity, where in some cases antioxidants prevent cancer and others may promote cancer.

Contrast this to the frequent alt-med claim that antioxidants prevent cancer and are virtually always good.

Dr. Morrison’s talk touched upon one of the most contentious issues in cancer today, namely the cancer stem cell hypothesis. This hypothesis goes something like this. There exist within cancer a population of cells that behave like stem cells. They are self-regenerating and each is capable of dividing indefinitely and recapitulating a tumor, while the vast majority of tumor cells have only limited replicative potential. The population of cells that can actually produce new tumors may be very small, much less than 1% of the cells in any given tumor. This concept has been most validated in leukemias, although there is good evidence that breast and a variety of other cancers may follow a stem cell-like model.

Cancer stem cell

Under the stem cell model of cancer, these stem cells are highly resistant to chemotherapy, which wipes out all the non-stem tumor cells but leaves a few tumor stem cells, which can rapidly grow and then recreate the tumor, even from a single cell. In essence, the stem cell model postulates a hierarchy among tumor cells, as contrasted to the previous model, which was a more stochastic model in which any tumor cell could produce a tumor. To boil the concept down, in the stochastic model, any given cell in a tumor could be viewed as having, for example, a 1% chance of being able to form a new tumor if transplanted, while in the stem cell model only 1% of the cells of a given tumor can form new tumors, but they do so with very high efficiency. Moreover, these cancer stem cells have various protein and genetic markers that distinguish them from other cells in the same cancer.

The concept of the cancer stem cell is rather controversial. Personally, although the evidence has persuaded me that there is such a thing as what is commonly called a “cancer stem cell,” from my perspective I view the term as a poor descriptor of this cell mainly for semantic reasons. The term “stem cell” implies unlimited ability to produce different tissue types, which is not what this model is about at all. It’s long been known that tumors are made up of different populations of cells with different characteristics, and it’s not such a stretch to accept that many tumors might have a subpopulation of cells that are most responsible for tumor growth, with most of the other cells remaining quiescent or only slowly dividing. What Dr. Morrison argued is that some cancers follow a more “stem cell” model, while others follow a more stochastic model. He used the example of melanoma to illustrate this point: over 30% of the cells in a given melanoma studied can produce new tumors. While this observation might be consistent with the existence of a melanoma stem cell that makes up 30% of a typical melanoma, Dr. Morrison was unable to find any markers to distinguish the cells that could form tumors from those that could not, and he checked over 50 markers. While this does not entirely rule out a stem cell model (it’s possible that he hasn’t yet found the right marker), it is more consistent with a stochastic model, in which each cell in the melanoma has a 30% chance of being able to form a tumor when transplanted.

Why is this important? It’s important because it has great relevance to treatment. If a tumor is driven by stem cells, then to eradicate the tumor it is necessary to eliminate the stem cells. If it is driven by a more stochastic mechanism, a non-stem cell mechanism, then a “kill ‘em all” approach is more likely to succeed. Of course, it wouldn’t surprise me if it turns out that most tumors actually fall somewhere on a continuum between being stem cell-driven and being stochastic. Cancer is just that complex. The term “either-or” rarely, if ever, applies to it.

Dr. Coussens’ talk is fascinating for what it revealed about the immune system and cancer. How many times have you heard “alternative medicine” believers and promoters brag that this nostrum or that potion “boosts the immune system”? As we’ve said before here, it’s a meaningless claim, because sometimes boosting the immune system is bad, as in autoimmune diseases. In cancer, it’s long been known that inflammation, particularly chronic inflammation, can lead to cancer. One of the most classic examples of this phenomenon is how gastroesophageal reflux disease (GERD) can lead to inflammation in the lower esophagus, which can lead to a change in the cells there known as Barrett’s esophagus, which can ultimately lead to esophageal cancer. Inflammation is a function of the immune system; consequently, when you take anti-inflammatories, you are suppressing part of the immune system on purpose in order to decrease inflammation. In any case, Dr. Coussens discussed how activation of certain parts of the immune system can suppress cancer development, while activation of other parts can promote tumor progression. This slide, taken on my iPhone, demonstrates the concept:

Dr. Balmain echoed this message but came at it from a different angle, namely from the complexity of changes in gene expression in cancer, and how a highly complex interaction between inflammation, stromal cells, the immune response, metabolism, and changes in gene expression in a tissue, specifically skin, can influence susceptibility to cancer. One of the big disappointments in cancer research is that relatively few cancers have easily identifiable genes driving them, even though many tumors have a strong heritable component. The reason may well be due to the inheritance of multiple susceptibility genes of low penetrance, meaning that they don’t individually have a strong effect on the characteristics of a cell. Cancer actually involves changes in the expression levels of hundreds, if not thousands, of different genes. In fact, the way we now look at cancer is through network analysis of the levels of thousands of genes in the cell. We’ve gone from looking at single genes to looking at thousands upon thousands of genes. As Dr. Balmain concluded, cancer susceptibility and progression depend upon the emergent properties of many genes, each of which individually has a small effect, and these genetic variants affect the tumor cell, the microenvironment surrounding the tumor cell, or both. Moreover, depending upon the tumor type and situation, inflammatory networks can play opposite roles, either promoting or inhibiting tumor susceptibility and progression.

Is that complicated enough for you yet?

Then let’s move on beyond this talk. On Friday, a bunch of us on our floor on the cancer institute got together to discuss interesting stuff we saw and learned at AACR this year. One topic that came up is the Cancer Genome Atlas, or TCGA (you gene geeks out there may find the initials amusing, but they explain why the word “the” was included). The idea behind the project is to sequence the genomes of many, many cancers. You might wonder why it’s necessary to sequence so many cancer genomes, and it’s not an unreasonable question. The reason is that so many cancers are driven by different mutations that it’s unlikely that any two tumors have the same set of mutations driving them. Consequently, TCGA seeks to sequence at least 500 cancers for each cancer type studied. It started with a pilot project and has since been expanded to 20 different tumors. By sequencing lots and lots of tumors, or so the idea goes, we can identify commonly occurring mutations and sets of mutated genes, perhaps even across cancers, that can be targeted for therapy. At the very least, it is thought that we will be able to develop a greater understanding of the complexity of cancer.

I must admit that when I first heard of TCGA, I was skeptical. To me, it struck me as perhaps the largest fishing expedition in the history of cancer research. Moreover, even this massive undertaking is only part of the picture. As I alluded to earlier, the metabolism of cancer cells is often hugely abnormal, and a “chicken or the egg” argument continues to some extent even now about whether it is the metabolic abnormalities that drive mutations or the mutations that produce metabolic abnormalities. More likely, it’s a little of both, the exact proportion of which depending upon the tumor cell. None of this even considers influences outside of the genome (epigenetic influences) or differences in how proteins are made. Part of our discussion also pointed out that so many mutations have been associated with cancer and that they are often so different in different tumors, even from the same tissue, that trying to figure out which mutations found in TCGA are even relevant to cancer and which ones are actually driving the development, progression, and spread of cancer will be a daunting task, every bit as challenging as the Manhattan Project or sending a man to the moon in less than a decade. In fact, when you consider how vastly, hugely, mind-bogglingly complicated cancer is, it’s amazing that we do as well as we do now and that we’ve made as much progress as we have, arguments over whether we are too conservative or whether pursuing riskier research strategies will bear fruit faster notwithstanding.

Compare this to the view of many practitioners of unscientific medicine. My favorite example of a vastly, hugely, mind-bogglingly simple pseudo-explanation for cancer is that of the late Hulda Clark, who claimed to be able to cure all cancers (not just all cancers, but all disease) but who died of multiple myeloma herself. Her idea was that all cancer is caused by a liver fluke, which she would claim to be able to kill (and thus cure the cancer) with device she called her “Zapper,” a cheap little electrical gadget that looked as though it were assembled from spare parts at Radio Shack.

Another quack, Nicholas Gonzalez, claims that all cancer is due to a deficiency in pancreatic enzymes, for which he prescribes pancreatic enzyme replacement, up to 150 supplement pills a day, a “nutritional” regimen consisting of various vegetable and fruit juices , and a “detoxification” regimen including coffee enemas. He made a name for himself with a cherry-picked case series of his own patients that appeared to have survived pancreatic cancer far longer than is generally anticipated based on historical controls. This lead to a highly unethical clinical trial that ultimately showed that Gonzalez’s patients did considerably worse than conventional therapy, as poor as conventional science-based therapy does against pancreatic cancer.

These are not the only ones, of course. Still another quack, Robert O. Young, ascribes all cancer to “acidity” in the blood, and his treatment is always diet and bicarbonate to try to “alkalinize” the blood:

Young even goes so far as to describe cancer as a “poisonous acidic liquid,” states that “there is no such thing as a cancer cell” and that cancer cells are cells that have been “spoiled by acid.” To him, the tumor is the “body’s protective mechanism to encapsulate spoiled or poisoned cells from excess acid that has not been properly eliminated through urination, perspiration, defecation or respiration.” Young’s ideas have sucked in unwitting cancer patients, including one named Kim Tinkham, who even appeared on Oprah’s show a couple of years ago. (In addition, Young also doesn’t believe that sepsis is caused by bacterial infection.) On a related note, another quack named Tullio Simoncini espouses a variant of Robert Young’s ideas in that he believes that all cancer is a fungus. The similarity is that he prescribes “alkalinization” for the fungus, some of which can involve injecting sodium bicarbonate directly into tumors.

If there’s one difference between science-based medicine and quackery when it comes to cancer, it’s that science-based medicine appreciates the sheer complexity of tumors, while quacks often go for risibly simplistic pseudo-explanations of cancer. The complexity of cancer as a set of related diseases is incredible. Indeed, one has to respect it and even stand in awe at its ability to grow, evolve, and ultimately develop resistance to almost any treatment we can come up with. That’s not to say that the situation is hopeless, but it is an explanation as to why, nearly 40 years after Nixon’s war on cancer commenced, our progress against this foe has been incremental. Despite this record, I remain nonetheless optimistic and expect this situation to change within my lifetime. The reason is that we are finally developing the tools, both scientific and technological, along with the computational power to analyze the data, that hold out hope of an understanding of different cancers deep enough to make real progress in reducing the incidence, morbidity, and mortality from cancer. This isn’t any comfort to patients suffering from cancer now or to those who have (as I have) lost loved ones to cancer, but it does give me hope that, should I be one of the unlucky ones who develop cancer, my chances of survival will be better than at any time in history.

No quack can even come close to giving me that sort of hope.

To be blunt up front – SBM is not apologetic about the pharmaceutical industry. We get zero funding from any company, and have no ties of any kind to “big pharma.” In today’s world I have to spend time making that clear, because despite the reality critics are free to assume and falsely claim that our message is coming straight from the bowels of hell (a.k.a. the pharmaceutical industry).

We promote science-based medicine and criticize pharmaceutical companies along with everyone else when they place other concerns ahead of scientific validity, or promote bad science, for whatever reason.

It has become fashionable, however, to not only criticize the pharmaceutical industry but to demonize them – and the term “big pharma” has come to represent this demonization. Cynicism is a cheap imitation of skepticism – it is the assumption of the worst, without careful thought or any hint of fairness.

A recent article by Martha Rosenberg is an excellent representation of the mindless demonization of the pharmaceutical industry – good for scoring cheap points, but very counterproductive. She essentially accuses big pharma of inventing diseases in order to sell their products.

The premise strikes me as profoundly naive – which diagnostic entities are considered legitimate diseases is actually a complex question that is debated within the medical field. Rosenberg acts as if diseases can be invented out of whole cloth and then imposed upon medicine by a pharmaceutical executive. It is a grand-conspiracy type of thinking which erodes under scrutiny.

After hinting at anti-vaccine leanings, she writes:

Now pharma is back to creating new diseases, patients, risks and “awareness campaigns” faster than you can say thimerosal (the vaccine preservative that started the backlash.)

No – thimerosal did not start the backlash, Andrew Wakefield demonstrably did, with the MMR vaccine that never contained thimerosal. Thimerosal was simply act 2, after the evidence failed to find a link between MMR and autism (and of course there is also no link between thimerosal and autism either). But Rosenberg acts as if the anti-vaccine movement is a justified backlash against the excesses of big pharma – nice historical revisionism.

The sad fact is, Rosenberg might have a kernel of a legitimate point if she did not come across with her anti-scientific conspiracy mongering. That is why such demonization is so counterproductive – it actually backfires and let’s pharmaceutical companies off the hook for their real excesses.

Harriet Hall, for example, wrote an excellent piece on osteopenia – (Osteoporosis Drugs: Good Medicine or Big Pharma Scam?) which takes a properly nuanced and balanced approach to such questions. Do we really need to be treating pre-osteoporosis? The evidence should ultimately guide us. What pharma is guilty of doing is jumping prematurely on the bandwagon of a questionable diagnosis because it is a new market for them.

I think the same is true of the drugs that are now approved for the treatment of fibromyalgia – a controversial diagnosis, to say the least. But here we see more complexity and nuance. The FDA requires that a drug be indicated to treat a disease – not a syndrome or symptom. So there is no drug indicated for treating neuropathic pain as a symptom – drugs have to be indicated for diabetic neuropathy or post-herpetic neuralgia.

This forces pharmaceutical companies to find a disease, even when they have a drug that can potentially alleviate a symptom. Fibromyalgia is the perfect example of this – the very diagnosis itself is mostly used as a garbage pail diagnosis for vague syndromes of muscle pain and tenderness with fatigue and poor sleep. But you cannot get FDA approval to treat vague muscle pain.

Meanwhile, doctors are struggling to understand these syndromes and come up with a proper system of labeling what we find. We don’t want to prematurely use the “disease” label, but we also need to recognize patterns of patient complaints. I prefer terms like “myofascial pain syndrome” because it says what it is without implying a specific disease.

But regulation exists in its own world, and the FDA demands a disease label. So we have drugs, which are likely fine for the symptomatic treatment of myofascial pain, indicated for a dubious diagnosis (at least as it is often applied) like fibromyalgia. But it is doctors that invented the concept of fibromyalgia, and we still debate about it.

Rosenberg, however, cuts through all this nuance and goes for the simplistic and cynical conspiracy theory – pharma “invented” fibromyalgia to sell its drugs. She writes:

Nothing proves pharma’s when-the-medication-is-ready credo better than the legions of people who have fibromyalgia now that Cymbalta, Savella and Lyrica are available to treat it.

This is more historical revisionism. Having lived, and practiced medicine, through the fibromyalgia controversy it is clear that what happened is fibromyalgia became a popular diagnosis for the common vague syndrome I described above. Much after fibromyalgia became a popular diagnosis, some pharmaceutical companies saw it as a potential market. Rosenberg therefore has it backwards.

What we do have to recognize is that, now that there are drugs indicated for fibromyalgia, those pharmaceutical companies that make those drugs are invested in the reality and popularity of the diagnosis. They may therefore seek to distort the debate in that direction.

Rosenberg also embarrasses herself by criticizing the notion that there is an epidemic of sleep disorders in our society – the evidence suggests that there is, and it is under-treated. She further goes after adult ADHD and adult autism. The alternative is that autism and ADHD are childhood diseases only and always spontaneously resolve by adulthood – a scientifically untenable, and even laughable, position.

She further completely distorts the notion of “treatment resistant” conditions. She misinterprets that fact that many drugs are initially approved for adjunctive (add-on) therapy. This is not because the notion of “treatment resistance” was invented by big pharma. It is partly due to the fact that it is easier to do clinical trials where a new treatment is added to an established treatment, rather than to prove equivalence as stand alone therapy. So pharmaceutical companies go after the low-hanging fruit to maximize their return on investment.

Also – some patients are difficult to treat, and when one approach is not adequate it is nice to have more options. Rosenberg somehow turns this into a negative.

Conclusion

Rosenberg’s approach to this complex issue is simplistic, naive, and conspiracy-mongering. She brings no useful insight to the discussion.  She also demonstrates nicely the method of “demonizing” a convenient target – re-write history, white wash over all complexity and nuance, and cast everything into a maximally sinister light.

But further Rosenberg shows that taking such an approach is highly counterproductive. The pharmaceutical industry, like every industry, needs an effective watchdog to guard against abuse and excess. I also think they require thoughtful and effective regulation (although this question is difficult to disentangle from political ideology).

Rosenberg and other big pharma conspiracy theorists make ineffective watchdogs and critics, because their criticisms are paper thin and easily countered . By not recognizing the complexity of the issues involved, or making any attempt at fairness, Rosenberg is easily dismissed.

If I were a conspiracy nut I might even suspect that people like Rosenberg are actually fronts for big pharma, used to create a straw man of criticism that they can then easily knock down to show that all criticism is weak and invalid.

Back in 2008 I wrote on Near Death Experiences (NDE’s).  I have an interest in this topic as I have frequent exposure to near death; my wife has a predilection for watching Judge Judy.  Since 2008 there have been a few studies on the topic of NDE’s as researchers try and find evidence that consciousness transcends the brain, if that is what a NDE represents. I have also been ill for most of the last week and have not had the usual time to spend generating typos to drive some readers to distraction.  Fortunately, I have a miracle cure that is 100% effective in resolving all my self -limited illnesses: time.  It passed and with it the illness.  As a result I am about 10 days behind in the commitments in my life, so this will be a shorter than usual post.

As will come as no surprise to anyone who reads this blog regularly, I am of the opinion that NDE’s are almost certainly physiologic in origin.  I see no reason why consciousness should exist beyond physiologic brain function.  I am not sympathetic to the whole mind-brain dichotomy and see no reason why the mind is not the result of brain function.  No one ever speaks of the lung-gas exchange dichotomy or the kidney-urine production dichotomy.  But that is my bias, and I mention it at the beginning of the post in the interest of openness.

There is an enormous popular literature on NDE’s, but little in the way of science, probably,  I would guess, is that it is difficult to prospectively find subjects upon which to do studies.

There are people, however, who are going to die and it is nice to allow them to go gentle into that good night. I appreciate the efforts of palliative care specialists, as while I have never particularly worried about being dead, the process of getting there has never seemed particularly inviting.  Part of ensuring that patients are comfortable is to monitor their cerebral function to make sure the remain unaware.  This technique was developed by anesthesiologists who did not want their patients to become conscious during surgery yet have no ability to communicate that they were now aware that their appendix was being removed.

Dying patients had their brain function monitored to make sure they remained unconscious as they died.  If you decide to remove a patient from the ventilator as an example, you do not want them to be aware.

As the brain dies, there appears to be a last, short, burst of a of electrical activity.

“…loss of blood pressure, as monitored by indwelling arterial line, was followed by a decline is BIS/PSI activity followed by a transient spike in BIS/PSI activity that approached levels normally associated with consciousness. This spike in electroencephalogram (EEG) activity had short duration and the activity then declined to a level of activity associated with burst suppression.”

A last gasp of activity before the void.  What is happening? What does this burst represent? Is the world being observed one last time? Does the patient see themselves from afar?  Are they going to the light?  Are memories reviewed or being formed? No one knows.  Everyone died and are unable to report what they thought or experienced with the burst of activity.  But one could speculate. And one does

“We speculate that this level of BIS/SEDline activity is related to the cellular loss of membrane polarization due to hypoxemia. We further speculate that since this increase in electrical activity occurred when there wash no blood pressure, patients who suffer “near death” experiences may be recalling the aggregate memory of the synaptic activity associated with this terminal but potentially reversible hypoxemia.”

So perhaps the NDE is the last flurry of electrical activity by the brain and, if the patient were brought back from the grave, they would recall this activity as a NDE. Or not.  Like most of what occurs in the minds of the dying, it is lost to death.

NDE’s can be induced by drugs.  Ketamine, an anesthetic drug, can also cause a reaction similar to an NDE.  Ketamine can cause  visual distortions and a lost sense of time, sense, and identity.  Ketamine works as a NMDA receptor antagonist, similar to  the action the more familiar drugs dextromethorphan, phencyclidine (PCP), and nitrous oxide.  All these drugs can cause a dissociative state.  I remember when I had nitrous oxide for my wisdom teeth extractions, I became convinced that I was not in the dental chair, but was somehow outside looking in on the oral surgery.  To ‘prove’  I was in the chair, I kept lifting my hands up and waving them, to the distraction of the oral surgeon.  I had a similar reaction to indomethacin, a sense that I was in the corner of the room looking down at me.  It is most odd.

Ketamine can cause NDE’s.

“We aimed here at assessing, in a sample of ketamine misusers, concordance between the typical near-death experience (NDE) features and the on-drug psychoactive effects the subjects experienced. In 2003-2005, a sample of previous ketamine misusers recollecting a ketamine-related NDE were recruited through snowballing and screened with the means of the Greyson NDE Scale; 125 participants made an initial contact with the researcher and 50 reported a minimum score of seven at the “Greyson NDE Scale”. Interviewees were in the range 21-66 years old; 27 participants (54%) were educated at BA level, 18 (36%) had an MSc, and 5 (10%) a PhD. Eight (16%) interviewees had a definite religious background. An average lifetime ketamine intake of 140 occasions was reported by the interviewees, who typically presented with a polydrug, including cannabis and MDMA/ecstasy, misuse history. In 45 (90%) cases, the NDE occurred during the first few occasions of intake. Most frequent features of reported NDE states included: altered perception of time (90%), strong sense of detaching from own physical body (88%), and a sense of peace/joy (76% of subjects). Although results here described were elicited from a self-selected, nonrandomized, limited size sample of misusers, we suggest that recreational ketamine intake may be associated with occurrence of near-death related states.”

Of course, just because James Randi can bend a spoon using prestidigitation  doesn’t mean that Uri Geller  isn’t bending spoons with his mind.  Similarly, just because NDE’s can be mimicked in ketamine abusers, er, I mean misusers, doesn’t mean that ‘real’ NDE’s are not the consciousness going towards the hereafter.  But I am an Occam kind of guy; why should entities be multiplied beyond what is necessary?

Numerous physiologic parameters  go awry as you die and all your body functions fail.  Many tightly controlled parameters become progressively deranged: pH, C02, sodium, etc. Could these derangement’s have something to do with the physiology of NDE’s?

In a recent study they evaluated  52 patients who survived an out of hospital cardiac arrest, of whom 11, or 21% had an NDE.  As a group, the NDE’s had both higher CO2 levels and lower O2 levels in the blood. They also found increased potassium in those with NDE’s.

They note prior studies that demonstrate that low levels of oxygen can result in NDE ’s, perhaps by way of the NMDA receptor as well.  Low oxygen and high CO2 may be a plausible physiologic partial explanation for NDE’s. Whether some brains are predisposed to NDE’s (since some patients had more than one, poor guys, nearly dying more than once) or there are other factors has yet to be elucidated.

The high potassium? In the discussion they comment,

“Alternative theories found the explanation for NDEs in quantum theory, which suggests that consciousness may arise from quantum processes within neuronal microtubules. The recent work of Bernroider and Roy suggests that quantum entanglement in the ion channels (especially in the potassium channel) of brain cells underlies information processing in the brain and, ultimately, also consciousness. Although untenable and purely theoretic, this possible connection between potassium channels in the brain and the mechanism of consciousness (and therefore the possible mechanism of NDEs) deserves further investigation.”

Once you invoke quantum mechanics for any process macroscopic process in medicine (except, perhaps, MRI’s), you lose credibility. Exactly why an untenable explanation deserves further investigation is not explained.

Potentially psychologic factors were not associated with NDE’s in this study.  ”Sex, level of education, fear of death, time until ROSC, and religious belief” were not associated with an NDE, lending credence to that idea that NDE’s are a physiologic response rather than spiritual response, although I suspect the authors lean towards the spiritual side.

“Clearly, the presence of NDEs pushes the current knowledge of human consciousness and mind-brain relation to the edge of our understanding.”

To my mechanistic, reductionist way of thinking, NDE’s are the last gasp of activity of a dying brain. Like a cramp in an ischemic leg, it does not push the muscle-contraction relation to the edge of out understanding.

Again, association is not causation, but there is an interesting rat study that suggests that both low pH and increase C02 combine to inhibit NMDA receptors, just like ketamine.

“BACKGROUND: Carbon dioxide (CO2) dose-dependently decreases minimum alveolar concentration (MAC) of anaesthetics in rats. CO2 also dose-dependently decreases cerebrospinal fluid pH. N-methyl-D-aspartate (NMDA) channels exhibit pH sensitivity and are putative targets for inhaled anaesthetics. We hypothesized that CO2 dose-dependently decreases rat NMDA channel current via an acidifying effect at concentrations relevant to CO2 MAC.

METHODS: To test this hypothesis, we studied rat NR1/NR2A glutamate receptors expressed in voltage-clamped Xenopus oocytes. To measure pH effects, we used perfusates adjusted between 7.3 and 5.3 with HCl. To measure CO2 effects, we used equimolar sodium perfusates containing either 0 or 24 mM NaHCO3 and CO2 between 0% and 87% atm. Solution compositions were measured using a blood gas analyser with values corrected using a calibrated pH meter and gas chromatograph with solutions at 37 degrees C.

RESULTS: We found that decreasing pH decreased NMDA current. Moreover, pH effects produced by adding CO2 to NaHCO3-containing perfusates were identical to those produced by adding HCl to normal perfusates. The pH inhibiting 50% of NMDA current was 6.52. The CO2 concentration inhibiting 50% of rat NMDA current was 63% for solutions with 24 mM NaHCO3. CO2 exhibited a linear dose-dependent NMDA response analogous to that observed for in vivo CO2 anaesthetic potency in rats.

CONCLUSIONS: CO2 and hydrogen ions act via the same mechanism to inhibit NMDA receptors. Moreover, CO2 inhibits rat NMDA receptors in a manner that is consistent with CO2 MAC-sparing effects in rats.”

NDE’s will unlikely be an area of research that will ever lead to definitive conclusions.  Dead men tell no tales and those that survive are unlikely to volunteer their brains for further evaluation, and most patients to survive a cardiac arrest are in no condition to be used in acute clinical studies.

NDE’s appear to be reproducible by medications and are probably the response of the dying brain to an inhospitable metabolic milieu.  However, like Houdini, when I die, if I can come back, I will come back and tell you about my dying.  In the meantime,  if I see the light, I’m not going towards it, no matter how inviting.