For the last four years I have served in a volunteer capacity among a panel of pharmacotherapy experts queried regularly by the ABC News Medical Unit about breaking or upcoming news involving the efficacy and safety of drugs and supplements. Where appropriate, I provide background information that informs the story. My incentive is largely to put my time where my mouth is when I say that scientists need to take a more active role in making sure medical stories are reported accurately. An additional dividend is paid to my students who then benefit from my presentation of the science behind timely medical developments.

On occasion, perhaps once or twice a year, I’ll be asked for an on-camera interview. Even when this occurs, the resulting story will contain no more than 15 seconds of the interview and some summary by the reporter of other issues we discussed. I take this responsibility very seriously and prepare as much as I can given the deadlines of the press and my daily education and research schedule. But given airtime constraints, much of what I prepare would normally end up in the abyss of my files and come out in the classroom when I lecture about that particular topic. However, blogging now allows us to expand further on stories where we are consulted, giving us an opportunity to air, albeit to a smaller audience, the information we found important from our perspective. Authoring a blog, therefore, takes away the excuse some scientists and physicians have in not wanting to talk to the press: “There’s never enough airtime to tell the whole story the way I would tell it.”

This post was informed by one of those brief appearances, this time on ABC World News Sunday with Dan Harris. The interview was solicited last weekend following the release of information obtained during the execution of a search warrant in lodging occupied by the self-help guru, James Arthur Ray, who led an Arizona sweat lodge ceremony last October where three people ultimately died and almost two dozen were hospitalized. The segment was not archived to the World News website but some ABC affiliates subsequently aired truncated versions of the story.
———————————–

On October 8, 2009, paramedics responded to a 911 call at a mystical retreat being held at Angel Valley Spiritual Retreat Center in West Sedona, Arizona, a stunningly beautiful area known widely as a mecca for New Age enthusiasts. Eyewitness accounts compiled in this October 21 New York Times article describes what medics encountered upon arriving at a 415-square-foot “sweat lodge” on the center’s grounds:

Midway through a two-hour sweat lodge ceremony intended to be a rebirthing experience, participants say, some people began to fall desperately ill from the heat, even as their leader, James Arthur Ray, a nationally known New Age guru, urged them to press on.

“There were people throwing up everywhere,” said Dr. Beverley Bunn, 43, an orthodontist from Texas, who said she struggled to remain conscious in the sweat lodge, a makeshift structure covered with blankets and plastic and heated with fiery rocks.

Dr. Bunn said Mr. Ray told the more than 50 people jammed into the small structure — people who had just completed a 36-hour “vision quest” in which they fasted alone in the desert — that vomiting “was good for you, that you are purging what your body doesn’t want, what it doesn’t need.” But by the end of the ordeal on Oct. 8, emergency crews had taken 21 people to hospitals. Three have since died.

Participants paid $9,695 each to attend a “Spiritual Warrior” retreat led by Mr. Ray, an event whose next offering continues to be advertised on the website for James Ray International, Inc.

Yes, the 2010 event is still scheduled for September 18-23, 2010 and registration remains open.

But I wouldn’t put up my ten grand just yet because an investigation of Mr. Ray is ongoing and the Yavapati County Sheriff’s Office has recently released the affidavit from a search warrant executed shortly after this tragedy.

This December 30 New York Times article displays the 33-page search affidavit and this January 3 Prescott News article has several photographs and an excellent distillation of the affidavit.

Many other news sources will provide you with details on the circumstances of the tragedy with eyewitness reports and you can read elsewhere of Mr. Ray’s appearances on The Oprah Winfrey Show associated with the book, The Secret by Rhonda Byrne.

But here we would like to discuss some of the pharmacology associated with the Sedona tragedy. Lynne LaMaster in the Prescott News notes that according to the search warrant documents, investigators were originally looking for:

“A saleable/useable quantity of unlawful drugs including but not limited to marijuana, methamphetamine and peyote, paraphernalia for packaging, manicuring, weighing, distributing, including but not limited to scales, baggies, grinders, bindles, envelopes, seals paraphernalia used to administer the drug, i.e., syringes, cotton swabs, alcohol swabs, spoons, razor blades, tubes.”

While investigators did not appear to find any overtly psychoactive substances, they did find a veritable cornucopia of prescription drugs, dietary supplements, and syringes, with prescriptions in the name of Mr. Ray. But it wasn’t the supplements that caught my eye. It was this letter from a Michigan doctor of osteopathy:

Dr. Crisler operates the website, allthingsmale.com, and offers in-clinic and online consultations. The frontpage of his site argues strongly that he is in the business of anti-aging therapies as shown lecturing to the American Academy of Anti-Aging Medicine and offering subscriptions to Life Extension Magazine. Further exploration of his website reveals that he specializes further in assessment of low testosterone levels, or hypogonadism.

Testosterone cypionate, hGH, hCG, Arimidex (anastrozole) and finasteride (sold previously as Propecia or Proscar, but now available generically). OK, that’s starting to make sense. Testosterone and human growth hormone (hGH) are anabolic agents. That is, they enhance the development of lean, skeletal muscle mass. The larger cocktail is a typical bodybuilding/anti-aging regimen that is also purported to enhance sex drive. But you might have some questions at first glance.

(For pharmacology students and professors, dissecting the endocrine pharmacology of this combination would make a great comprehensive qualifying examination question for graduate candidacy.)

Arimidex/anastrozole? Isn’t that used to treat estrogen-dependent breast cancer?

Finasteride? Isn’t that used to treat prostate cancer?

Let’s take a closer look at some of these drugs.

Testosterone cypionate is known as a “depot” form of testosterone that has a half-life of 5-8 days, sold as DEPO®-Testosterone in the US. Testosterone, the steroid hormone primarily responsible for secondary sex characteristics in men, is not active when taken orally because it is rapidly metabolized by the liver. Therefore, if one wishes to boost testosterone, it is commonly formulated into a gel or patch that slowly releases the hormone across the skin. But it is more effectively delivered by injection, usually into muscle. When combined with a fat-soluble compound like cypionic acid, the testosterone is slowly released from the injection site. According to a PowerPoint presentation available at Dr. Crisler’s website (here, 4.5MB), his regimen employs weekly injections of 100 mg testosterone cypionate, about double the manufacturer’s recommendation for treating clinical hypogonadism.

When I was interviewed by Dan Harris for ABC World News Sunday last weekend, we discussed in footage that did not appear whether testosterone qualified as an “anabolic steroid.” The public normally thinks of ultrapotent, clandestine compounds as being the anabolic steroids used by athletes. But in purely pharmacological terms, testosterone is a steroid based on its chemical structure and it has anabolic, or tissue-building, activity. However, testosterone is an anabolic steroid that we make naturally, men and women.

Hence, testosterone is an endogenous anabolic steroid. When injected as testosterone cypionate, this would be called the exogenous supplementation of an endogenous steroid. But true bodybuilders wouldn’t bother with something like testosterone when more potent and effective synthetic anabolic steroids are available on the clandestine market.

Arimidex (anastrozole) is classified as an “aromatase inhibitor.” You may not know that testosterone is the starting material for estradiol, the steroid hormone primarily responsible for secondary sex characteristics in women. Testosterone, which we all make from cholesterol as the starting material, is converted to estrogen by aromatase or CYP19, an enzyme that is highly abundant in the ovaries. When a woman is diagnosed with a form of breast cancer that required estrogen to grow, aromatase inhibitors are given to prevent the ovaries from making more estrogen from testosterone (Older drugs such as tamoxifen can also be given as they directly block the effects of estrogen on breast cancer cells themselves.)

We do not know if Mr. Ray was among the approximately 1% of breast cancers that occur in men. Former drummer of the rock band KISS, Peter Criss, is the most recently public of male breast cancer patients in the US.

However, it does not appear that Dr. Crisler is a board-certified oncologist, so there must be some other reason that he prescribed Arimidex to Mr. Ray. Men have some testosterone that gets converted to estrogen but usually it’s not enough to cause estrogenic side effects such as gynecomastia and testicular shrinkage. But when taking supplemental, supraphysiological doses of testosterone, the small amount of aromatase that men have will convert enough of it to estradiol such that they may experience some feminizing effects.

Interestingly, Dr. Crisler notes on slide #66 of his aforementioned PowerPoint presentation that anastrozole’s #1 use worldwide is in testosterone replacement therapy regimens. Unfortunately, a citation is not available to support that statement.

Finasteride prevents conversion by 5-alpha-reductase of testosterone to dihydrotestosterone or DHT, a form of the hormone that can cause benign prostatic hypertrophy, can promote prostate cancer, and is also partly responsible for hair loss. Hence, finasteride combats several side effects of testosterone supplementation. So, these testosterone injections can be combined with anastrozole and finasteride to maximize testosterone’s anabolic effect while minimizing “unsightly” side effects.

Human growth hormone (hGH) is a peptide normally produced in the pituitary gland that is also anabolic on its own and augments the muscle-building effects of testosterone.

Human chorionic gonadotropin or hCG is normally the hormone produced by the placenta during pregnancy and is the hormone detected in the urine by home and clinical pregnancy tests. Yes, men taking this hormone would give a positive pregnancy test.

Understanding why hCG might be given in this cocktail requires that we revisit the hypothalamic-pituitary-gonadal axis (HPGA). Gonadotropin-releasing hormone, or GnRH, is produced in the hypothalamus of the brain and signals that pituitary gland to synthesize and release several peptide hormones that each share a common subunit: LH, FSH, TSH, and hCG. LH, or luteinizing hormone, when released from the pituitary gland and causes the testes to create mature spermatozoa and release testosterone. However, when too much testosterone is produced, or too much is available from external injection, a negative feedback loop suppresses LH secretion. Suppression of LH over time will cause testicular atrophy. It is thought that providing hCG will provide more of the subunit shared with LH, restoring LH levels. I am not convinced that this actually occurs. Restoring LH also is purported to increase the conversion of cholesterol to pregnenolone, a precursor or building block of testosterone. Believe it or not, this is an oversimplification of the pathway but I hope that gives you an idea of the rationale behind hCG use.

There were also some other drugs found in Ray’s room at the lodge prescribed by other physicians that included Diovan (valsartan), an antihypertensive of that competitively binds receptors for an endogenous vasocontrictor, angiotensin II, and an injectable relative of vitamin B12 called methylcobalamin. Although we don’t know for certain if Ray was taking the drugs prescribed by Dr. Crisler, investigators did at least find anastrozole and genotropin brand of hGH, Propecia brand of finasteride, together with pregnenolone, the testosterone precursor. Also found were bags, suitcases, and pill boxes of energy supplements and amino acids. The complete litany of objects confiscated from his possession are detailed at the Prescott News website.

As mentioned at the outset, one of the biggest reasons investigators were interested in any drugs that might have been in Ray’s possession was that there may have been psychoactive substances that could have impaired his judgment or that of followers/clients in the sweat lodge at the retreat. Ray was reported by several eyewitnesses as being aggressive and aloof, and even unhelpful when medics arrived at the sweat lodge. Dan Harris at ABC News asked me if I thought that Ray’s pharmacopeia might have contributed to his state of mind.

This is very difficult to do for a plethora of reasons, not the least of which because I am not a physician nor am I privy to what drugs he was actually taking or his basal personality characteristics. However, I am a pharmacologist and did train in endocrinology during my postdoctoral fellowship and can make some general comments.

A person taking an anabolic steroid regimen (recall that testosterone is a natural anabolic steroid) is prone to mood swings, anxiety, and aggressive behavior. In “TRT: A Recipe For Success,” a Word document available at All Things Male, Dr. Crisler apparently makes note that the intent is not to create an anabolic steroid cycle but rather testosterone replacement therapy, where testosterone levels are targeted to the upper-level of a normal range. Unfortunately, we cannot be sure if Mr. Ray was taking the drugs as directed or at doses greater than those recommended.

A physician colleague also reminded me that some of the drugs on the search warrant could alone cause electrolyte disturbances that could be exacerbated by being in an enclosed area with hot stones where other people were vomiting and begging to get out after fasting for 36 hours. Specifically, testosterone can cause sodium retention and Diovan/valsartan can cause potassium retention. These ionic imbalances can certainly influence one’s state of mind and one can speculate that these imbalances would be made worse by fasting and dehydration.

Off-label drug prescribing
This case also raises some questions as to how these drugs were prescribed in the first place. Sources close to Ray told ABC News that the “practical mystic” was being treated for a hormonal imbalance.

It is peculiar why a man of Ray’s means living in Carlsbad, CA, would be prescribed drugs by an internet physician in Michigan rather than seeing a board-certified endocrinologist or urologist at one of the outstanding medical centers in southern California.

Nevertheless, there are no laws that would have prevented Dr. Crisler from prescribing this regimen to Mr. Ray. To the contrary, physicians in the United States, whether they are MDs or DOs, are granted the latitude to prescribe any FDA-approved medicine for any indication they see fit. While it is illegal for drug companies themselves to promote “off-label” uses of drugs (i.e., indications for which the company has not received explicit FDA approval), a physician can legally prescribe a breast cancer drug to a man wishing to build lean muscle mass. I will leave it to my physician colleagues to comment on whether this falls under the standards of medical practice. In fact, the ethics of off-label prescribing would be an excellent separate issue to discuss in another post.

But let us not forget that this is a very sad case where three people lost their lives and nearly two dozen people were hospitalized. Press accounts of the sweat lodge incident and subsequent investigation suggest that blame and potential criminal penalties will fall where they may. The Camp Verde Journal noted in its 2009 roundup that:

Lawsuits have been filed by survivors, victims’ families and the Black Hills Sioux Nation, alleging Ray “committed fraud by impersonating an Indian,” thus violating the 1868 Treaty of Fort Laramie.

What we have offered here is a perspective on the pharmacology and toxicology of prescription hormone products and considerations of issues raised in publicly available documents and questions posed of us by the press. It is likely that several factors conspired to end up with this loss of life. As always, tragic events are what drive changes in laws and regulations.

The following is a collaborative effort by Peter Lipson, MD, a usual contributor to Science-Based Medicine, and Ames Grawert, JD, a soon-to-be-sworn-in attorney working in New York City.

Proponents of science-based medicine have always had one major problem—human beings are natural scientists, but we are also very prone to cognitive mis-steps. When we follow the scientific method we have developed, we succeed very well in understanding and manipulating our environment. When we follow our instincts instead, we frequently fail to understand cause and effect. This is how people on the fringes of medicine and science survive—intentionally or otherwise, they exploit our natural tendency to have too much faith in our own non-systematic observations.

One of the most important examples of this is the anti-vaccination movement (hereafter called the “infectious disease promotion movement” or IDPM). There have always been those suspicious of medicine and science, but the IDPM has taken this a step farther. They encourage people to “go with the gut”, ignoring centuries of science and public health data in favor of superstition. It’s not hard to exploit a parent’s fears. But exploiting these fears leads to real harm as many of us in the blogosphere have documented (and documented, and documented).

The IDPM is so fixed on their false beliefs that vaccination causes some sort of serious harm that they cannot be swayed by evidence. As each piece of their hypothesis is disproved, they move on to the next. Thimerosal doesn’t lead to autism? Then maybe it’s “the toxins”. Once the idea is fixed, there is no way to dislodge it. It simply shifts around a bit.

Since there is no science to lend legitimacy to the infectious disease promoters, they must rely on appeals to emotion. Most of their websites are full of testimonials, misinformation, and outright hostility. And when they really get backed into a corner, rather than hunkering down to do some real science, they sue.

Dr. Paul Offit is a nationally known expert on vaccination. He was featured in an excellent article by WIRED reporter Amy Wallace in which he said, among other things:

She lies.

The “she” in this instance is Barbara Loe Fisher, one of the leaders of the infectious disease promotion movement. She didn’t like this at all. Among her complaints she alleges the following:

The purpose of the Wired article was to create the impression that anyone not in support of universal and mandatory vaccination is irrational, uneducated, unscientific, controlled by fear and a danger to the public health. Wallace and Offit combined in an effort to defame and discredit those not in favor of universal and mandatory vaccination and singled out Plaintiff Fisher, whom the article describes as the “movement’s brain,” and the “media’s go-to interview for … ‘parents [sic] rights’” for condemnation as a liar.

To many physicians and scientists, this type of claim is hard to understand. Science is a process for finding and understanding facts. People can become emotionally tied to their work but science doesn’t care, and scientists often have vigorous debates about their work. Real scientists and real doctors must have thick skins.

So when someone is so attached to their own scientific opinion that they feel a need to use the legal system to protect their beliefs, many of us are left scratching our heads. Why wouldn’t she just try to find evidence to support her beliefs? How can a court possibly have something useful to say about a scientific question? What the Hell?

If you’re thinking that the law shouldn’t work this way — that angry combatants in the battle of ideas shouldn’t be able to leverage defamation law into silencing their more strident critics — you’re right. And it doesn’t. For better or worse, the American first amendment is a vigorous creature. Where other countries would hold defendants liable for negligently false and offensive speech, American law prefers that ideas be spoken, and their value decided by informed citizens, rather than lawyers and judges. This is actually a relatively novel topic in conflict of laws jurisprudence, and regardless of whether its assumption about the intellectual capacity of our public is accurate, it’s a uniquely American approach to the law, and one that Fisher completely ignores.
(FYI — all cases noted below in parentheses are Supreme Court cases, and therefore circumscribe any state defamation law. We don’t even need to reach beyond federal constitutional law to show where Fisher goes wrong.)

Virginia’s defamation laws follow the traditional American model, (although it eliminates the slander/libel, or speech/print distinction). Virginia therefore requires a showing of objective falsity, and a degree of malice, before defamation can be proven. The latter is keyed partially to whether the person pleading defamation is a “public person.” Because citizens should be free to question their leaders, as a matter of free speech, courts will only hold a defendant liable for defaming a public figure if the defamation occurs with actual “Sullivan” malice (referring to a famous Supreme Court case).

Accordingly, it becomes important to define a “public person.” While a private person speaking on a public matter — e.g., a small-time attorney commenting on a high-profile case — counts as “private” (Gertz v. Robert Welch), someone who voluntarily inserts herself in the role of shaping public opinion is a public person (Curtis Publishing v. Butts).

This distinction exists precisely because of people like Fisher. While she’s not a household name, she styles herself an opinion-maker, and has taken the requisite actions to make herself just that.

Critically, when it comes to public figures, the first amendment protects hyperbole, and some pretty wicked satire, too (N.Y. Times v. Sullivan; Hustler Magazine v. Falwell). A statement about someone’s character and honesty — “she lies” — may be offensive. But it’s this kind of vigorous dialogue that the first amendment not only protects, but encourages. Any conclusion to the contrary would hold our capacity for public debate hostage to a few sensitive players who “can’t take the heat.”

If you want a poignant example of just what Fisher’s argument would deprive us of, look no farther than her complaint. While talking about alleged distortions in the Wired interview, she writes:

Although before the Wired article appeared Defendant Wallace interviewed Plaintiff Fisher at length and derived substantial information from her concerning the risks and rights issues that mandatory vaccination begets, she chose not to include content reflecting that information in her article. (emphasis ours)

Give her credit for honesty: Fisher isn’t hiding the fact that, if we accept her argument, the editorial decisions of newspapers are now suddenly subject to judicial review. It may be that American defamation law is too generous, providing too much room for offense. But the line for which Fisher advocates would change one problem for a far more grave one.

In critiquing Fisher’s decision to “lawyer up,” we might also consider her choice of forum. Why federal court? First, note that the sole basis for federal jurisdiction in Fisher’s complaint is “diversity of citizenship.” She’s not pleading a violation of federal law; she’s pleading state-law defamation, but because the Constitution’s framers imagined federal court as a neutral ground between citizens of different states, federal jurisdiction is proper.

In diversity cases, federal courts apply state substantive law (there is no federal common law*). So she’s not trying to avoid state law. I suspect this is a prestige thing. Suing in federal court sounds better than suing in state court, requires better lawyers, and therefore costs more. Call it the Birther/Orly Taitz instinct. Even though litigating in federal court is impossible given the nature of her claim, she’s spurned the (slightly) more plausible venue of state court for the glory of federal court. It’s not gone well. Count this as still further prove that Fisher’s real desire is publicity, and the slim chance of vindication — not the redress of any real legal grievance.

Fisher’s actions betray a fundamental misunderstanding of both science and law. Science requires conflict, and the law does not protect us from the consequences of our ideas or the negative opinions of others. A free society cannot thrive on suppression of conflict, and science cannot progress without an atmosphere that allows vigorous, sometimes painful, debate.

Even before knowing the outcome (which is almost certainly going to sting for Fisher), this case is a major victory for those who favor free speech and the role it plays in science. It highlights the desperation of those whose cult-like beliefs are being discarded by the reality-based community. As the foundations of their beliefs rot, they cling to the hope that the law will save them from the onslaught of science. But they are likely to discover a painful fact: just as you have a right to your own beliefs, others have the right to remark on their arbitrariness and idiocy. Science, like the law, allows us to have our own opinions, but not our own facts.

For further analysis:

• Neurologica Blog
  
• Respectful Insolence
• Terra Sigillata

Imagine if we could save lives from a dread and often fatal disease simply by performing a minor surgical procedure. People would hail this simple victory and rush to adopt it… Not exactly. The disease is HIV and the simple surgical procedure is circumcision and anti-circ activists oppose it under almost any circumstances.

In this month’s edition of the Archives of Pediatrics and Adolescent Medicine, Tobian, Gray and Quinn present a compelling case for neonatal circumcision. The paper is entitled Male Circumcision for the Prevention of Acquisition and Transmission of Sexually Transmitted Infections. The authors report:

The American Academy of Pediatrics (AAP) male circumcision policy states that while there are potential medical benefits of newborn male circumcision, the data are insufficient to recommend routine neonatal circumcision. Since 2005, however, 3 randomized trials have evaluated male circumcision for prevention of sexually transmitted infections. The trials found that circumcision decreases human immunodeficiency virus acquisition by 53% to 60%, herpes simplex virus type 2 acquisition by 28% to 34%, and human papillomavirus prevalence by 32% to 35% in men. Among female partners of circumcised men, bacterial vaginosis was reduced by 40%, and Trichomonas vaginalis infection was reduced by 48%. Genital ulcer disease was also reduced among males and their female partners. These findings are also supported by observational studies conducted in the United States. The AAP policy has a major impact on neonatal circumcision in the United States. This review evaluates the recent data that support revision of the AAP policy to fully reflect the evidence of long-term health benefits of male circumcision.

The AAP had long recommended male circumcision for prevention of urinary tract infections in young boys, but backed down in 1999, partly in response to pressure from anti-circumcision activists. According to circumcision.org:

Based on a review of medical and psychological literature and our own research and experience, we conclude that circumcision causes serious, generally unrecognized harm and is not advisable.

Anti-circ activists have employed inflammatory language to express their opinion. Circumcision is “mutilation” and parents who choose to circumcise their sons are “mutilators”. But the benefits of circumcision are real and clinically important. As Tobian, et al. explain:

The biological mechanisms whereby circumcision could reduce viral STIs may be due to anatomic and/or cellular factors. The foreskin is retracted over the shaft during intercourse and this exposes the preputial mucosa to vaginal and cervical fluids.61 It has been hypothesized that viral infections may enter the mucosa through microtears in the preputial mucosa. The moist subpreputial cavity may also provide a favorable environment for viral survival. The inner mucosa of the foreskin is lightly keratinized compared with the epithelium of the shaft, coronal sulcus, and glans, which may facilitate mucosal access of HIV, HSV-2, or HPV. The mucosa of the foreskin also contains a high density of dendritic (Langerhans) cells, macrophages, and CD4_ T cells, which are all targets of HIV …

Anti-circ activists are convinced that circumcision reduces sexual satisfaction. Until recently, it was difficult to study that claim because very few men were circumcised after becoming sexually active, making it almost impossible to determine the sensory effect of circumcision. But recent studies make it clear that sexual satisfaction is not affect by circumcision:

… [T]here were no reported differences in sexual satisfaction in the randomized study arms in either the Ugandan or Kenyan male circumcision trials or among men before and after they were circumcised. In addition, it has been hypothesized that behavioral disinhibition may counteract any protective effects of male circumcision. However, there was no consistent or substantial evidence of change in sexual behavior after circumcision in the Kenyan or Ugandan randomized controlled trials.

Tobian et al. call on the AAP to revise its policy to reflect the latest scientific evidence:

The World Health Organization/Joint United Nations Program on HIV/AIDS has concluded that “the research evidence that male circumcision is efficacious in reducing sexual transmission of HIV from women to men is compelling … and has been proven beyond reasonable doubt.” In 2007, the American Urological Association revised their policy to state that “circumcision should be presented as an option for health benefits.” However, the AAP, American College of Obstetricians and Gynecologists, and American Medical Association are likely to have the greatest influence on parental decisions and insurance coverage for neonatal circumcision in the United States. With the mounting evidence that male circumcision decreases viral STIs, genital ulcer disease, and penile inflammatory disorders in men, and bacterial vaginosis, T vaginalis infection, and genital ulcer disease in their female partners, it is time for the AAP policy to fully reflect these current data.

The AAP should heed the authors’ call.

In the most recent issue of The Journal of clinical Oncology is a study comparing acupuncture to Effexor in the treatment of vasomotor symptoms (hot flashes) in women with breast cancer who cannot take hormone replacement therapy. The study found that the two treatments are equivalent, with longer duration and fewer side effects from acupuncture. However, the study is designed as a pilot study (very preliminary) and therefore the conclusions are highly unreliable – given prior research, this raises the question as to why the study was performed at all.

The study included only 50 women, which is a small number for a clinical trial and alone means this is at best a preliminary study. There were 25 women randomized to one of two arms – either acupuncture or Effexor (which is standard treatment for vasomotor symptoms in women with breast cancer). However, the two arms were not blinded in any way, and there was no acupuncture control group – no sham or placebo acupuncture.

It is unclear why the researchers undertook a small unblinded study such as this, given that previous studies were better designed.

Acupuncture for Hot Flashes in Other Conditions

The largest literature for acupuncture and vasomotor symptoms is not in cancer patients, but in post-menopausal women. It is unclear if these two groups are comparable for treatment effects, but at least acupuncture for any vasomotor symptoms touches on the plausibility of this treatment in any context.

A recent systematic review of the literature included six trials in which acupuncture was compared to sham acupuncture – 5 of the 6 studies were negative. The reviewers concluded:

There is no evidence from RCTs that acupuncture is an effective treatment in comparison to sham acupuncture for reducing menopausal hot flashes. Some studies have shown that acupuncture therapies are better than hormone therapy for reducing vasomotor symptoms. However, the number of RCTs compared with a nonpenetrating placebo control needle or hormone therapy was too small, and the methodological quality of some of the RCTs was poor. Further evaluation of the effects of acupuncture on vasomotor menopausal symptoms based on a well-controlled placebo trial is therefore warranted.

This would seem to be sufficient evidence to conclude that acupuncture lacks efficacy. For those who believe that further research is required, it only makes sense to perform larger and more rigorous studies.

Acupuncture has also been studied for the treatment of hot flashes in men being treated for prostate cancer. A systematic review of this research concludes:

The evidence is not convincing to suggest acupuncture is an effective treatment for hot flush in patients with PC. Further research is required to investigate whether acupuncture has hot-flush-specific effects.

There was much less literature to review in this case, and there were no large blinded studies.

Acupuncture for Hot Flashes in Breast Cancer

A recent systematic review of studies looking at acupuncture for breast cancer side effects concluded:

In conclusion, the evidence is not convincing to suggest acupuncture is an effective treatment of hot flash in patients with breast cancer. Further research is required to investigate whether there are specific effects of acupuncture for treating hot flash in patients with breast cancer.

There were only three controlled trials comparing acupuncture to sham acupuncture, one positive, and two negative. The review also included some studies of electroacupuncture – but I maintain that electroacupuncture, which uses electrical stimulation through acupuncture needles, is not acupuncture (it’s electrical stimulation) and should not be considered in the same therapeutic category.

Conclusion

The history of acupuncture research in general has been that the technology of performing acupuncture studies and properly blinding them has actually improved. At first blinded sham acupuncture was the standard, but that was improved by sheathed non-penetrating acupuncture needles allowing for double-blinding.

Also, the general trend within clinical research of any question is to progress from small unblinded pilot studies to progressively larger and more rigorous studies, if warranted, until there are a few large well-designed trials that together sufficiently settle an issue.

Overall, the results of acupuncture for any indication are very similar to the results I outline above for hot flashes – small studies with mixed results, followed by better-designed studies that are mostly negative. For any indication the evidence is either inadequate or shows that acupuncture does not work.

This study is therefore of dubious utility. It is a very preliminary study in an area where there is already several more rigorously designed studies, trending negative. Given the overall acupuncture research, and the minimal prior plausibility, in my opinion there is already sufficient evidence to conclude that acupuncture probably does not work for hot flashes in patients with breast cancer. However, if researchers feel that there is some potential to acupuncture and more research is deserved, the only utility would be from a large rigorously designed trial – which this study definitely is not.

In short, this study changes nothing and is a step backwards. It does, however, result in another round of press releases with the very misleading title that acupuncture works for hot flashes.

A recent story on NPR accused the drug manufacturer Merck of inventing a disease, osteopenia, in order to sell its drug Fosamax. It showed how the definition of what constitutes a disease evolves, and the role that drug companies can play in that evolution.

Osteoporosis is a reduction in bone mineral density that leads to fractures. The most serious are hip fractures, which require surgery, have complications like blood clots, and carry a high mortality. Many of those who survive never walk again. Vertebral fractures are common in the osteoporotic elderly and are responsible for dowager’s hump and loss of height. There is also an increased risk of wrist and rib fractures.

Bone density tends to decrease with age. Postmenopausal women are particularly susceptible to osteoporosis when their production of estrogen declines. The risk is increased in people taking corticosteroids and in people with certain diseases like rheumatoid arthritis. Other risk factors are European or Asian ancestry, smoking, excess alcohol, a family history of fractures, vitamin D deficiency, too much or too little exercise, malnutrition, and low body weight.

When a measurement like bone density varies widely in a population and decreases with age, how can we decide where to draw the line and call it abnormal? When does it become a disease requiring treatment?

For a long time, the diagnosis of osteoporosis depended on the occurrence of a fracture. In 1992 a group of experts convened by the World Health Organization agreed to define osteoporosis as a bone density 2.5 standard deviations below that of an average 30 year old white woman. They defined osteopenia as a bone density one standard deviation below that of an average 30-year-old white woman. The decision to use one standard deviation and 2.5 standard deviations was arbitrary, and it was meant as a tool to measure the emergence of a problem in a population rather than to have precise diagnostic or therapeutic significance for an individual. Nevertheless, these criteria were widely interpreted to mean that half the population has a disease they need to worry about.

Bisphosphonate drugs like Merck’s Fosamax and Sally Field’s beloved Boniva were intended to reduce the risk of fractures in patients with osteoporosis. They are effective in reducing spine fractures and in increasing bone density measurements, but some studies have shown no reduction in non-spine fractures, which are more common, and in the case of hip fractures, more significant. A British Medical Journal article pointed out,

Two thirds of vertebral fractures are subclinical or asymptomatic and may not affect quality of life. As a consequence showing that drugs reduce vertebral fractures may not be as important to patients as it seems.

According to a table published by the USPSTF (US Preventive Services Task Force), among women aged 50-54, 60 women need to be treated to prevent one vertebral fracture and 227 to prevent one hip fracture. Among women aged 65-69, 30 must be treated to prevent one vertebral fracture and 88 must be treated to prevent one hip fracture. Sally is 63: the numbers for her age group are 30 and 121. One wonders if she is aware of these numbers.

These drugs are not benign. To prevent ulceration of the esophagus, for 30 minutes after taking Fosamax patients must avoid eating or drinking anything but plain water; they must not lie down or recline, or take any other medications during that time. Bisphosphonates have been linked to osteonecrosis of the jaw. There are as yet no long-term studies. Case reports suggest the possibility that they might paradoxically increase fractures in the long run. By one estimate, the NNH (Number Needed to Harm) is 16 as measured by discontinuing treatment due to adverse effects.

When Merck started marketing Fosamax, not many women were being screened for osteoporosis because the standard DEXA (dual energy x-ray absorptiometry) test required expensive equipment and was not readily available. They thought if they could increase the rate of diagnosis they could sell more pills. Merck promoted the development of small, less expensive scanners that could be used on a heel or wrist in a doctor’s office. Merck even set up a nonprofit organization called the Bone Measurement Institute, which worked to spread the use of these machines and bring down the price of bone exams. Unfortunately, the results of those scans did not correlate well to the results of the gold standard DEXA scan.

A doctor quoted by NPR said,

The problem with the smaller peripheral machines is that taking a measurement of someone’s heel or forearm isn’t going to tell you what you need to know about the bones in the parts of the body that, if fractured, increase a woman’s risk of death — the hip and spine.

Who should be screened? The USPSTF found that, for women 55 to 59 years of age, the number needed to screen (NNS) over five years was more than 4,000 to prevent one hip fracture and 1,300 to prevent one vertebral fracture. The NNS to prevent one hip fracture over five years declines with age, to 1,856 for women 60 to 64 years of age, 731 for women 65 to 69 years of age, and 143 for women 75 to 79 years of age.

The USPSTF currently recommends that women aged 65 and older be screened routinely for osteoporosis. It recommends that routine screening begin at age 60 for women at increased risk for osteoporotic fractures (there is a handy online FRAX tool for estimating an individual’s risk of osteoporotic fractures). It found insufficient evidence to make any recommendations for younger women or for men. Meanwhile, direct-to-public ultrasound screening companies have jumped on the bandwagon and are offering poor quality osteoporosis screening to men and women of all ages, with innumerable false positives requiring further testing and unnecessary worry.

The results of the scans promoted by Merck were reported either as normal bone density, osteopenia, or osteoporosis. Osteopenia carries only a small increased risk of fractures, but the assumption was that left untreated it would progress to osteoporosis. It is really more of a risk factor for osteoporosis than a disease in its own right. Some women diagnosed with osteopenia may not even have bone loss; they may just be at the low end of normal on a wide spectrum. But osteopenia sounds abnormal, and it sounds like a diagnosis, and it sounds to a lot of people like it needs treating. A new disease was born with a ready-made treatment.

There are other pharmaceutical options for osteoporosis. Estrogens reduce osteoporosis risk but carry too many other risks to be used for that indication alone. Raloxifene is a selective estrogen receptor modifier that has estrogenic effects on bone but anti-estrogenic effects on the uterus and breast. It reduces the risk of vertebral fractures but not other fractures. It increases the risk of thromboembolism and fatal stroke although it does not reduce the overall death rate. Another option is calcitonin, but it is less effective.

Pharmaceutical treatments are not the only option. Weight-bearing exercise, prevention of falls, quitting cigarettes, curtailing alcohol, and ensuring adequate intake of calcium and vitamin D are all beneficial. A recent study showed that higher doses of vitamin D supplements (over 400 IU a day) reduced fractures by 20%.

Merck’s actions may have been misguided, but I don’t see this as a scam. Merck employees were trying to make money for the company, but that doesn’t mean they weren’t also genuinely trying to do the right thing to help patients. They had a product that they thought would prevent fractures and save lives, and they wanted to get it to everyone who could benefit. In their enthusiasm, they overshot and went beyond the science.

The NPR article admitted that there are two sides to this story.

…drug companies produce incredible drugs that can greatly relieve suffering. But one way they profit from those drugs is to extend their use to as many people as possible, which frequently means that medications are used in populations with milder and milder versions of a disease, so that the risks of medicating can come to outweigh the benefits.

Big Pharma advertises but it is doctors who write the prescriptions: when drugs are over-prescribed, only the prescribers are to blame. What should doctors do? In the first place, they should be recommending preventive lifestyle changes to all their patients. They should stick to the best science-based practices and evaluate the evidence for themselves rather than being influenced by Sally Field or by Big Pharma propaganda. They should prescribe drug treatments only when fracture risk is significant, when a fracture has already occurred, or when they think bone density is significantly low (still a judgment call). They should explain the gray areas to their patients and involve them in the decision to treat. They should think in terms of number needed to treat and number needed to harm. And they should be aware of the games Big Pharma plays.

In my five years in the blogosphere, two years blogging for SBM, and over a decade in Internet discussion forums about medicine and “alternative” medicine, I’ve learned a few things. One thing that I’ve learned is that one of the biggest differences between those whose world view is based on science and who therefore promote science-based medicine and those promoting pseudoscience, quackery, and anti-science is that science inculcates in its adherents a culture of free, open, and vigorous debate. Indeed, to outsiders, this debate can seem (and sometimes is) vicious. In other words, if you’re going to be a scientist, you need to have a thick skin because you will have to defend your hypotheses and conclusions, sometimes against some very hostile other scientists. That same attitude of a Darwinian struggle between scientific ideas, with only those best supported by evidence and with the most explanatory power surviving, is a world view that those not steeped in science have a hard time understanding.

Among those who don’t understand science, few have a harder time with the rough-and-tumble debate over evidence and science that routinely goes on among scientists than those advocating pseudoscience. Indeed, in marked contrast to scientists, they tend to cultivate cultures of the echo chamber. Examples abound and include discussion forums devoted to “alternative” medicine like CureZone, where never is heard a discouraging word — because anyone expressing too much skepticism about the prevailing view on such forums invariably finds himself first shunned by other members of the discussion forums and then, if he persists, booted from the forum by the moderators. In marked contrast, on skeptical forums, most of the time almost anything goes. True, the occasional supporter of woo who finds his way onto a skeptical forum will face a lot of criticism, some of it brutal. However, rarely will such a person be banned, unless he commits offenses unrelated to his questioning of scientific dogma, such as insulting or abusive behavior towards other forum participants or trolling. Such people may annoy the heck out of us skeptics sometimes, but on the other hand, they do actually from time to time challenge us to defend our science and prevent us from becoming too complacent. Indeed, that’s what I like about skeptics and being a scientist. Nothing or no one is sacred.

In marked contrast, supporters of pseudoscience are very much characterized by their aversion to scientific debate. The reason is obvious. They don’t have the goods. (If they did, what they’re advocating wouldn’t be pseudoscience.) They can’t win on science, reason, and evidence. The result is that they often end up forming communities that exist more to support their pseudoscience than to discover what does and does not actually work. Indeed, Prometheus describes this phenomenon well as he’s seen it in “autism biomed” discussion forums.

The same sort of group dynamics occurs in forums like CureZone and many others. Those who try to apply science and skepticism to the prevailing dogma of the group usually end up banned or give up in disgust. Indeed, at the anti-vaccine crank blog Age of Autism, comments are ruthlessly censored, and anyone who disagrees too strongly with the prevailing “wisdom” that vaccines cause autism will soon find himself or herself permanently banned. One consequence of this can be that the adherents of such views become progressively less able to defend their views in an evidence- and science-based argument, because they simply aren’t used to having them challenged based on evidence and science. Indeed some no longer even know how to react to criticism other than by lashing out. We’ve seen this before on this very blog, where anti-vaccine activist J.B. Handley lashed out at Steve Novella, while from time to time various anti-vaccine activists, J.B. Handley included, and promoters of pseudoscience and quackery periodically launch prolonged ad hominem attacks on me^{1,2,3,4,5,6,7,8,9,10}.

Another consequence is that promoters of unscientific and anti-scientific “medical” modalities have a tendency to be lawsuit-happy. We at SBM have written about this time and time again, both here and on individual bloggers’ blogs. The most recent and famous victim of this tendency is Simon Singh, who is being sued by the British Chiropractic Association for pointing out that there is no evidence behind their claims to be able to treat allergies and colic and quite correctly characterized such claims as “bogus.” Thanks to Britain’s notoriously plaintiff-friendly libel laws, Singh is fighting an uphill battle, too, and may very well lose. Fortunately, his case has become a cause célèbre, and Sense About Science has rallied public opinion in his favor and, more importantly, of reforming the U.K.’s antiquated anti-free speech libel laws — please sign the petition. However, Singh’s case is simply the most famous current example of how promoters of pseudoscience try to suppress criticism with legal threats or action. There have been several others before, including Andy Lewis of Quackometer, whose ISP caved in to legal threats from the highly dubious Dr. Joseph Chikelue Obi (who bills himself as the “world’s top expert in nutritional immunomudulation“). This came on hot on the heels of legal thuggery directed against him by the Society of Homeopaths. In both of these cases, the attempted legal action backfired spectacularly, as dozens, perhaps hundreds, of bloggers republished the posts verbatim that the Society of Homeopaths and “Dr.” Obi had successfully suppressed. Another example includes Kathleen Seidel, who was subject to a frivolous and punitive subpoena by lawyer Clifford Shoemaker, who is well known for bringing lawsuits based on the pseudoscience that vaccines cause autism. Fortunately, Shoemaker overreached and was forced to retreat in shame.

And I haven’t even mentioned über-quack Matthias Rath trying to silence Ben Goldacre through litigation

The most recent flavor of anti-science groups using the law to silence critics seems to be anti-vaccine activists. And, I’m sad to report that this time around it is Barbara Loe Fisher of the organization with the most Orwellian name, the National Vaccine Information Center (NVIC), who is suing Dr. Paul Offit; Amy Wallace, who quoted him in her excellent article published in WIRED Magazine in October (for which J.B. Handley launched misogynistic attacks on her); and Condé Naste, WIRED’s publisher. Here is the legal complaint (scrubbed of home addresses of the private parties involved).

This is not the first time an anti-vaccine activist has sued Dr. Offit. Just last year, Handley sued Dr. Paul Offit for a passage in his 2008 book Autism’s False Prophets, which included highly unflattering portraits (and, in my opinion, justifiably so) of anti-vaccinationists like Mr. Handley, including a discussion of a threatening post by Handley posted to an anti-vaccine mailing list, in which he said to the “neurodiverse folks monitoring this list”:

We will bring the full resources of myself and Generation Rescue to stop this. We will sue you for libel and we will go after your homes and assets. My lawyers live to investigate and sue people like you.

This, of course, sums up the attitude of all too many anti-science activists. They can’t win on the science; so they try to suppress criticism through legal action. Sadly, it’s their most potent weapon, certainly far more potent than any scientific argument they can come up with, given that even in the relatively defendant-friendly U.S. libel suits can be so intimidating that they will effectively silence criticism.

I don’t know enough of the details of the suit to determine whether Handley’s case had any merit or not, and I’m not a lawyer anyway. I tend to doubt that it did. Regardless of the merit of his suit (or, more probably, the lack thereof), I am pretty sure I have deduced Handley’s intent, as his e-mail and postings on AoA certainly leave no doubt as to his attitude. I also know that it’s very interesting that, as Squillo points out, Handley’s lawsuit was not filed on the basis of libel, but rather on “false light invasion of privacy” rather than for libel (a form of defamation), probably because false light is less well-defined than libel and easier to prevail on, perhaps as a result of Dr. Offit’s lawyer’s response. Whatever the case, Dr. Offit and his lawyers decided to settle rather than fight, with the settlement being an apology, an agreement to correct the passage in dispute, and a $5,000 donation to one of Jenny McCarthy’s favored autism charities, all of which to me sounds very much like a token settlement. I may be totally wrong about this, but my guess is that Dr. Offit just didn’t want to go through the pain of a full trial, which is, of course, the point of such legal actions; being sued is painful for anyone, and many decide it’s easier to cave than to fight, even when they have a strong case. My second guess is that Handley may have had just enough of a case plus a set of pockets deep enough to make a lot of trouble but probably not a good enough case to have had a high likelihood of prevailing if it had gone to trial. Otherwise, given his visceral hatred of Dr. Offit, I highly doubt that Handley would have agreed to such a tiny token settlement. (Another possibility to be considered is that Handley didn’t really want Generation Rescue and himself to be subject to discovery regarding the incidents at the heart of the disputed passage had the legal case moved forward.) On the other hand, Offit’s settling is a huge propaganda victory for Handley, which he has been trumpeting on his blog.

Unfortunately, Handley’s apparent success appears to have emboldened other anti-vaccine activists, and this, I suspect, is why Barbara Loe Fisher likely decided that she might be able to cause Dr. Offit some trouble. So cause him trouble she did by suing over this passage from Amy Wallace’s article:

Paul Offit has a slightly nasal voice and a forceful delivery that conspire to make him sound remarkably like Hawkeye Pierce, the cantankerous doctor played by Alan Alda on the TV series M*A*S*H. As a young man, Offit was a big fan of the show (though he felt then, and does now, that Hawkeye was “much cooler than me”). Offit is quick-witted, funny, and — despite a generally mild-mannered mien — sometimes so assertive as to seem brash. “Scientists, bound only by reason, are society’s true anarchists,” he has written — and he clearly sees himself as one. “Kaflooey theories” make him crazy, especially if they catch on. Fisher, who has long been the media’s go-to interview for what some in the autism arena call “parents rights,” makes him particularly nuts, as in “You just want to scream.” The reason? “She lies,” he says flatly.

“Barbara Loe Fisher inflames people against me. And wrongly. I’m in this for the same reason she is. I care about kids. Does she think Merck is paying me to speak about vaccines? Is that the logic?” he asks, exasperated. (Merck is doing no such thing). But when it comes to mandating vaccinations, Offit says, Fisher is right about him: He is an adamant supporter.

Regular readers may have noticed that I almost never accuse anyone of lying. The reason is that I tend to believe that most anti-vaccine activists really and truly believe in their pseudoscience. Consequently, when they spread misinformation and outright nonsense, they are not technically lying, at least not most of the time, because they have no clue that what they are saying is false. Indeed, although I do not know the specifics upon which Dr. Offit based his claim that Loe Fisher “lies” (although having read some of the vitriolic attacks on Dr. Offit by members of the anti-vaccine movement I can certainly understand why he might come to that conclusion), I do know that she is profoundly wrong about the science of vaccines and, utterly impervious to any science contradicting her viewpoint, spreads misinformation, so much so that whether Loe Fisher believes what she says or knows it to be false almost becomes a moot point when so much egregious misinformation and pseudoscience is spread against the backdrop of mountains of evidence showing that they are not scientifically valid. The end effect is more or less the same in a practical sense, although whether it is in a legal sense I do not know.

Even so, in her complaint Loe Fisher takes takes Jenny McCarthy’s disingenuous claim that she is “not anti-vaccine, but pro-safe vaccine” to whole new heights of bizarre contortion. I’ve written about this technique before. Fisher is very clever and couches her views in rhetoric of freedom and “informed consent.” Yet, it is very clear from the NVIC website what its true agenda is. For instance, there is a “memorial” for “vaccine victims,” which states:

They are the men, women, and children who have died or been injured by vaccines in nations around the world for the past 200 years. This is a virtual Memorial dedicated to those whose lives have been forever changed by vaccines they were often required by law to use.

And concludes:

Our hope is that, by honoring those who are casualties of mass vaccination policies, there will be greater public awareness of the need to value and care as much about those who are harmed by the complications of vaccines as we care about those who are harmed by the complications of infectious diseases. This International Memorial for Vaccine Victims is offered to the world as testimony of the need to protect the biological integrity of life on this planet.

The NVIC also runs a website called Stand Up! Be Counted!, which states: “No Forced Vaccination. Not in America.” It also uses common anti-vaccine tropes, such as confusing correlation with causation for the “autism epidemic.” Meanwhile the NVIC page about the H1N1 vaccine cites dubious studies on mercury in vaccines, in particular the discredited Hewitson study that I blogged about here and here. Then there’s the Vaccine Law Firm Directory she maintains of lawyers ready to sue for vaccine injury. But perhaps most telling of all is the recent NVIC conference, in which luminaries of the anti-vaccine fringe presented their views and “data,” and in which the man who started the fear that the MMR vaccine causes autism based on the shoddiest of science and whom Barbara Loe Fisher herself has vociferously defended, namely Andrew Wakefield, was given NVIC’s Humanitarian Award. The conference also included total cranks such as Gary Null, who is anti-vaccine to the core, an HIV/AIDS denialist, coffee enema advocate, and supporter of cancer quackery, and David Ayoub, whose claim to fame is that he thinks that mass vaccination programs are a plot by the Illuminati, complete with black helicopters. Quite frankly, from my point of view, if Barbara Loe Fisher isn’t anti-vaccine, she sure has an amazingly odd way of showing it. It would be very interesting to ask her whether there is anything or any evidence that could ever persuade her that vaccination is far safer than the diseases vaccinated against. I tend to doubt it, although I have no doubt, given her silver tongue, that she’d dance around the question quite skillfully, move the goal posts, or propose impossible-to-meet (in the real world, at least) standard of evidence.

My guess is that Loe Fisher’s lawsuit has very little to do with her reputation. After all, among real scientists knowledgeable about vaccination (as opposed to anti-vaccine “scientists” like Andrew Wakefield) her reputation is that of a promoter of pseudoscience; in other words, her only scientific reputation is a bad one. Moreover, among Loe Fisher’s core constituency, I highly doubt that Dr. Offit’s saying “she lies” about her would have any effect whatsoever on its opinion of her veracity, other than, perhaps, to make her fans love and believe her all the more. After all, in the circles that she travels, Dr. Offit is viewed as practically akin to Satan himself and routinely castigated as “Dr. Proffit.” However, having her veracity called into doubt by a real vaccine scientist could potentially hurt Loe Fisher in her efforts to win mainstream acceptance, and that is probably the real concern driving the lawsuit.

Another reason that Fisher’s frequent, impassioned, indignant denials that she is anti-vaccine are hard to believe is that she is very one-sided in her application of her appeals to freedom. She states over and over again that she is for “informed consent” and the right of parents to express “philosophical exemptions.” No doubt a libertarian argument could be made on political and philosophical grounds to support such a position. But, as PalMD shows, when a private institution decides that it will require that students be fully vaccinated according to the recommended schedule before they can attend school, suddenly Fisher isn’t so supportive of the whole freedom thing anymore. For example, when a Jewish school in Pittsburgh decided that it would not accept philosphical exemptions, would require that its students, other than those with legtimate medical exemptions, be fully vaccinated, and would not accept a letter from anyone other than a child’s primary care physician in order to grant a medical exemption, Fisher was most displeased:

According to Loe Fisher, the federal vaccine injury compensation program, established by the National Childhood Vaccine Injury Act of 1986, has paid more than $2 billion to families of children who have been injured or died as a result of vaccination.

“Vaccination should not be separated out from the informed consent paradigm,” she said.

Since the establishment of the CDC and American Academy of Pediatrics recommendations regarding vaccination requirements, Loe Fisher continued, families seeking medical exemption from vaccination have found it rough going.

Because it’s hard for a family to find a physician to provide a medical exemption, Loe Fisher said, many must rely on the religious or philosophical exemption, available in almost all states, to avoid vaccination.

She is not in favor of a private school refusing to accept those exemptions which are provided for by state law.

“It is questionable for a school to narrow those exemptions and not allow a parent who believes a child is at risk to take an exemption,” Loe Fisher said.

In other words, Fisher is against the government’s mandating vaccination before a child can attend school, public or private, but if the administration of a private school voluntarily decides without any government laws or pressure that it is going to require vaccination of its students before admission and not accept philosphical exemptions, she thinks that the government should have the power to enforce philosophical vaccine exemptions on it. Her advocacy of freedom with respect to vaccination is rather one-sided, don’t you think? After all, I bet Loe Fisher supports the right of private schools, such as Waldorf Schools, that do not require vaccination, often have high percentages of unvaccinated children, and, of late, have become incubators for outbreaks of vaccine-preventable diseases, not to require that her students be vaccinated. Thus, her support for “vaccine choice” except when it is the choice of a private institution to mandate vaccines casts her assertion in her complaint that she “does not seek to prohibit or advise against vaccination but to ensure that vaccination is voluntary and that it proceeds following fully informed consent” in a rather dubious light and contributes to the overall impression that she is in reality not a “vaccine safety” activist, but an anti-vaccine activist.

In my opinion, after having read her website and seen her quoted in many interviews, the bottom line is that Barbara Loe Fisher is anti-vaccine. True, she’s good at cloaking what I consider to be her anti-vaccine views in rhetoric of “freedom” and “informed consent,” but whenever push comes to shove, she’s against vaccines and clearly thinks that they do more harm than good. Nowhere have I ever seen her say that she supports a single vaccination as routine. Not one. Her entire organization supports the scientifically discredited notion that vaccines cause autism and holds conferences with anti-vaccine speakers. It’s hard not to conclude from this that she is anti-vaccine. Moreover, Barbara Loe Fisher is one to talk about libel, after what she said about Dr. Offit the very article by Amy Wallace over which she is suing:

Against this backdrop, Fisher, a skilled debater who often faces down articulate, well-informed scientists on live TV, mentioned Offit frequently. She called him the leading “pro-forced-vaccination proponent” and cast him as a man who walks in lockstep with the pharmaceutical companies and demonizes caring parents.

Maybe Dr. Offit should countersue for libel. It sounds as though he may have a case. After all, on the NVIC website, there is this little tidbit as well:

Offit’s attempt to exonerate DPT is part of a larger effort to convince the public – and drug company stockholders – that most vaccines, including his own, have no risks whatsoever.

I’d love to see Loe Fisher present evidence that Dr. Offit has ever said that most vaccines, including his own, have no risks whatsoever. But attacking Dr. Offit in such terms is not enough for Loe Fisher. As Kim Wombles points out, Loe Fisher sees her fight against vaccine mandates in apocalyptic terms, as she describes on the NVIC website:

The discrimination begins, always, with the majority in a society pointing the finger at a minority for somehow endangering the public health and welfare. Individuals in the minority group are singled out as different – ethnically, biologically, spiritually, morally – from the majority. The human impulse to fear, judge, marginalize or eliminate those different from the rest has left a blood soaked trail winding throughout the entire history of man from the Great Inquisition to the Holocaust; from the killing fields of Cambodia to Rwanda, Serbia and Tibet; while the persecution of those with leprosy, TB, AIDS, mental illness, and handicaps continues in every society.

Later in the same article, I found this quote by Loe Fisher likening Andrew Wakefield to a victim of the Inquisition:

I thought of the persecution of Andrew Wakefield, M.D., who is being punished by his British colleagues for daring to report an association between the MMR (measles-mumps-rubella) vaccine and neuroimmune dysfunction, including inflammatory bowel disease and autism. Like when the heads of heretics were impaled upon stakes on the Tower of London as a warning for all to see, the Wakefield inquisition is a spectacle designed to persuade all doctors contemplating questioning the safety of current mass vaccination policies to remain silent.

And this allusion to the Holocaust:

Holocaust survivor Elie Weisel has said “When you take an idea or a concept and turn it into an abstraction, that opens the way to take human beings and turn them, also, into abstractions.”

Individuals harmed by vaccines are not abstractions. They are human beings who deserve to be spared a lifetime of suffering rather than being thrown under the bus to prop up forced mass vaccination policies that fail to acknowledge biodiversity within the family of man.

When Barbara Loe Fisher likens the supporters of vaccination programs who correctly criticize her and those holding views similar to hers as “anti-vaccine” to Nazis or the Inquisition and their criticism to what the Nazis did to the Jews during the Holocaust or the Inquisition did to heretics, when she likens criticism of her stance on vaccines to the genocides in Cambodia and Rwanda, she shouldn’t be too surprised when a lot of people conclude that she is anti-vaccine, not pro-safe vaccine.

Just like those of the Society of Homeopaths, “Dr.” Obi, the British Chiropractors Association against Simon Singh, or Matthias Rath against Ben Goldacre, Loe Fisher’s lawsuit is also likely more about shutting up critics than it is about protecting her reputation. Clearly, Wallace’s article hurt the anti-vaccine movement. Moreover, if there’s one good thing about 2009, it’s that more and more mainstream media outlets stopped portraying the anti-vaccine movement as poor, persecuted parents and more and more portrayed it as a threat to public health based on pseudoscience, which it is. Yes, it’s true that individual stories from the movement can be very sad and compelling; many of these parents and their children have had a horribly rough time. However, we do not have to downplay their difficulties or insult them personally to point out that they are profoundly wrong based on science when they blame vaccines for their children’s autism and that their activities do represent a serious threat to public health. More and more reporters, like Trine Tsouderos and Amy Wallace, have come to realize that. Such reporters represent a threat. Moreover, demonizing these journalists online, as the anti-vaccine movement tried to do with Amy Wallace and Trine Tsouderos (the latter of whom was included in a Photoshopped collage with Steve Novella preparing to make a Thanksgiving feast of a baby), doesn’t work very well. That leaves lawsuits to intimidate those who would speak out and discourage other media outlets from writing similar stories.

I wonder. Sense About Science did a fantastic job of publicizing the Simon Singh libel case and using it to promote the need for reforming the U.K.’s libel laws. I wonder if it’s time for a similar movement right here in the U.S. to prevent promoters of pseudoscience from using the law to intimidate and harass defenders of science-based medicine. Although Dr. Offit probably has the financial means to defend himself, there are a lot of writers and bloggers who do not, should someone with deep pockets decide to try to silence them with a frivolous lawsuit. We definitely have a problem here, and I predict it’s going to get worse as pseudoscience movements like the anti-vaccine movement rightly become more and more marginalized.

I’m a translational researcher. To those of you who aren’t familiar with what that means, it means (I hope) that I study potential therapies in the lab and try to translate them into actual therapies that will cure patients of breast cancer — or, at the very least, improve their odds of survival or prolong survival when cure is not possible. Translational research is extremely important; indeed, it is the life blood of science-based medicine, with basic science producing the discoveries and clinical research the applications of these discoveries. When it works, it’s the way that science leads medicine to advance. However, sometimes I think that it’s a bit oversold. For one thing, it’s not easy, and it’s not always obvious what basic science findings can be translated into useful therapies, be it for cancer (my specialty) or any other disease. For another thing, it takes a long time. The problem is that the hype about how much we as a nation invest in translational research all too often leads to a not unreasonable expectation that there will be a rapid return on that investment. Such an expectation is often not realized, at least not as fast and frequently as we would like, and the reason has little to do with the quality of the science being funded. It has arguably more to do with how long it takes for a basic science observation to follow the long and winding road to producing a viable therapy. But how long is that long and winding road?

A lot longer than many, even many scientists, realize. At least, that’s the case if a paper from about a year ago by John Ioannidis in Science is any indication. The article appeared in the Policy Forum in the September 5 issue and is entitled Life Cycle of Translational Research for Medical Interventions. As you may recall, Dr. Ioannidis made a name for himself a couple of years ago by publishing a pair of articles provocatively entitled Contradicted and Initially Stronger Effects in Highly Cited Clinical Research and Why Most Published Research Findings Are False, which Steve Novella blogged about a couple of years ago.

Dr. Ioannidis lays it out right in the first paragraph:

Despite a major interest in translational research (1-3), development of new, effective medical interventions is difficult. Of 101 very promising claims of new discoveries with clear clinical potential that were made in major basic science journals between 1979 and 1983, only five resulted in interventions with licensed clinical use by 2003 and only one had extensive clinical use (4). Drug discovery faces major challenges (5-8). Moreover, for several interventions supported by high-profile clinical studies, subsequent evidence from larger and/or better studies contradicts their effectiveness or shows smaller benefits (9). The problem seems to be even greater for nonrandomized studies (9).

In order to figure out how long translational research can take to come to fruition, Dr. Ioannidis looked at some fairly high profile therapies (defined as therapies claimed to be effective in at least one study about it that has been cited 1,000 or more times) between 1990 to 2004. The reason that this particular definition was chosen is to use studies for which a milestone at which a therapy is widely recognized to be effective and safe. That, by the paper’s definition, is the point at which a basic science finding has finally been completely “translated” into an accepted therapy. The problem then becomes to identify exactly when such therapies began as a grain of a basic science finding or an idea based on basic science observations. This is not always easy to identify. In the case of one of my major areas of research interest, tumor angiogenesis, it’s relatively easy to cite Dr. Judah Folkman’s famous 1971 paper proposing the targeting of tumor angiogenesis as a therapy for cancer. Oh, we could quibble over whether that was truly the beginning. After all, it was hypothesized that angiogenesis was important to tumor growth decades before. However, the 1971 paper was the first explicit proposal to develop strategies to target tumor angiogenesis to treat cancer. Be that as it may, I’ve mentioned before that it was thirty years before an actual therapy used in humans was developed as an example of just how long it can take.

Dr. Ioannidis has tried to quantify this gap in a more general manner, which he refers to as the “translation lag.” What he found is quite sobering for people who are anxious for the rapid translation of basic science:

To place each discovery in time, we identified the year when the earliest journal publication on preparation, isolation, or synthesis appeared or the earliest patent was awarded (whichever occurred first). Overall, the median translation lag was 24 years (interquartile range, 14 to 44 years) between first description and earliest highly cited article (see the chart). This was longer on average (median 44 versus 17 years) for those interventions that were fully or partially “refuted” (contradicted or having initially stronger effects) than for nonrefuted ones (replicated or remaining unchallenged) (P = 0.004).

In a secondary analysis, we defined the time of discovery as the first description (publication or awarded patent) of any agent in the wider intervention class (those with similar characteristics and mode of action). Early translational work may be performed with different agents in the same class compared with those that eventually get translated into postulated high-profile clinical benefits. Analyses using information on the wider class of agents showed even longer translation lag, with median of 27 (interquartile range, 21 to 50) years and similar prolongations of the translation lag for refuted interventions.

This is represented in this table:

One thing that you may notice on the table above that Dr. Ioannidis also did was that he also looked at some treatments or interventions that had been highly cited and were later refuted. What makes this interesting is that therapies that were never later refuted by clinical trials after the highly cited clinical trial that was used to support their use had a markedly shorter translation lag, 16.5 years (range 4 to 50 years) in the main analysis and 22 years (range 6 to 50 years) if the wider class of drugs is considered. In contrast, for remedies whose efficacy was later refuted, the translation lag was 44 years, as mentioned in the passage cited above. What could be the explanation? Dr. Ioannidis speculates:

We observed that most highly cited claims that were eventually refuted had a very slow translation history preceding them [e.g., flavonoids, vitamin E, and estrogens were already available for many decades before observational (nonrandomized) studies claimed implausibly large survival benefits in the 1990s]. We conclude that claims for large benefits from old interventions require extra caution as they are likely to be exaggerated.

I’m half tempted to mention that there is a bit of an elephant in the room here in that it makes one wonder about complementary and alternative medicine, and how the existing studies would fare in this sort of analysis. Of course, one would be unlikely to find a paper on a CAM intervention cited 1,000 times showing efficacy. (In fact, for some it would be hard to find a paper strongly demonstrating efficacy of most CAM therapies.) But think of it this way: Many of these therapies have been around for hundreds of years, and there hasn’t been compelling evidence of their efficacy. Think of homeopathy, for instance. Samuel Hahnemann thought of it over 200 years ago, and we still don’t have evidence of its efficacy.

I know, I know, I’m dragging one of my personal peeves into this, and it is ridiculous to use the term “science” or “translational research” in referring to something like homeopathy, but I couldn’t resist. Mea culpa.

We can quibble about whether his methodology was the most appropriate or whether he picked the correct milestones to compare, but what Dr. Ioannidis shows is that, in essence, a lot of “translational” research takes close to two decades to bear fruit, and it’s fairly uncommon for it to take less than a decade. Moreover, as Dr. Ionnidis points out, less than 5% of promising claims based on basic science ever come to fruition as actual therapies. In other words, translational research is hard. Few promising ideas make it to therapies, and it takes a long time for those that do. Indeed, Dr. Ioannidis makes this recommendation:

Our analysis documents objectively show the long length of time that passes between discovery and translation. As scientists, we should convey to our funders and the public the immense difficulty of the scientific discovery process. Successful translation is demanding and takes a lot of effort and time even under the best circumstances; making unrealistic promises for quick discoveries and cures may damage the credibility of science in the eyes of the public.

His other recommendations are rather obvious: multidisciplinary collaborations with focused targets, incentives for testing claims in high quality, unbiased research, and the that large clinical trials with repeatability are required to demonstrate the efficacy of therapies. One recommendation, however, caught my eye:

New drug discovery is probably essential for common diseases where the existing drug armamentarium has been already extensively screened. Conversely, for uncommon and neglected diseases, the existing drug options may remain largely untested, and old drugs may find interesting new uses (12-14).

Actually, that’s a recommendation that’s been pretty obvious for a long time. For common diseases, existing drugs and related drugs have been tested and retested, and many, many variations on the old have been tried. For substantial breakthroughs, something new is required. Unfortunately, the profit incentive in drug manufacturing tends too much towards “me-too” drugs. The second part is actually very relevant to what I do. Testing such “off-label uses” of drugs can yield surprising results. Indeed, one of my two research projects is based on exactly such an off-label use. However, ironically it is a treatment for a very common disease, breast cancer, that I am testing; so Dr. Ioannidis is not entirely correct. Interesting new uses for drugs do not always make themselves known in uncommon and neglected diseases.

Regardless, however, what the public needs to understand is that translational research takes a long time. What they also need to understand is that the foundation upon which translational research rests is a strong core of basic science research. Without a wide variety of basic science findings upon which to base treatments, translational research has little to choose from in moving such findings to the next step. Contrary to popular belief as well, when there are robust basic science findings upon which to base a potential therapy, the road from laboratory bench discovery to usable therapy is long and winding.

REFERENCE:

D. G. Contopoulos-Ioannidis, G. A. Alexiou, T. C. Gouvias, J. P. A. Ioannidis (2008). Life Cycle of Translational Research for Medical Interventions Science, 321 (5894), 1298-1299 DOI: 10.1126/science.1160622

Causation is not so simple to determine as one would think. A mantra at SBM is ‘association is not causation’ and much of the belief in the efficacy of a variety of quack nostrums occurs because improvement occurs after use of a nostrum, therefore improvement occurs because of use of a nostrum. It is why vaccines as a cause of autism are so compelling to some. Vaccines are given at the same time autism starts to manifest. It would require more intellectual power than I have not to conclude, wrongly, that vaccines caused the autism. Concluding causation from sequential events is how the human mind works, and reality, as we know and ignore, constantly conspires to fool us into making false causal connections. In Infectious Diseases I see the error almost daily. The patient had a fever, patient was given antibiotics, fever went away. Therefore the antibiotics treated an infection. Well, maybe, maybe not. One of my mantras is ‘antibiotics are not antipyretics’ and you must be very careful before concluding that the fever went away because of the penacephalone.

I blog and podcast in large part to educate myself. It is amazing how much I learn in the process of preparing for one of the entries in my multimedia medical empire. Areas of knowledge that I had no idea existed can be revealed for exploration. I do not have formal training in epidemiology, although part of my job is hospital epidemiology. Like much of medicine, I acquired what I do know from on-the-job training and lots of reading. So imagine my surprise and delight to discover Hill’s Criteria of Causation, thanks to its application to chiropractic subluxation.

In 1965, Austin Bradford Hill published “The Environment and Disease: Association or Causation?” Dr. Hill, an occupational physician, sought to answer the questions (another discussion of the paper here):

How in the first place do we detect these relationships between sickness, injury and conditions of work? How do we determine what are physical, chemical and psychological hazards of occupation, and in particular those that are rare and not easily recognized?…In other words we see that the event B is associated with the environmental feature A, that, to take a specific example, some form of respiratory illness is associated with a dust in the environment. In what circumstances can we pass from this observed association to a verdict of causation? Upon what basis should be proceed to do so?

He then proceeds to list criteria (he refers to them as viewpoints) that help in determining causation. I like frameworks for thinking about processes. They provide a starting point for considering problems. Becoming a doctor is, in part, internalizing frameworks. Early in training you carry lists and papers that remind you how to evaluate acidosis, or the physiology of heart failure or suspected meningitis. After time and repetition these lists are internalized and you can evaluate the problems without resorting to lists. As an intern one of the papers I carried around was The New England Journal of Medicine article on the physiology of the Swan-Ganz catheter, and I would refer to it with each patient who had a Swan. One day I did not need to refer to the paper. I had internalized the information, and tossed the paper into the trash. Frameworks are not the be all and end all, but do serve as foundation upon which to build ideas. Part of being a specialist is to recognize when the framework doesn’t apply. However, I never had a formal framework for thinking about what constitutes causality in medicine. It is worth reading in the original if no other reason as an appreciation of a time when the medical literature was not dry as dust and devoid of humor and style. Current medical journal writing is often an excellent replacement for Ambien, even when you are fascinated by the topic. To call it the medical ‘literature’ is to refer to the phone book as literature.

The viewpoints to consider in determining if association is due to causation:

1) Strength. How strong is the association between the cause and the effect? Hill uses the example of chimney sweeps, who died of scrotal cancer at rates 400 times the normal population. It killed Bert, or so I was lead to believe. He points out that a strong association like scrotal cancer and chimney sweeps is good evidence in favor of causality from an environmental exposure. He also points to that small effects in a population can still be considered strong associations and uses the death rates from Snows evaluation of the 1855 cholera outbreak, where the death rates from the contaminated water were 17/10,000 vs. 5/10,000 in the general population. Not a huge increase in mortality, but a strong association none the less.

The strength of ‘alternative’ therapies usually hovers around background noise, usually at the level of personal experience. If acupuncture or homeopathy were 400 times superior to placebo, there would no discussion of its validity. Many medical therapies are not 400 times as effective as placebo, but the strength of the association between cause and effect is well above background noise.

2) Consistency. Almost every study should support the association for there to be causation. He uses the example of cigarettes as a cause of lung cancer as an example, “The Advisory Committee to the Surgeon-General of the United States Public Health Service found the association of smoking with cancer of the lung in 29 retrospective and 7 prospective inquiries.” From the vantage point of 2009, where the carcinogenic effects of cigarettes are well established, this example is amusing, but instructive. Over time, as studies progressed, there was a consistent association between smoking and cancer.

He also warns about the importance of a good control group, the inclusion of which often spells the death of ‘alternative’ therapy efficacy, as the recent studies in acupuncture have demonstrated:

Patients admitted to hospital for operation for peptic ulcer are questioned about recent domestic anxieties or crises that may have precipitated the acute illness. As controls, patients admitted for operation for a simple hernia are similarly quizzed. But, as Heady points out, the two groups may not be in pari materia. If your wife ran off with the lodger last week you still have to take your perforated ulcer to hospital without delay. But with a hernia you might prefer to stay at home for a while‚ to mourn (or celebrate) the event. No number of exact repetitions would remove or necessarily reveal that fallacy.

As readers of this blog are probably aware, there is one consistent result in ‘alternative’ therapies: increasing the quality of the study decreases the efficacy until the best studies show no effect.

3) Specificity. Since diseases can have multiple etiologies and therapies can have multiple effects, this is a weaker criteria. However, given the knowledge of physiology and biochemistry since 1965, we have more sophisticated techniques for measuring and determining specificity. From the perspective of opportunistic infections, with no knowledge of viral pathophysiology, HIV is hardly a specific cause of disease. GIven the ability to measure HIV viral load and an understanding of the consequences of HIV depletion of CD4 cells, HIV has high specificity for causing AIDS.

“In short, if specificity exists we may be able to draw conclusions without hesitation; if it is not apparent, we are not thereby necessarily left sitting irresolutely on the fence.”

As Dr Hall has discussed, many ‘alternative’ medical paradigms completely lack specificity and are the one true cause or treatment of all diseases, be it subluxation, a liver fluke, or colonic toxin build up. Fools all; infections are the one true cause of all disease.

4) Temporality. The order should be exposure, disease, treatment, resolution. Cause should proceed effect.

Does a particular diet lead to disease or do the early stages of the disease lead to those particular dietetic habits? Does a particular occupation or occupational environment promote infection by the tubercle bacillus or are the men and women who select that kind of work more liable to contract tuberculosis whatever the environment‚ or, indeed, have they already contracted it? This temporal problem may not arise often, but it certainly needs to be remembered

5) Biological gradient. Also known as dose-response. A little exposure should result in a little effect, a large exposure should cause a large effect. Certainly well known to anyone who drinks alcohol; I suppose all homeopaths must be teetotallers.

The comparison would be weakened, though not necessarily destroyed, if it depended upon, say, a much heavier death rate in light smokers and a lower rate in heavier smokers. We should then need to envisage some much more complex relationship to satisfy the cause and effect hypothesis. The clear dose-response curve admits of a simple explanation and obviously puts the case in a clearer light.

Most ‘alternative’ therapies are binary and have no gradient of effect. I suppose that a chiropractor could say your spine is partly unsubluxed as a result of half a spinal manipulation or an acupuncturist saying, your chi is partly unblocked as I used too few needles. I suppose. I assume a reader will comment on the validity of this observation.

6) Plausibility. The effect must have biologic plausibility. I would take it a slightly differently: not only should it be biologically plausible, but should not violate well known laws of the universe. Hill points out “but this is a feature I am convinced we cannot demand. What is biologically plausible depends upon the biological knowledge of the day.”

Yet there is a difference between what is not yet known but possible — for example Helicobacter as a cause of gastric ulcers, which is odd but not impossible — and what almost certainly will never known because it cannot exist without a radical rewrite of all of science: meridians or water memory, which are odd and impossible. I know that there are more things in heaven and earth than are dreamt of in my philosophy. But you have to prove it to me.

In short, the association we observe may be one new to science or medicine and we must not dismiss it too light-heartedly as just too odd. As Sherlock Holmes advised Dr. Watson, “when you have eliminated the impossible, whatever remains, however improbable, must be the truth.” I nice quote, but not necessarily the case. Sometimes what remains is, however improbable, still nonsense. Which leads to:

7) Coherence. “On the other hand the cause-and-effect interpretation of our data should not seriously conflict with the generally known facts of the natural history and biology of the disease.”

I have discussed in prior entries that those who call themselves ‘holistic’ rarely are and a good physician understands a disease from the microscopic to the entire world. I know cholera, for example, from the level of the effect of the toxin on cellular receptors to the world wide changes in potable water that lead to the spread of disease and much in between. There is a coherence of understanding of the disease.

In a wider field John Snow‚ epidemiological observations on the conveyance of cholera by water from the Broad Street Pump would have been put almost beyond dispute if Robert Koch had been then around to isolate the vibrio from the baby nappies, the well itself and the gentleman in delicate health from Brighton. Yet the fact that Koch‚ work was to be awaited another thirty years did not really weaken the epidemiological case though it made it more difficult to establish against the criticisms of the day.

Ignoring most anatomy or physiology or other biologic understanding, most ‘alternative’ therapies have no coherence when placed in the context of the known universe. Homeopathy is, above all, totally incoherent.

Experiment. Always nice. Written in 1965, before the massive increase in biomedical research funding, experiments were not as vital in understanding diseases and treatments as they are today.

Unfortunately for most ‘alternative’ medicine, experiments rarely support their theory or efficacy. Not that it ever matters to the practitioners. I think about how my practice has changed over the last 25 years: adding, subtracting and modifying what I do as the data comes in. Consider the 44,000 articles in Pubmed in infectious disease that are published last year. I wonder how much chiropractic (233 articles on 2009) or acupuncture (1000 articles in 2009) or naturopathy (19 articles in 2009) or homeopathy (162 articles in 2009) practice changed as a result of published studies. It cannot be all that hard to keep up and, so, change accordingly.

9) Analogy. If one virus, for example, can cause a disease, then it is reasonable to suggest that a second virus could be responsible for a similar disease. Analogy is not the same as metaphor: both are the preferred methods of understanding ‘alternative’ therapies, but with little comparison to objective reality. He clearly states these are guidelines, and not to be followed blindly.

What I do not believe‚ and this has been suggested, that we can usefully lay down some hard-and-fast rules of evidence that must be obeyed before we can accept cause and effect. None of my nine viewpoints can bring indisputable evidence for or against the cause-and-effect hypothesis and none can be required as a sine qua non. What they can do, with greater or less strength, is to help us to make up our minds on the fundamental question, is there any other way of explaining the set of facts before us, is there any other answer equally, or more, likely than cause and effect?

The importance of considering all the data, the preponderance of information, in deciding cause and effect.

Hill is also not enthusiastic about statistics, the dreaded p-value:

No formal tests of significance can answer those questions. Such tests can, and should, remind us of the effects that the play of chance can create, and they will instruct us in the likely magnitude of those effects. Beyond that they contribute nothing to the, proof‚ of our hypothesis … Between the two world wars there was a strong case for emphasizing to the clinician and other research workers the importance of not overlooking the effects of the play of chance upon their data. Perhaps too often generalities were based upon two men and a laboratory dog while the treatment of choice was deducted from a difference between two bedfuls of patients and might easily have no true meaning. It was therefore a useful corrective for statisticians to stress, and to teach the needs for, tests of significance merely to serve as guides to caution before drawing a conclusion, before inflating the particular to the general… Yet there are innumerable situations in which (tests of significance) are totally unnecessary‚ because the difference is grotesquely obvious, because it is negligible, or because, whether it be formally significant or not, it is too small to be of any practical importance… What is worse the glitter of the t table diverts attention from the inadequacies of the fare.

Statistically significant nonsense is still nonsense. The article puts into perspective the ongoing problem of the meta-analysis. I always say that the meta-analysis is good for a general understanding of an intervention but rarely provides definitive answers. When meta-analyses are compared to subsequent randomized controlled trials, the meta-analyses got it wrong 35% of the time. As a result, I think meta-analyses are great if they support your prior beliefs and can be safely ignored if they contradict them. That is the problem with meta-analyses, they are good at the mathematics/statistics of multiple studies but fail to take into consideration the other viewpoints as enumerated by Dr. Hill. Far be it from me to suggest that the Cochrane reviews may be wanting as they are often considered the be all end all of analysis, but their reviews in the few areas I know a little about always leave me unsatisfied.

Dr Hill ends with a discussion on the importance of then using the information of when association merges into causation and to consider at what point we need to act on the information. Stopping a nausea medication because it may cause birth defects has a different impact than stopping the burning of fuels in the home as cause of lung disease. In the end we have to act on our information, even if it is always incomplete.

All scientific work is incomplete, whether it be observational or experimental. All scientific work is liable to be upset or modified by advancing knowledge. That does not confer upon us a freedom to ignore the knowledge we already have, or to postpone the action that it appears to demand at a given time.

Who knows, asked Robert Browning, but the world may end tonight? True, but on available evidence most of us make ready to commute on 8:30 the next day.

8:30. It was a more leisurely era.

The explicit application of Hill’s criteria is uncommon, at least if ‘Hill’s criteria’ is used as search criteria on Pubmed. There are areas on medicine that are not clearcut as to causality. Do some therapies work? And if so, in what populations? Is X the cause of disease Y?

Recently, Hill’s Criteria were applied to chiropractic subluxation, and subluxation was found wanting. In Chiropractic theory, spinal subluxation is considered to be the cause of nearly all disease. As readers of this blog know, subluxation was made up by DD Palmer and

The Association of Chiropractic Colleges paradigm statement (ACC Paradigm) suggested that, chiropractic is concerned with the preservation and restoration of health, and focuses particular attention on the subluxation. It also defined a subluxation as “a complex of functional and/or structural and/or pathological articular changes that compromise neural integrity and may influence organ system function and general health.

Subluxation is the basis of the practice of chiropractic. It there is no subluxation, the raison d’etre for chiropractic disappears with a pop or perhaps a crack.

So when Timothy A Mirtz et. al searched the literature looking for support for the most fundamental support for the practice of chiropractic and came up with bupkis, well, imagine if the literature search for germs as a cause of infection or atherosclerosis as a cause of heart attack and found nothing. Zip. Nil. Nada. Diddley squat.

What would happen to Infectious Diseases or Cardiology? I would hope they would disappear as specialty. If there is no basis for the practice, it should be abandoned. Right?

What is the support for subluxation, using Hills ever so helpful viewpoints? I will summarize with the table from article

As the conclusion states,

There is a significant lack of evidence in the literature to fulfill Hill’s criteria of causation as regards chiropractic subluxation. No supportive evidence is found for the chiropractic subluxation being associated with any disease process or of creating suboptimal health conditions requiring intervention. Regardless of popular appeal this leaves the subluxation construct in the realm of unsupported speculation. This lack of supportive evidence suggests the subluxation construct has no valid clinical applicability.

So why continue with chiropractic, at least based on the treatment of subluxation? Got me. And pay for it with tax dollars or insurance premiums? If chiropractic is based entirely on nothing substantial, then nothing is what should reasonably be paid.

One wonders about other alternative therapies: homeopathy, acupuncture, various energy therapies etc. Even if a meta-analysis demonstrated marginal statistical benefit, when Hills viewpoints are considered, I doubt any would hold up.

We survived almost all of human history without it. Yet in the last 100 years people have allowed themselves to be hoodwinked by a huge corporate conspiracy into believing that we “need” their products. They cite studies and claim we don’t understand science; they ignore ancient folk wisdom and have no respect for our intuition. They peddle their products without regard to the dramatic increase in chronic diseases and weakened immune systems of recent decades. I’m speaking, of course, of “Big Floss.”

It’s time to take our mouths back from corporate domination. It’s time for alternative dentistry.

To hear the corporate “tools” of Big Floss tell it, we need to use their products not simply every day, but many times a day. They’ve created a seemingly limitless array of products that they are forcing, literally, down our throats. Toothbrushes, toothpaste, floss, mouth wash! There appears to be no end to the number and type of products they insist we must buy to fuel their corporate ambitions. And even if we behave like sheep and buy their tainted wares, their allies the dentists insists that we must visit them not merely once a year, but twice.

We’re supposed to believe that we benefit from this meddling with the natural order. Really? So please explain how the human race survived just fine to this point without Big Floss. Clearly we didn’t need toothbrushes to survive and even thrive. So why, suddenly, should we be gullible enough to believe that every person should brush his or her teeth after every meal? Has there been even a single randomized controlled double blind study that proved that brushing saves teeth? No, there hasn’t.

Big Floss insists that it has a product for every person, often more than one. Toothpaste to prevent cavities, toothpaste for kids, toothpaste for dentures. Is there any limit to what they will sell in order to increase their profits? And are we really supposed to believe that four out of five dentists recommend Crest? Where’s the data for that claim?

They tricked people into brushing ever day and using toothpaste each time, but that’s not enough for Big Floss. They say that toothpaste prevents plaque buildup and then they turn around and insist that we need mouthwash, too, to kill the harmful germs that cause plaque. Do we look that gullible? And what’s wrong with plaque anyway? It’s natural and probably exists to strengthen our immune system, which has been weakened by constant exposure to toxins and Frankenfood.

Big Floss is not content with tricking us into buying toothbrushes, toothpaste, floss and mouthwash. They insist that we see a dentist twice a year. If their products are so great, why would we ever need to see a dentist? We wouldn’t, but the unholy alliance of Big Floss and Dentistry has colluded to increase the profits of both. Don’t believe me? The dentist always tells you that you should brush every day, and Big Floss always recommends dental checkups. What more evidence do you need?

It’s time to end our reliance on Big Floss. It’s time for alternative dentistry. Those who truly educate themselves about teeth in nature know that toothbrushes and toothpaste are unnecessary. If our ancestors didn’t need them, we don’t need them, either. We can care for our teeth with a diet of fruit, vegetables and vitamin supplements.

In the rare situation in which more is needed, we can dose ourselves with ancient herbs or pull out rotten teeth the natural way, by tying a string around the both the tooth and the doorknob and giving the door a big shove. Forget novocaine. Why would we dose ourselves with medication to numb the pain of a tooth extraction? Those who really care about their teeth want to savor every natural feeling, not deaden it with chemicals.

And let’s not forget preventive care. If you want to be sure that you have healthy teeth, all you need to do is buy powdered Bio-identical Teeth®. Unlike artificial toothpastes or mouthwashes, powdered Bio-identical Teeth® is all natural, made from human teeth with no fillers or animal products. Because it is “bio-identical” it is more effective than artificial toothpaste could even be.

It’s time to unite and fight the corporate conspiracy of Big Floss. No more toothbrushes, no more toothpaste, and no more visits to the dentist. Let’s live as Nature intended with no artificial colors or preservatives. Let’s care for our teeth naturally for as long as they last.

Brought to you as a public service by the American Pureed Food Industry

(This piece is satire.)

Another one bites the dust.

The National Center for Complementary and Alternative Medicine (NCCAM) is generally a waste of taxpayer money, but they have sponsored several well-designed large trials of popular herbal supplements. And one by one these studies have shown these popular products, such as echinacea for the common cold, to be ineffective.

To add to the list, published in JAMA this week are the results of the largest and longest trial to date of Gingko biloba for the improvement of cognitive function and to treat, prevent, or reduce the effects of Alzheimers disease or other dementia. The results of the study are completely negative.

The study was very rigorous – a consensus trial designed to address all the criticisms of prior smaller studies. It was a direct comparison of Gingko biloba at 120mg twice a day, double blind, randomized, multi-center trial involving 3019 subjects aged 72-96 for a median of 6.1 years. Subjects were followed with standardized tests of cognitive function.

The results are easy to report – every measure showed no difference between G biloba and placebo. There was no difference in cognitive function, risk of developing dementia, rate of progression of dementia or normal cognitive decline with aging. Usually such studies involve some random noise in the results, especially when several outcomes are measured. But with such a large study, random fluctuations should average out, and that is exactly what happened.

Gingko biloba has been used for centuries as a medical herb, and the most popular claim made for its use was to enhance cognitive function. The justification for this claim was always thin – G biloba has a mild blood thinning effect. It was therefore claimed that the herbal drug would enhance blood flow to the brain and improve brain function.

However, this is not a plausible mechanism. The brain exquisitely regulates its own bloodflow, and suboptimal perfusion results in a widening of the blood vessels to increase flow. This autoregulation would not be enhanced by mild blood thinning in a healthy individual.

In someone with severe atherosclerosis or narrowing of the arteries, to the point where autoregulation of blood flow is not able to optimize perfusion of brain tissue, the result is typically stroke-like symptoms. In this situation a blood thinner may improve perfusion, and generally drugs like aspirin are prescribed.

This, of course, implies that if simple blood thinning could improve cognitive function, then aspirin would be more effective at this than G biloba. In any case, this putative mechanism was never very plausible.

More recent studies have found that G biloba has some anti-oxidant effects. However, anti-oxidants as a class have not been found to be effective for cognitive function or any other clinical outcome. So this too lacks plausibility.

It was also found that G biloba can reduce amyloid aggregation. Amyloid plaques build up in the neurons of patients with Alzheimers disease, so this is a plausible mechanism for slowing the progression of some forms of dementia. However, as we now know this does not translate into a measurable clinical effect.

The lessons from this study and the lack of effect for Ginkgo biloba should learned and generalized.

Historical use of an herbal drug is not sufficient evidence for its effectiveness.

Preliminary, small, or poorly designed studies are unreliable, and often result in false positives. Only large definitive trials are reliable.

Finding a potential mechanism for a drug, herbal or otherwise, is not a sufficient basis for a clinical claim – you need clinical trials with actual people to support such claims. Further, if researchers go looking for potential mechanisms to explain a putative action of a drug or supplement, it is not surprising that they will find some. Drugs typically have many biochemical actions in the body, and finding an effect is not surprising. There is also likely confirmation bias and the file-drawer effect at work – favoring the publishing of interesting and positive studies.

In the end – all the ancient wisdom, small studies, and putative mechanisms meant nothing. They were all trumped by a large and impeccably designed study that shows Gingko biloba is of no measurable benefit for cognitive function.

These results call into question the practice in many countries of allowing pharmacological agents like G biloba to be marketed as supplements with health claims prior to being adequately studied. The European and US markets for G biloba are in the hundreds of millions of dollars per year. It will be interesting to see what happens following this study.

The study did find that G biloba was generally safe. However, it should be noted that G biloba, although sold in the US as a supplement, should be considered a drug. It does have an anti-platelet blood-thinning effect and should not be taken prior to surgery. However, because many people think of herbs as supplements and not drugs, patients rarely disclose their supplements to their doctors, and doctors fail to take a supplement history. Safety is therefore still an issue.

Herbs and botanicals have been and can be a valuable source for useful pharmacological agents. However, regulating and using them as supplements has many flaws – as the history of Gingko biloba once again highlights.

Editor’s note: Since I happen to be on vacation (sort of–in reality I plan on spending most of next week holed up in my Sanctum Sanctorum at home writing a grant that’s due in February) and because readership tends to be down during the week between Christmas and New Years’ Day, I thought I’d resurrect something from well over three years ago and revise it to fit this particular blog. In doing so, I hope to provide you with something amusing to read, as well as something to link to time and time again whenever you want to refer to a particular gambit beloved by promoters of quackery and pseudoscience. I present here….The “Pharma Shill” Gambit! Enjoy!

I’ve mentioned before on this blog at least once that I cut my skeptical teeth, so to speak, on Usenet, that vast untamed and largely unmoderated territory full of tens of thousands of discussion newsgroups which used to be a lot more active before the rise of the World Wide Web and then later blogs. These days, few ISPs even offer much in the way of Usenet access; it’s become pretty much irrelevant since Google archived Usenet in the form of Google Groups. My forays into skepticism started out with combatting Holocaust denial on a newsgroup known as alt.revisionism (as good an excuse as any to remind you that nearly all Holocaust “revisionism” isn’t historical revisionism but is actually denial) and then branched out into more general skepticism, particularly about the claims of creationists and, of course, promoters of “alternative” medicine, the latter of which ultimately led me to being the editor of this wild and woolly thing we call the Science-Based Medicine blog. After I began to participate in the debates in the main newsgroup where alternative medicine is discussed, misc.health.alternative, it didn’t take me long to encounter a favorite tactic of promoters of alt-med who were not happy with one who insists on evidence-based medicine and who therefore questions claims that are obviously not based in valid science: The “Pharma Shill” Gambit. This is a technique of ad hominem attack in which a defender of “alternative” medicine, offended by your questioning of, for instance, his/her favorite herb, colon or liver flush technique, zapper, or cancer “cure,” tries to “poison the well” by implying or outright stating you must be in the pay of a pharmaceutical company, hired for nefarious purposes.

Since I entered the blogosphere several years ago under another guise, I’ve only occasionally checked back at my old stomping ground, mainly because blogging is so much less constraining than posting to Usenet, where mostly I used to respond to the posts of others, rather than writing about what I wanted to write about. A while back, though, out of curiosity I checked back and found this interesting little tidbit from a poster calling himself PeterB that demonstrated such a perfect example of the “pharma shill” gambit that I thought it might serve as a perfect example of the sort of thing I’ve had to put up with ever since I started speaking out against quackery:

To : All participants and readers of misc.health.alternative + other health-related newsgroups

Please be aware that many comments and responses posted to this forum are not those of casual posters interested in an honest exchange. A number of individuals with ties to industry are engaging an effort to shape public sentiment about the risks of mainstream medicine while denigrating the benefits and validity of natural medicine. I refer to these individuals broadly as “Pharma Bloggers”(*). Pharma Bloggers on usenet don’t promote a specific company or product, as might be the case with standard “blogging” on a weblog. Most of these people are likely to have an association with a PR campaign whose “blogging” efforts are underwritten by the media and marketing groups of industry. They are not difficult to identify due to specific patterns of behaviour in posting.

Here are a few points to remember while participating in usenet newsgroups:

1. Pharma Bloggers on usenet use intimidation, mockery, and insults to silence those who express belief or interest in natural medicine.
2. Pharma Bloggers on usenet attack those who question the effectiveness of mainstream medicine and defend disease-management “healthcare” as the only viable form of medicine.
3. Pharma Bloggers on usenet post the majority of their responses simply to bury the comments of others; they also strive obsessively to have the last word.
4. Pharma Bloggers on usenet are much faster at posting than casual participants; they almost always respond first to a new thread, question, or observation.
5. Pharma Bloggers on usenet use multiple “bloggers” in a swap-&-relay fashion to create an aura of the “consensus view” in an effort to isolate posters who question the value of mainstream medicine. You will see this tactic used more often than any other.

Tip: If you find yourself reading a response that is unusually dramatic in tone, or inexplicably vicious toward other posters, and if that response is a defense of mainstream medicine, you can be sure you have stumbled upon a “Pharma Blogger.” Unfortunately, there are more of these individuals posting to usenet on a daily basis than virtually anyone else, which is why I am posting this alert. If you find it odd that so few people on health-related usenet newsgroups are expressing an interest in natural medicine, it isn’t because they aren’t there, it’s because they have been intimidated into silence. The Pharma Bloggers have over-run the various newsgroups with their industrial brand of dogma, mockery, and ridicule. Many casual posters are simply frightened away. That’s one of the goals of Pharma Blogging.

(*) Pharma Blogger: An individual who uses the Internet to: 1) promote and defend maintstream medicine while denigrating natural medicine approaches; 2) attack others who express a preference for natural medicine, or who question the value of mainstream medicine; and 3) cite a variety of “junk medical science” funded by industry for the purpose of establishing markets for marginally effective, and often dangerous, medical products and devices.

PeterB

See what I had to deal with? First, let me just mention that I realize that astroturf campaigns do exist, but, quite frankly, die-hard defenders of alt-med on Usenet like PeterB tend to be interested in such Internet PR efforts only as a means of smearing those who criticize them for their claims or who have the temerity to ask them to provide scientific studies to back up their assertions. To them, everyone who questions them is probably part of an astroturf campaign. It goes with the conspiracy-mongering proclivities so common among cranks.

This sort of obvious pre-emptive ad hominem attack (again, a.k.a. the logical fallacy of poisoning the well) would be utterly laughable if it were not so common. I sometimes get the impression that PeterB and his compatriots must think that there are hordes of “pharma shills” sitting behind banks of computers (remember the claim “more of these individuals posting to Usenet than anyone else”), waiting to pounce the instant anyone like PeterB starts posting critiques of big pharma or praising herbal “cures.” (Yes, that they seem to think they are worth that sort of effort implies PeterB and others like them do seem to have an inflated view of their own importance.) My usual first response to such gambits tends to be facetious and runs along the lines of asking, “Where do I sign up to become a pharma shill? How do I get me a piece of that action? After all, why should I waste my time seeing patients and working like a dog to do science, publish papers, and write grants and then only having a couple of hours in the evenings to blog, when I could make big bucks ruthlessly mocking online dissent against big pharma full time while sitting back in my pajamas and sipping a big hot mug of coffee? Count me in!” (Expect to see my words posted somewhere out of context to make it seem as though I was being serious about this.)

However, facetiousness usually just infuriates people like PeterB to new heights of “pharma shill” accusations. At that point, it’s time to try to be rational, hard as it may be in the face of such provocation, but I try. First, a lot of this smear tends to be a case of projection, of the pot calling the kettle black. For example, #1, #2, and #3 are more typical of supporters of alt-med than of anyone who questions alt-med claims. Indeed, the denizens of misc.health.alternative who are most pro-alternative medicine tend to react quite defensively to questioning of their assertions. They are often like a group of Cyber Sisters (except that they are comprised of both men and women) ruthlessly descending upon anyone who questions the dogma of their favorite alternative medicine, criticizes their behavior, or suggests that maybe, just maybe, conventional medicine might have value. (No, those on “our side” are not entirely innocent, but in my experience the certain promoters of alt-med tend to be quicker with the ad hominem.) One reason for this, I suspect, is that many of them are also active on moderated groups such as CureZone.com, where anyone questioning the alt-med treatment du jour too long or too vigorously will be banned from the discussion groups, thus providing a nice, safe, cuddly environment, where never is heard a discouraging word towards quackery. #4 and #5 are clearly designed to imply that the so-called “Pharma Bloggers” either don’t have a regular job (why else would they have so much time?) or that they are working for big pharma. Of course, they never provide any evidence to support their accusations. In fact, they almost never provide even any reasoning to support their accusations more substantive than variations on “he’s criticizing alternative medicine a lot so he must be a pharma shill.”

The “pharma shill” gambit, like other varieties of ad hominem or well-poisoning rhetoric, conveniently frees defenders of “alternative” medicine from having to argue for their favorite remedies on the science and clinical studies supporting them (which in most cases tend to be badly designed or nonexistent). It’s a technique that’s not just limited to them, either. Anti-vaccination cranks and mercury/autism conspiracy theorists like it too, and, indeed, I have been the subject of some particularly vicious attacks over the years at the hands of the anti-vaccine movement^1,2, Generation Rescue and its founder J. B. Handley in particular^3,4,5, all of whom appear to be trying very hard to poison my Google reputation. (Indeed, another such attack rolled in just today, courtesy of AoA hanger-on Harold Doherty.) Moreover, J.B. Handley, in particular, has also attacked our very own Steve Novella. More recently, the late Hulda Clark’s former attack Chihuahua Tim Bolen appears to have decided for some reason that I have been named the heir apparent to Dr. Stephen Barrett. While I’m flattered that he somehow seems to think this, I’ll have to be at this for many more years and become much more effective even to approach Barrett’s legacy. Be that as it may, you have to have a tough skin if you’re going to try to combat the infiltration of pseudoscience into medicine.

Skeptico pointed out, even if a newsgroup denizen were a pharma shill, that wouldn’t necessarily invalidate his argument. Yes, in the case of a true “shill” who does not reveal that he works for a pharmaceutical company and pretends to be “objective,” it would be entirely appropriate to “out” that person with extreme prejudice, so that his bias could be taken into account. That being said, I’ll take this opportunity to point out that I have never over the last decade observed such a person in action, which tells me that they are probably a lot less common than people like PeterB like to claim. Even in the case of a real shill, however, this sort of “outing” is not a refutation of that person’s arguments; it merely serves to increase appropriately the level of skepticism about what that person is saying. Such an “outing” still leaves the task of actually using evidence, logic, and sound arguments to refute what that person is saying, something boosters of alt-med rarely even attempt to do. It’s far easier to fling the accusation of “pharma shill” about and see if they can get it to stick, as PeterB and his ilk do.

No doubt, may of our readers here at SBM have heard of Godwin’s Law, which states:

As an online discussion grows longer, the probability of a comparison involving Nazis or Hitler approaches 1.

Over the years, an assumed corollary to Godwin’s Law has become commonly accepted that in essence states that once such an “argumentum ad Nazium” is made, the discussion thread is over, and whoever brought up the Hitler or Nazi analogy first automatically loses the debate. Recently, this corollary was the basis of Scopie’s Law, which is more relevant to the topics covered on this blog and states:

In any discussion involving science or medicine, citing Whale.to as a credible source loses you the argument immediately …and gets you laughed out of the room.

Over time, I and others have suggested that, although Whale.to is clearly The One Quack Site To Rule Them All, there are at least a few other sites whose promotion of pseudoscience lead them to deserve to be included in Scopie’s Law, such as NaturalNews.com, Mercola.com, and the anti-vaccine crank blog Age of Autism. However, I think that there’s another law, a law similar to the original formulation of Godwin’s Law, that applies to virtually any online discussion of anything resembling alternative medicine. Perhaps we could dub it “Gorski’s Law,” and this is what I propose it to say:

As an online discussion of health, in particular vaccines or alternative medicine, grows longer, the probability of the invocation of the ‘pharma shill gambit’ approaches one.

If there’s an exception to this law, other than in moderated forums and (usually but not always) here at SBM, I haven’t found it yet.

The Graston Technique® is a modification of traditional hands-on soft tissue mobilization that uses specifically designed instruments to allow the therapist to introduce a controlled amount of microtrauma into an area of excessive scar and/or soft tissue fibrosis, hoping that this will invoke an inflammatory response that will augment the healing process. It is also intended to reduce the stress on the therapist’s hands.

Microtrauma? Hurting people to make them better? I know sometimes an improperly healed bone must be re-broken so it can re-heal in proper alignment, but this is different. It bothers me that they are further injuring already damaged soft tissues and hoping (1) that the new injury will heal, (2) that that will help the older injury heal, and (3) that it can somehow avoid stimulating the deposition of just that much more scar tissue and fibrosis. It seems to violate the “primum non nocere” principle. It is unpalatable. Of course that wouldn’t matter if the evidence showed it was effective. Does it?

Soft tissue mobilization is widely used in physical therapy, although the evidence is sparse. According to one PT website,

Soft tissue mobilization breaks up inelastic or fibrous muscle tissue such as scar tissue, move tissue fluids, and relax muscle tension. This procedure consists of rhythmic stretching and deep pressure.

A related modality is Active Release Techniques® (ART) a patented hands-on treatment. The Graston Technique appears to be just another technique in this family of techniques: one that adds a special instrument to the procedure.

The Graston Technique website tells us it is used by more than 6,500 clinicians worldwide—including athletic trainers, chiropractors, hand therapists, occupational and physical therapists. It tells us the Graston Technique® instruments, much like a tuning fork, resonate in the clinician’s hands allowing the clinician to isolate adhesions and restrictions, and treat them very precisely. It tells us the treatment is clinically proven and it has resolved 87% or more of all conditions treated. (This claim is supported only by this “outcome data” chart with no explanation of what the data mean or where they come from.)

You must pay $495 for 12 hours of training to become qualified to treat and to purchase the set of instruments. The price of the instruments is $2755 — for six curved pieces of steel.

Research listed on Graston Technique Website:

The website lists articles in the popular press, poster presentations, and testimonials, but only 3 citations that appear to be acceptable evidence from peer-reviewed journals. I will call them (1) (2) and (3). A closer look reveals that they are not what they seem.

(1) and (2) are listed as having been published in the “Journal of the American College of Sports Medicine.” There is no such journal. They obviously meant the journal Medicine and Science in Sports and Exercise which is the official journal of the American College of Sports Medicine. Study (2), by Sevier et al., was not listed in the table of contents of that journal for the issue cited (Vol 27, No. 5, 1995) and was not found by searching the journal’s entire website. It was also not listed on PubMed. If such an article exists, it apparently was not published in a peer-reviewed journal, and certainly not in the journal they say it was published in.

(1) is listed as having been published in the “Journal of the American College of Sports Medicine” in 1995. It was indeed published in the journal Medicine and Science in Sports and Medicine, but it was not published in 1995 as the citation indicates, but in 1997. It is, in fact, the same study as (3). The citation for (3) is the only correct one.

So the company’s own website offers us only one scientific article from a 12-year-old peer-reviewed study, and it turns out to be a controlled study of 20 rats. They gave half of them an Achilles tendon “injury” by injecting collagenase and treated half of those with Graston Technique. They found microscopic evidence of increased fibroblast proliferation in those treated with the Graston Technique instruments, and there was also an improvement in the animals’ gait. They killed the rats to do the microscopic studies, so there was no data about long-term outcomes. The authors ended the abstract with this disclaimer:

Although healing in rats may not translate directly to healing in humans, the findings of this study suggest that ASTM [augmented soft tissue mobilization] may promote healing via increased fibroblast recruitment.

Research Found in PubMed

A PubMed search for “Graston” brought up 7 articles. 5 were case reports, one was a description of the design of a proposed trial, and the only one that was a clinical study was a pilot study that was not very informative.

1. A case report of treatment of a tibialis posterior strain in an athlete. I thought this one was really funny. In addition to the Graston technique, the patient received acupuncture, electrical stimulation, Active Release Technique((R)), ultrasound therapy with Traumeel (a mixture of 14 homeopathic remedies), and rehabilitation. So in addition to wondering if the patient would have recovered just as fast with no treatment, we are left wondering which of these modalities or which combination of them was helpful, if any.

2. A report of three case studies.

3. Not a trial, but a description of the design of a proposed trial.

4. Case report of treating trigger thumb with both Graston and ART (active release techniques).

5. Case report of a volleyball player with costochondritis that concluded “This athlete seemed to respond positively to manipulation, soft tissue mobilization, and taping.”

6. This pilot study in patients with carpal tunnel syndrome compared soft tissue mobilization by manual techniques to STM by the Graston Technique and found no difference in clinical improvements. Instead of concluding that the Graston Technique offered no advantage over the other treatment, it concluded that it had substantiated the clinical efficacy of both. The abstract doesn’t mention the number of subjects.

7. Another case report.

There was one other study that my search failed to bring up because the abstract did not mention Graston Technique but it did use GT instruments and has been cited by GT therapists as supporting evidence (that’s how I found out about it). It was a mouse study that instead of showing that GT is clinically effective seems to show the opposite. It found favorable effects on early collagen formation and organization, but minimal to no effect on the final outcome of healing.

Summary of the Evidence

It really all boils down to a handful of mice pro, a handful of mice con, one human pilot study showing no advantage over manual mobilization, and a lot of testimonials. Would you be willing to try a new pharmaceutical treatment on the basis of nothing but one favorable mouse study out of two, and one pilot study? Would you agree to let someone deliberately injure you on such flimsy evidence? I would be very happy if the Graston Technique proves useful, but for the time being it must be considered experimental.

A Media Story that Wasn’t

And now for the rest of the story. A physical therapist approached the editor of her local newspaper asking him to do a story featuring her and this wonderful new treatment. The editor had never heard of it, but amazingly he had heard of me, and he contacted me with questions. I had never heard of it either, but I did some quick research and told him I couldn’t find much in the way of evidence. He told the physical therapist that before he could agree to write about it he needed to see some evidence. She submitted 8 items as supporting evidence. The editor forwarded them to me for comment. I commented, rather impolitely:

This isn’t supporting evidence. It’s bullshit.

1. The cover letter consists of nothing but a protracted logical fallacy: the argument from popularity. The fact that lots of people use it and think it works does not constitute evidence that it actually works. Lots of people used bloodletting and thought it worked. Lots of people believe in astrology.

2. The rat study I referred to, by Loghmani and Warden. The last sentence says “Careful interpretation of this controlled animal study is warranted until its findings are confirmed by clinical studies.” Not even the authors are claiming it is an effective treatment for humans!

3. A testimonial from Golf Digest? Come on!

4. A description of how the Graston Technique is applied.

5. Another copy of the same Loghmani/Warden rat study. Didn’t she even realize she had already provided a copy? Did she hope you wouldn’t notice and would just be impressed by the sheer number of documents?

6. A meaningless table of “outcomes” with no explanation of where the numbers came from and no controls.

7. Something they label a “case report” which does not at all fit the definition of a case report. It is a journalistic report of the preliminary phase of an unfinished 3 part study by the same author, Loghmani, in rats. It does not provide the kind of information one would expect from a scientific paper and does not follow the accepted format. It was not published in a peer-reviewed journal, but in an in-house quarterly publication by Graston Technique. It is 4 years old — by now that study should have been finished and published in a peer-reviewed journal. Why wasn’t it?

8. A description of the technique with a testimonial, published in a popular health magazine. It quotes the same researcher, Loghmani. He says “The approach SEEMS to be effective.” It offers nothing in the way of evidence.

To put this into perspective, the only actual evidence the physical therapist has offered is one study in rats. Would you want to take a pharmaceutical that had only been tested in one rat study?

In summary, there is nothing here that could be considered evidence for clinical benefits to humans. As the Aetna insurance company says, this technique must be considered “experimental and investigational, because there is inadequate evidence in the peer-reviewed published medical literature of… effectiveness.”

In my opinion, experimental treatments like this should be limited to controlled research studies. That way we could learn once and for all if it was effective and safe. To forge ahead beyond the evidence and just treat people as she is doing amounts to using people as guinea pigs in an uncontrolled experiment without informed consent.

If you run an article, you will be giving her free advertising for an unproven treatment that she is misrepresenting as proven and effective.

The editor responded,

Thank you so much. Your assessment is exactly what I needed to keep this story out of the paper.

A reader recently sent in a link to a New York Times article that discussed an alternative breathing technique developed in Russia for the treatment of asthma called the Buteyko Method, or the Buteyko Breathing Technique (BBT), and asked for an evaluation of the claims on SBM.  This post will attempt to be a reasonably comprehensive evaluation of Buteyko and his therapy so that subsequent discussions, should they be necessary, may be more terse.

The NYT article is primarily an anecdote of a friend of the author who suffered from severe asthma, but who had improved since he began using the BBT.  The author briefly discusses asthma, the history and theory behind Buteyko and hyperventilation before wrapping up with an attempt to provide evidence to support the legitimacy of the story.  The friend’s pulmonologist is quoted to confirm that “based on objective data, his breathing has improved…”  She cites controlled clinical trials “in Australia and elsewhere” where patients have reduced their use of medications, including a purported British study of 384 patients where patients had a 90% reduction in rescue inhaler use and 50% reduction in steroids.  She ends by pointing out that the British Thoracic Society has given BBT a “B” rating, and an admonition to “the pharmaceutically supported American medical community to explore this nondrug technique.”

Never having heard of BBT before, the NYT article left me with several questions.  Who was Buteyko?  How did he develop the BBT?  What is BBT, what does it claim to do, and how does it claim to work?  Is the evidence as presented in the NYT article accurate? And finally, what evidence exists within the literature that BBT is an effective treatment for asthma?

Who was Konstantin Buteyko?

Given the relative obscurity of BBT in the US and in modern medicine in general, I am using the sites of Buteyko’s primary presence in the US, the Buteyko Center, and the Buteyko Institute of Breathing and Health as my primary sources of its theory and history.

Buteyko’s story is proudly presented in great length (but frequently lacking in critical detail) on the Buteyko Center website.  I encourage you to read it in its entirety for full effect, for it is fascinating and bears a striking similarity to that of the other founding figures of alt med belief systems (D.D. Palmer, Hulda Clarke, Mikao Usui, Samuel Hahnemann). What follows are the high points from a full bio on Buteyko by Sasha Yakovlev-Fredrickson, a Buteyko Specialist at the Buteyko Center USA.

Born in 1923 in the Ukraine, he trained as a mechanic until World War II, where he served in the Soviet military on the Eastern Front and became fascinated by the injuries he witnessed.  After the war ended he joined the First Medical Institute in Moscow and began his medical training.

Somehow, while still a medical student he is said to have specialized in hypertension.  Around the same time and while still in his 20’s, he is diagnosed with “a severe and lethal form” of hypertension that left him with months to live in 1952.  We are given no more detail, and the story is already bordering on medical incoherence.

His discovery apparently came in a moment of insight, or perhaps revelation.  One night in 1952, as he stood alone staring out at the night sky and contemplating his illness, he was dazzled by a bright light, and that “in the midst of his impending demise” he noticed that he was breathing heavily as was struck with the revelation that the heavy breathing he was experiencing was not a symptom, but the cause of his problems.  He intentionally slowed his breathing, and as he did so, he felt immediately better.  Following this revelation we are told that he went around the hospital telling people to breathe more slowly and that they immediately felt better as well.  Based on these experiences he created the Buteyko Breathing Technique.

It might be that he stumbled in this moment onto an immensely powerful and hitherto unknown insight into human pathophysiology.  On the other hand, there may a more simple explanation. We have in Buteyko a young man recently returned from the battle lines of WW II, suffering from hypertension (extremely uncommon in a young man), who is experiencing hyperventilation, flashing lights, and an apparent feeling of impending doom.  One would be hard pressed to find a better setup for and description of a panic attack.  Slow, controlled breathing that Buteyko described using can not only resolve the acute symptoms of a panic attack, but can also return a sense of control to the person afflicted, reducing their anxiety, and potentially alleviating hypertension.  Panic attack or stroke of stunning inspiration; Occam’s razor might have something to say on the matter.

Nevertheless, smitten with his new theory and armed with his very personal n=1, Buteyko began to treat patients.  The subsequent decades of his life are full of stories of persecution and suppression, physical intimidation and destruction of his laboratory, professional sabotage and fears of incarceration.  Undaunted, Buteyko continued using and promoting his therapy, and supposedly discovered that BBT could cure at least 150 different diseases and disorders!  Buteyko compared himself to Dr Semmelweis, and the power of his technique to atomic energy.  In 1987, having obtained a “top secret” patent on BBT from the Soviet government, he established the Buteyko clinic.

Never one to rest on his laurels, Buteyko continued to explore the power of BBT.  He is said to have hardly slept, and to have lived without food for 50 days at a time.  It is further claimed that he became an advanced spiritual practitioner with the ability to read people’s thoughts, predict the future, and at one point declared that civilization would die if we didn’t stop hyperventilating.

I’ll let these claims stand on their own without further comment, other than to reflect on the reliability of the mind that makes such statements.

What is Buteyko Breathing Therapy?

Eccentricity of the eponymous inventor of BBT aside, what can we say about the therapy itself?

How Buteyko researched and practiced his treatment from his revelation in 1952 until the establishment of his clinic in 1987 is obscure at best.  Per the history given on the Buteyko Center site, at the same time that he is enduring professional ridicule and sabotage and hiding his practice from the government for fear of imprisonment, he is also able to treat enough people to discern over 150 different uses for BBT and be offered (and then refuse) a job with the Russian Space Agency.  Despite what one would expect to be a wealth of data to support claims of efficacy for so many different conditions, Buteyko himself never published a single paper, and not until 1995 does any reference to his name appear in the medical literature.

Even according to the history provided by the Buteyko Center, not until 1981, nearly 30 years after Buteyko’s revelation/discovery was a second trial conducted regarding BBT’s efficacy; it is never peer reviewed or published.  The same source then tells that soon after acquiring his “top secret” patent for BBT, in 1985 the Soviet Public Health Ministry issued a recommendation that all medical professionals treat patients with his method.  After establishing his clinic in 1987 he treated people with asthma, allergies, hypertension, kidney problems, cardiac problems, gastrological problems, immune deficiency, cancer, and even victims of Chernobyl and AIDS patients.

The list of diseases treated by BBT didn’t end there.  On the Buteyko site you can peruse the list of 150 curable diseases and conditions Buteyko believed he could treat.

But what is BBT?  How can one therapy treat the varied legion of diseases on that list?  Again, I’ll let the Buteyko Center and the BIBH speak for themselves on the matter here and here.

As you can see if you follow the links, there is a lot of talk about hyperventilation, but they are rather sparse on the details.  If you want the details, break out your wallet.  The Buteyko Center and BIBH are willing to start doling out details in exchange for the digits on you credit card.

What of BBT’s Physiologic Plausibility?

So BBT’s origins are highly dubious, but what of its plausibility?

Let’s examine the physiologic explanation provided by the Buteyko Center for why it cures not only asthma, but all of the myriad conditions listed on their site.  They are kind enough to have Ira Packman, M.D. provide an explanation for doctors derived from that of Buteyko himself that can be found here.  (Buteyko’s is here.)

The explanation can be distilled down to this:

-When people hyperventilate, their arterial CO2 drops, making their blood alkaline.

-An alkaline pH increases hemoglobin’s affinity for oxygen.

-If hemoglobin holds onto oxygen more tightly, it won’t release as much to tissues.

-Less oxygen released by hemoglobin will cause hypoxic damage to tissues.

-Kidneys will try to correct the alkalosis by eliminating bicarbonate.

-Along with bicarbonate loss phosphorus and magnesium will be lost.

-Hypophosphatemia will compromise the creation of ATP.

-A lack of ATP will impair the function of afflicted tissues.

-A low level of CO2 can cause vasospasm and further reduce the blood supply to tissues.

Ignore the gross oversimplifications and important omissions in the explanation for the moment and take it at face value.  These are all testable hypotheses.  If Buteyko is correct, and chronic hyperventilation is the cause of all (or any) of the diseases listed on their site, then one would expect to see a high pH, low CO2, low bicarbonate, low phosphorus, low magnesium, and signs of anaerobic metabolism such as a low mixed venous O2 saturation or elevated serum lactate level.

These are extremely common labs that physicians (especially ICU physicians such as myself) are intimately familiar with.  According to Buteyko, this lab pattern should be a nearly universal feature of all disorders cured by BBT.  Guess how many actually routinely display anything remotely resembling it.

None.

This hypothesis also predicts that an asthmatic who begins to retain CO2 should have both their symptoms and pathophysiology improve.  In truth, elevation of CO2 in a symptomatic asthmatic is one of the more ominous signs in critical care medicine, and is the harbinger of respiratory failure and death.

What about the omissions and inaccuracies? First, the mechanisms Buteyko and Packman discuss to maintain blood pH are highly efficient, and are capable of correcting dramatic derangements in pH over the span of hours to days.  This is superbly demonstrated by chronic hypoventilation, where for a variety of reasons people retain carbon dioxide and yet have a normal pH.  With a normal pH the Bohr effect is neutralized.

Second, even if the Bohr effect remained in play, it is a minor determinant of oxygen delivery, easily compensated for by numerous other mechanisms, and insufficient to independently cause hypoxic injury or dysfunction.

Third, Packman says there is an “over excretion of bicarbonate.”  Even within his flawed concept of physiology, loss of bicarbonate would be an appropriate response to balance the blood’s pH, and the kidney will not overcompensate, therefore the term “over excretion” is inappropriate and implies a nonexistent pathology.

Fourth, the electrolyte interactions described by Packman are very confused.  The electrolytes most closely tied to the kidney’s bicarbonate management are sodium and chloride, not magnesium and phosphate.  Phosphorus does play a smaller role in the buffering capacity of the kidney, but contrary to Packman’s claim that a state of alkalosis will result in loss of phosphate, it is in fact when excessive hydrogen ions are secreted during a state of acidosis that phosphate is lost in the form of H₂PO₄^-.  It is true that hypophosphatemia can induce loss of bicarbonate through the actions of parathyroid hormone, but the inverse, that loss of bicarbonate induces phosphate loss, is not true.

Finally, though extreme hypophosphatemia can indeed compromise the body’s ability to create ATP, the resulting energy failure will cause a metabolic crisis which will not only be clinically and biochemically apparent, but which will cause the exact opposite pH-based effects upon which Buteyko’s hypothesis depends.

Now the lack of physiologic plausibility does not in and of itself mean that Buteyko method is ineffective.  What it does mean is that the physiologic explanation for its mechanism is likely dramatically wrong, and that the primary proponents of the technique have not only failed to recognize this fact, but have ignored elementary flaws in their hypothesis apparent in both theory and practice.

Buteyko Breathing Therapy and the Literature – Not Burdened by an Overabundance of Evidence

Buteyko and his devotees have made some remarkable claims while providing almost no evidence; an unrestricted Pubmed search of “Buteyko” yields a grand total of 21 hits.  But 21 is (slightly) more than zero, so let’s look at the published literature.  Virtually all of these 21 Pubmed hits discuss the use of BBT for asthma, as was indicated in the NYT article that triggered this post.  There are no published studies evaluating BBT for any of the other 149 diseases Buteyko claimed to cure.

The following are the sum total of published clinical trials regarding BBT’s use without regard to quality, design, size, bias, or result:

1) Buteyko breathing techniques in asthma: a blinded randomized controlled trial. Bowler SD et al. Med J Aust 1998:  39 subjects. Significant reduction in use of both chronic and rescue inhalers, but no change in lung function tests (PEF or FEV1) or end tidal CO2.

2) Effect of two breathing exercises (Buteyko and pranayama) in asthma: a randomized controlled trial. Cooper S. et al. Thorax 2003. 90 subjects enrolled, 69 completed the study.  Improved symptoms and reduced bronchodilator use with BBT, but no change in lung function tests (FEV1), number of exacerbations or amount of steroids used.

3) Buteyko Breathing Technique for asthma: an effective intervention. McHugh P et al. N Z Med J. 2003. McHugh: 38 subjects. 50% reduction in steroids and 85% reduction in rescue inhaler use at 6 months in BBT compared to no change in steroid use and 37% reduction in rescue inhalers in the control group, but no change in pulmonary function tests (FEV1).

4) A clinical trial of the Buteyko Breathing Technique in asthma as taught by a video. Opat AJ et al. J Asthma 2000. Opat: 36 subjects.  Participants viewed a video of BBT or a placebo video twice daily for 4 weeks.  Modest improvement in quality of life and a reduction in bronchodilator use, but no improvement in pulmonary function tests.

5) A randomized controlled trial of the Buteyko technique as an adjunct to conventional management of asthma. Cowie RL et al. Respir Med. 2008.  129 subjects.  Significant reduction in the amount of steroid used in BBT group, but no difference in asthma control between the two groups.

6) Effect of mouth taping at night on asthma control – a randomized single-blind crossover study. Cooper S. Respir Med. 2009.  51 subjects.  No difference in pulmonary function tests or symptom scores resulted from forced nasal breathing overnight.

7) Investigating the claims of Konstantin Buteyko, M.D., Ph.D.: the relationship of breath holding time to end tidal CO2 and other proposed measures of dysfunctional breathing. Courtney R et al. J Altern Complement Med. 2008.  83 subjects.  Breath Holding Time as defined by Buteyko was found to have the exact opposite correlation with alveolar CO2 that his theories predicted it would have.

8 ) The effects of carbon dioxide on exercise-induced asthma: an unlikely explanation for the effects of Buteyko breathing training. Al-Delaimy WK et al. Med J Aust. 2001. 10 subjects.  Patients were supplemented with CO2 to test Buteyko’s hypothesis that a higher CO2 would result in a reduction in asthma symptoms. Breathing 3% CO2 did not prevent exercise-induced asthma.

Notably absent from this list is the British study containing 384 patients touted and linked to in the NYT article.  As it turns out, that was not a peer-reviewed study, but instead only an abstract at the 2003 British Thoracic Society Winter Meeting.  In spite of its remarkable results, it has not in the following 6 years been published in a peer-reviewed journal.  It is, for all intents and purposes, a non-study.

The three studies designed to test Buteyko’s proposed mechanisms of action (6, 7, and 8 ) do not support Buteyko’s theories, and are in keeping with my earlier analysis of its plausibility.

The five studies comparing BBT to a control for treatment of asthma (1-5) show a variable though reasonably consistent reduction in both rescue and maintenance drug use.  Even more consistent however is the utter lack of any change in the participant’s pulmonary function tests.

Given the most charitable interpretation and taken at face value, these studies imply that BBT can alter a patient’s perception of their symptoms, and perhaps prevent overuse of asthma medications.  However, they also provide evidence that BBT does very little to alter the underlying pathophysiology of asthma, and absolutely no evidence to support Buteyko’s claim that BBT can cure asthma.

Buteyko Breathing Therapy and Asthma – A Broken Clock is Still Right Two Seconds Per Day

Taken as a whole, this reading of the literature is in keeping with the British Thoracic Society’s Guidelines, which state:

The Buteyko breathing technique specifically focuses on control of hyperventilation and any ensuing hypocapnia. Four clinical trials suggest benefits in terms of reduced symptoms and bronchodilator usage but no effect on lung function.  Buteyko breathing technique may be considered to help patients to control the symptoms of asthma.  Grade B”

Though I think that the BTS authors were overly generous in ranking the four evaluated articles as 1+ level of evidence (meaning a well conducted meta-analysis, systematic review, or RCTs with a low risk of bias), their conclusions are not unreasonable within the framework of Evidence Based Medicine.

Of course, as I consider this small set of literature from the perspective of Science Based Medicine, I’m reminded of John Ioannidis’ essay “Why Most Published Research Findings Are False.”

…a research finding is less likely to be true when the studies conducted in a field are smaller; when effect sizes are smaller; when there is a greater number and lesser preselection of tested relationships; where there is greater flexibility in designs, definitions, outcomes, and analytical modes; when there is greater financial and other interest and prejudice; and when more teams are involved in a scientific field in chase of statistical significance.”

These studies can be found wanting on nearly every point outlined by Ioannidis. Already weak when viewed through the lens of Evidence Based Medicine, through that of Science Based Medicine the Buteyko literature looses much of its remaining impact.

SUMMARY

Buteyko reminds me in many ways of D.D. Palmer.  Starting from an erroneous observation, using flawed logic, lacking prior plausibility, forsaking scientific validation, and promoting their techniques as virtual panaceas, they each nevertheless may have found small medical niches where their techniques may have some limited utility.  Palmer’s niche appears to be treatment of low-back pain, and for Buteyko, it may be the symptomatic relief of mild asthma symptoms.

If however, you are looking for the Buteyko Breathing Technique to cure your asthma, I wouldn’t hold my breath.

As 2009 comes to an end, it seems that everyone is creating year-in-review lists. I thought I’d jump on the list band wagon and offer my purely subjective top 5 threats to rational thought in healthcare and medicine.

Of course, it strikes me as rather ironic that we’re having this discussion – who knew that medicine could be divorced from science in the first place? I thought the two went hand-in-hand, like a nice antigen and its receptor… and yet, here we are, on the verge of tremendous technological breakthroughs (thanks to advances in our understanding of molecular genetics, immunology, and biochemistry, etc.), faced with a growing number of people who prefer to resort to placebo-based remedies (such as heavy-metal laced herbs or vigorously shaken water) and Christian Science Prayer.

And so, without further ado, here’s my list of the top 5 threats to science in medicine for 2009 and beyond:

#1: Congress

Money is the most powerful gasoline that can be poured on the fire of pseudoscience. And thanks to Senator Tom Harkin, and a few merry enablers, there is now legislation in the Senate healthcare reform bill that would allocate tax dollars to disproven and unproven medical therapies. Healthcare providers recognized by CMS will include alternative medicine practitioners – many of whom can meet licensing requirements with online degrees from schools that do not teach actual science. They will be eligible to become primary care providers, use “doctor” in their self-designation, and do untold harm to patients nationwide through misdiagnosis and mistreatment.

Please refer to this post for detailed amendment language, and for goodness sake – call your congressman or woman and ask them to move to strike this language from the reconciled house and senate bills before it becomes law. Seriously. Go call them NOW.

#2:  Mainstream Media

For some reason, snake oil has captured the imagination of the mainstream media. Thanks to people like Oprah and the major news networks, there is a steady parade of pseudoscientific poppy cock being spoon fed to the public. And because of the lack of critical thinking taught in schools, Americans (on average) have a 6th grade understanding of medicine. They have a hard time distinguishing science from pseudoscience, and with the constant barrage of miracle cures, “scientific” breakthroughs, and conspiracy theories about anything that actually works (e.g. vaccines). They have become skeptical of science while often totally accepting of snake oil.

Before we become completely despairing of any sliver of health enlightenment reaching the public through mainstream media – let’s recall that 2009 brought us a handful of journalists willing to stand up for truth and critical thinking.Newsweek’s Weston Kosova, the Associated Press’ Marilynn Marchione, Wired’s Amy Wallace, Chicago Tribune’s Trine Tsouderos, and The Washington Post’s Clive Thompson deserve praise and encouragement for standing up for science.

#3: Academic Medical Centers

Often referred to by David Gorski as “Quackademic” Medical Centers – there is a growing trend among these centers to accept endowments for “integrative” approaches to medical care. Because of the economic realities of decreasing healthcare reimbursements – these once proud defenders of science are now accepting money to “study” implausible and often disproven medical treatments because they’re trendy. Scientists at these centers are forced to look the other way while patients (who trust the center’s reputation that took tens of decades to build) are exposed to placebo medicine under the guise of “holistic” healthcare.

I believe that patients are crying out for compassionate care – for more time with their providers, more dignity in their choices, and more participation in their care. In my opinion, these needs can and should be met by science-based professionals who offer patients the truth about the strengths and limitations of their options – there is no need to fill this emotional need with false cures and placebo treatments, and spin it as if the patient is getting better “integrated” care. Quackademic medicine is neither compassionate nor scientifically honest. It’s just a complex new way of providing placebo care to patients who need some common human kindness.

#4: NCCAM

Even though we’ve invested $2.5 billion tax payer dollars and 10+ years of time on studying complementary and alternative medicines – we have discovered NO single breakthrough in medical treatment as a result. Not only does this Institute appear to be a real waste of scarce resources, but In fact, the TACT trial (in particular) offers a stark example of the unethical practices that can arise when vigorous scientific standards are not met. Thanks to Dr. Atwood’s diligent review, we have a clear understanding of the shenanigans at play:

The NIH approved a research study (called the TACT Trial – Trial to Assess Chelation Therapy – a supposed treatment for arteriosclerosis) in which the treatment had no evidence for potential benefit, and clear evidence of potential harm – and even the risk of death. Amazingly, the researchers neglected to mention this risk in their informed consent document. The NIH awarded $30 million of our tax dollars to ~100 researchers to enroll 2000 patients in this risky study (ongoing from 2003-present). Even more astounding is the fact that several of the researchers have been disciplined for substandard practices by state medical boards; several have been involved in insurance fraud; at least 3 are convicted felons.

Many have called for defunding the NCCAM, and that certainly seems like a reasonable request under the circumstances of such a low ROI and ethical breaches.

#5: New Media

Just as mainstream media is beginning to fade in its influence and popularity, online and “new” media are making exponential leaps in influence.  The Huffington Post and Age Of Autism are two strongholds of health misinformation that come to mind. Of course, “user generated content” and unvetted health advice and claims are easily made by anyone anytime. And thanks to the magic of Google, a health claim need only be popular to be promoted. Truth, accuracy, and scientific rigor aren’t always rewarded in this brave new world of digital influence. Being right has been uncoupled from being influential. The “wisdom of crowds” now decides what people see first when they attempt to educate themselves about health matters.

And so, dear readers of Science-Based Medicine, we face formidable foes in our quest for honesty and integrity in medicine. I predict that the next decade will favor the organized, not the accurate. And so with that in mind, let us strive towards building our network of critical thinkers (in the government, media, research and clinical centers, and online), organizing our efforts to promote science and rational thought. We’ll each need to channel our inner “community organizer” to counter the pseudoscience movement. And we can win this, because in the end…

Science works.

They say that everything old is new again and that is certainly true in the world of “alternative” health. One of the axiomatic premises of contemporary “alternative” health puts its believers behind the times … by approximately 500 years.

A fundamental premise held by believers in “alternative” health is that we are swimming in a world of “toxins” and those “toxins” are causing disease. Like most premises in “alternative” health it has no basis in scientific fact; makes intuitive sense only if you are ignorant of medicine, science and statistics; and speaks to primitive fears and impulses.

The preoccupation with “toxins” is a direct lineal descendant of the obsession with evil humours and miasmas as causes of disease. It is hardly surprising that prior to the invention of the microscope the real causes of disease went undiscovered. The idea that disease is caused by tiny organisms that invade the body is not amenable to discovery in the absence of scientific instruments and scientific reasoning. And it goes without saying that the same people who were unaware that bacteria and viruses cause disease could not possibly imagine chromosomal defects, inborn errors of metabolism or genetic predispositions to disease.

Instead, people imagined that diseases were caused by excess evil humours, substances that were named, but never seen or identified in any way accessible to the senses. It was recognized that some diseases were contagious, and in that case, people invoked the idea of “miasmas” that somehow transmitted disease.

Even religion got into the act. Rather than attributing disease to evil humors of miasmas, religious authorities often claimed that disease was attributable to evil demons or to sin itself.

These theories shared several important features. The evil humours, miasmas, etc. were invisible, but all around us. They constantly threatened people, and those people had no way of fending off the threat. Indeed, they were often completely unaware of the threat that was actively harming them.

Evil humours, miasmas, demons, etc. were put to rest by the germ theory of disease. That was the first big breakthrough in our understanding that each disease was separate and has its own specific cause. The search for causes has taken us beyond bacteria and viruses, through errors of metabolism and chromosomal aberrations, right down to the level of the gene itself. We now understand that tiny defects in individual genes can cause disease or can increase the propensity to a specific disease.

But fear and superstition never die and the “alternative” health community has used that fear and superstition to resurrect primitive beliefs. It is axiomatic in the “alternative” health community that disease is caused by evil humours and miasmas. They just don’t call it that anymore; they call it “toxins.”

Toxins serve the same explanatory purpose as evil humours and miasmas. They are invisible, but all around us. They constantly threaten people, often people who unaware of their very existence. They are no longer viewed as evil in themselves, but it is axiomatic that they have be released into our environment by “evil” corporations.

There’s just one problem. “Toxins” are a figment of the imagination, in the exact same way that evil humours and miasmas were figments of the imagination.

Poisons exist, of course, but their existence is hardly a secret, and their actions are well known. Most poisons are naturally based, derived from plants or animals. Indeed, the chemicals responsible for more diseases than any others are nicotine (tobacco), alcohol (yeast) and opiates (poppies).

Nonetheless, “alternative” health advocates persist in subscribing to primitive theories of disease. For those who have limited understanding of science, primitive theories apparently make more sense.

Hence the obsession with “toxins” in foods, in vaccines, even “toxins” arising in the body itself. The height of inanity is the belief in “detoxifying” diets and colon cleansing. The human body does not produce “toxins.” That’s just a superstition of the “alternative” health community. The waste products produced by the human body are easily metabolized by organs such as the liver, and excreted by organs particularly designed for that purpose such as the kidneys.

“Alternative” health practitioners are nothing more than quacks and charlatans and their “remedies” are nothing more than snake oil. The fact that anyone in this day and age still believes in such crackpot theories is a tribute to the power of ignorance and superstition.

Evil humours and miasmas have not died, they’ve been reincarnated as “toxins.”

Peter Lipson reported Monday about new research suggesting that Multiple Sclerosis may be caused by venous blockage. He correctly characterized some of the hype surrounding this story as “irrational exuberance.”

This is a phenomenon all too common in the media – taking the preliminary research of an individual or group (always presented as a maverick) and declaring it a “stunning breakthrough,” combined with the ubiquitous personal anecdote of someone “saved” by the new treatment.

The medical community, meanwhile, responds with appropriate caution and healthy skepticism. Looks interesting – let’s see some more research. There is a reason for such a response from experts – experience.

We have been here before – lithium for ALS

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that results in the death of motor neurons, leading to weakness and ultimately paralysis or death. There is currently only one proven treatment for ALS, a drug called riluzole, and its effects are modest – prolonging tracheostomy-free survival by 2 months on average. So new treatments are welcome, to say the least, and there is ongoing research looking for possible treatments.

In February of 2008 I wrote about a preliminary study by Italian researcher, Fornai, in 44 patients with ALS, showing a dramatic improvement in outcome. This research followed a mouse study that also showed significant improvement.

Press reporting about this “breakthrough” research resulted in patients with ALS and their families contacting me and other neurologists asking how they could get treated.

Meanwhile, the reaction of the ALS research community was cautious but hopeful. It was felt that this preliminary research deserved further study, but was not enough to conclude that lithium was effective or to start treating patients with it.

The North East ALS Consortium (of which I am a member, although I did not participate in this study), based upon Fornai’s research, performed a randomized controlled multi-center trial of lithium in ALS. The results were dead negative – so negative that the trial was stopped early due to futility.

Here we have animal studies and preliminary human trials showing a dramatic improvement, and a follow-up larger and better controlled study showing zero effect. How do we reconcile these results?

Simple – preliminary data is unreliable, by definition. Most new ideas in medicine do not pan out. And as a result (and as John Ioannidis has taught us) most published studies are wrong. What is reliable are later, larger, more definitive trials, and specifically a consensus of results in the peer-reviewed literature after a question has had time to simmer and mature.

Zamboni and CCSVI

It should therefore be no surprise at all that the medical community is once again taking a cautious approach to preliminary research published by a single researcher claiming dramatic results from a revolutionary new idea. As Peter discussed, Dr. Zamboni, a neurosurgeon, believes he has found a cause and a cure for multiple sclerosis (MS) – a neurosurgical one.

Just like with lithium and ALS, his idea is an interesting one, and his preliminary data deserved to be taken seriously – which means replicating his research and doing follow up studies. He claims that patients with MS – 100% of the MS patients he has studied, but none of the controls – have blockages in the veins that drain blood from the brain. These blockages lead to blood backing up in the brain, which causes iron deposits, which results in inflammation and MS.

At this point there are many possibilities. It’s possible Dr. Zamboni is the victim of confirmation bias (I am always suspicious of 100% results) and his new condition – chronic cerebrospinal venous insufficiency or CCSVI is an illusion.

It is possible he has found a real pathological marker for MS but what he is seeing is the result of MS, not the cause of it. Inflammation is known to follow the venous system in MS, but there are explanations for this that have to do with the immune system in the central nervous system. Perhaps chronic inflammation from MS causes sclerosis in the veins and the blockage that Dr. Zamboni is finding.

If this is true then it is possible that the venous sclerosis is playing no or only a minimal role in MS pathology, and fixing them by opening them up with baloon angioplasty is of no benefit. It is also possible that even though the venous changes are cause by auto-immunity in MS, once they form they worsen the clinical syndrome, and treating CCSVI in MS will improve outcome, even if it does not cure the underlying cause driving the disease.

And it is possible that Dr. Zamboni has discovered the or an underlying cause of MS – that CCSVI is actually the primary driver of the disease. Or perhaps it just triggers the auto-immune response, but once triggered it is self-sustaining.

This is a huge range of possibilities, and it is definitely premature to come to the most extreme conclusion among them. We need time for the MS community to pick over Zamboni’s claims and research. While we do not know what ultimately causes MS, we have decades of high quality research characterizing its pathophysiology. How does this research square with Zamboni’s claims? Let’s wait and see.

Zamboni’s basic claims need to be replicated. And if warranted, clinical studies need to fully characterize the risks and benefits of any procedure to address alleged CCSVI. Perhaps it only has benefit is a sub-population of MS. Maybe it makes the disease worse. We won’t know until quality studies are done.

I am not holding my breath, just as I wasn’t with lithium for ALS, but I will certainly follow the research. I would love for Zamboni to be correct – if we can essentially cure MS with a one-time procedure that would be a huge boon to MS patients and save billions.

Help – the media is not being irresponsible!

The most absurd reaction to Zamboni’s research came from the Huffington Post. As Peter reported, Erika Milva wrote a rambling piece suggesting that the cautious responses of American media, MS societies, and the medical community were due to being risk-averse and the omnipresent (in the fantasies of many) Big Pharma conspiracy.

Milva could not understand why the media was not irresponsibly jumping over this story and hyping it, as some of the foreign press has. So I guess she decided to make up for this with maximal hysteria of her own.

But there is no mystery here. Zamboni’s claims are radical, and therefore by definition improbable. But more importantly, they are preliminary. That doesn’t mean they are wrong – it just means we do not yet know. Let’s wait for some quality research.

And that is one of the primary differences between science-based medicine and everything else – basing treatments on evidence, witholding judgment until reliable evidence is in, and not overreacting to every pilot study that pops up.

I will let you know in a couple of years how Zamboni’s claims have turned out.

Warning: If you are offended by humor that depends on psychiatric and medical diagnoses, read no further.

Disclaimer: Before anyone complains (and in this age of exaggerated political correctness, someone surely will), let me make it clear that I mean no disrespect to people suffering from the illnesses mentioned below. I have the greatest empathy for sick people, and I have encountered several of these conditions in my own family and have actually experienced four of them myself. Humor about them doesn’t offend me, and I hope it will not offend you. Also, my mention of Christmas and Hanukkah songs is not intended to endorse any religious belief.

=================

After a year of serious talk about mostly discouraging things, I thought it was time for a totally frivolous post to cheer us up with a little holiday humor. A friend sent me a list of “Christmas Carols for the Psych Ward.” I thought they were funny, and I’ve copied the best of them below. I’ve added a few of my own for other medical diagnoses, and then I added several about complementary and alternative medicine.

Christmas Carols for the Psych Ward

SCHIZOPHRENIA: Do You Hear What I Hear?

MULTIPLE PERSONALITY DISORDER: We Three Kings Disoriented Are

AMNESIA: I Don’t Know if I’ll be Home for Christmas

NARCISSISTIC: Hark the Herald Angels Sing About Me

MANIC: Deck the Halls and Walls and House and Lawn and Streets and Stores and Office and Town and Cars and Buses and Trucks and Trees and Fire Hydrants and….

PARANOID: Santa Claus is Coming to Get Me

OBSESSIVE COMPULSIVE DISORDER: Jingle Bells, Jingle Bells, Jingle Bells, Jingle Bells, Jingle Bells, Jingle Bells, Jingle Bells, Jingle Bells, Jingle Bells…

AUTISTIC: Jingle Bell Rock and Rock and Rock and Rock …

SENILE DEMENTIA: Walking in a Winter Wonderland Miles From My House In My Slippers and Robe

Christmas Carols for Other Medical Conditions

Argyria: Silver Balls

Mumps: The Chipmunk Song

Depression: Blue Christmas.

Rosacea: Rudolph the Red-Nosed Rhinophyma patient

Hypothyroidism: Baby It’s Cold Outside (and Inside too)

Obesity: We want some figgy pudding. (from We Wish You a Merry Christmas)

Scotomas (defects in visual field): O Holey Night

Edentulous: All I Want for Christmas Is My Two Front Teeth (along with the rest of them).

Alcoholic: Here We Come A-Wassailing

Deaf: Silent Night

Tinnitus: Jingle Bells

Narcolepsy: Shepherds! Shake Off Your Drowsy Sleep

Christmas Carols for Complementary and Alternative Medicine

Chiropractors: Grandma Got Run Over by a Reindeer (and we can fix the resulting subluxations).

Acupuncture: The Twelve Acupoints of Christmas

Homeopathy: Kissin’ By The Mistletoe [Viscum album, one drop of mistletoe extract diluted to 30C and deposited on a sugar pill. Shaken, not stirred.].

Customer for penis enlargement products: I Have a Little Dreidel

Probiotics: The Friendly Beasts

Colon cleansing: Come, All Ye Feces-full

Herbalists: “Greens/Leaves”

Faith healers: Rise Up (out of your wheelchairs) Shepherds and Follow

TCM practitioners: From East to West

CAM believers responding to SBM: You’re a Mean One, Mr. Grinch

=======

Playing with song titles can be great fun. Think up some of your own and post them in the comments section. It makes a great holiday pastime or party game.

Best Wishes for Whatever You Celebrate: Merry Christmas, Hanukkah, Newton’s Birthday and Winter Solstice to All!

Multiple sclerosis (MS) is fascinating illness that can range from mild annoyance to debilitating nightmare. The frightening nature and unclear cause of the disease makes it a magnet for questionable medical therapies (i.e. quackery). A piece published last week in (surprise!) the Huffington Post helps fuel the fires of suspicion and paranoia while failing to shed any light on the future of MS research.

Multiple sclerosis is a disease of the nervous system. Its victims develop symptoms based on what part of the nervous system is affected. For example, if MS attacks the optic nerve, a patient may experience blurry vision or blindness. If it affects the motor areas of the brain that controls the left leg, the patient will develop weakness in the left leg. Typically, the symptoms will last a certain period of time and then improve, but often not completely back to normal.

The exact initial cause of the disease isn’t known, but we do have a good understanding of of how the disease works. In MS, the immune system attacks the sheath surrounding certain types of nerve cells. This leads to “plaques” in nervous tissue such as the brain, and these plaques correspond to the symptoms of MS. The disease appears to result from a combination of a genetic predisposition and some sort of environmental insult, such as a viral infection. Many people have T-cells in their immune system that recognize myelin, the substance attacked in MS, but in MS these T-cells are more capable of attacking myelin. In order to do this effectively they must breach the “blood-brain barrier”, a system that keeps the circulation in the brain protected from toxins, infections, and the immune system. In MS, this barrier is breached, perhaps by infection, allowing T-cells into the brain to coordinate an attack on the nerve cells. Based on our still-incomplete knowledge of the disease, we have developed some pretty-effective treatments over the last decade or so. These treatments are based on drugs that affect the immune system. All of these drugs have significant side-effects and none is completely effective.  There are probably many different “kinds” of MS based on different genetics and different environmental triggers, so we have a long way to go in understanding the disease and developing treatments.Given the fear and debility associated with the disease, and our still-incomplete knowledge, it’s natural for people to look for (and see) patterns where none exist. Diseases like MS attract quackery (such as bee-sting therapy) and conspiracy theories, such as the one in the Huffington Post

It started with an article in the Globe and Mail, Canada’s national newspaper.  This article detailed some new MS researcher by an Italian doctor named (I kid you not) Zamboni.  Dr. Zamboni hypothesizes that MS may be at least partly due to a problem with venous blood flow in the brain, and that a surgical procedure can correct this blood flow and improve MS symptoms.  He has done some small studies to evaluate these claims.  These studies have not yet been replicated by other researchers, and it isn’t clear (at least to me) how plausible his hypothesis is.  Still, it is interesting, and the Globe and Mail article was fairly well-written, providing a counter-balance to Zamboni’s exuberance:

“I am confident that this could be a revolution for the research and diagnosis of multiple sclerosis,” Dr. Zamboni said in an interview.

Not everyone is so bullish: Skeptics warn the evidence is too scant and speculative to start rewriting medical textbooks. Even those intrigued by the theory caution that MS sufferers should not rush off to get the surgery – nicknamed the “liberation procedure” – until more research is done.

The National MS Society (US) is also taking a cautious approach and is facilitating further research into this new theory.

“Cautious” is not a word that ever applies to medical reporting in the Huffington Post. Erika Milva vilifies the American press and the MS society blaming entrenched interests for failing to jump on Zamboni’s ideas.

References

Frohman EM, Racke MK, & Raine CS (2006). Multiple sclerosis–the plaque and its pathogenesis. The New England journal of medicine, 354 (9), 942-55 PMID: 16510748

Zamboni, P., Galeotti, R., Menegatti, E., Malagoni, A., Tacconi, G., Dall’Ara, S., Bartolomei, I., & Salvi, F. (2008). Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis Journal of Neurology, Neurosurgery & Psychiatry, 80 (4), 392-399 DOI: 10.1136/jnnp.2008.157164

Zamboni, P., Galeotti, R., Menegatti, E., Malagoni, A., Gianesini, S., Bartolomei, I., Mascoli, F., & Salvi, F. (2009). A prospective open-label study of endovascular treatment of chronic cerebrospinal venous insufficiency Journal of Vascular Surgery, 50 (6), 1348-1358000 DOI: 10.1016/j.jvs.2009.07.096

Science-based medicine consists of a balancing of risks and benefits for various interventions. This is sometimes a difficult topic for the lay public to understand, and sometimes physicians even forget it. My anecdotal experience suggests that probably surgeons are usually more aware of this basic fact because our interventions generally involve taking sharp objects to people’s bodies and using steel to remove or rearrange parts of people’s anatomy for (hopefully) therapeutic effect. Ditto oncologists, who prescribe highly toxic substances to treat cancer, the idea being that these substances are more toxic to the cancer than they are to the patient. Often they are only marginally more toxic to the cancer than to the patient. However, if there’s one area where even physicians tend to forget that there is potential risk involved, it’s the area of diagnostic tests, in particular radiological diagnostic tests, such as X-rays, fluoroscopy, computed tomography (CT) scans, and the variety of ever more powerful diagnostic studies that have proliferated over since CT scans first entered medical practice in the 1970s. Since then, the crude images that the first CT scans produced have evolved, thanks to technology and ever greater computing power, to breathtaking three dimensional-views of the internal organs. Indeed, just since I finished medical school back in the late 1980s, I’m continually amazed at what these new imaging modalities can accomplish.

The downside of these imaging modalities is that most of them require the use of X-rays to produce their images. True, over the last 15 years or so MRI, which uses very strong magnetic fields and radiofrequency radiation rather than ionizing radiation to produce its images, has become increasingly prevalent. MRI is great because it produces more contrast between different kinds of soft tissue than CT scans do. However, CT tends to be superior for examining calcified organs, such as bone. (The breast surgeon in me notes that breast MRI is pretty much useless for detecting microcalcifications, an important possible indicator for cancer.) Also, MRI scans require a prolonged period of laying still in a very tight tube, which is a problem for patients with any degree of claustrophobia, although “open” MRIs are becoming increasingly available. More importantly for the quality of images, because they require a patient to lie more still than a CT, MRIs tend to be prone to more motion artifacts, which is perhaps why CT is more frequently used to image the abdomen other than large solid organs such as the liver. The point is that, although MRI is becoming more prevalent, CT scans aren’t going away any time soon. They have different strengths and weaknesses as imaging modalities and are therefore best suited for different, albeit overlapping, sets of indications.

Even so, it’s pretty amazing to consider how much these imaging modalities have changed medical practice in the last three decades. Before CT, surgeons often did exploratory surgery to diagnose a problem, often not knowing what they would find. They had to be ready for almost anything, and there were frequent surprises. (Some older surgeons lament that this has taken some of the excitement out of surgery, but there’s little doubt it’s better for the patients.) Another area where surgery used to be done routinely was in the staging of Hodgkin’s lymphoma. Patients underwent staging laparotomy, where the surgeon in essence carefully explored the abdomen, removed the spleen, and took biopsies of multiple areas in order to define precisely the extent of intraabdominal disease. Based on the results, the stage would be determined and therapy chosen. However, over the last 25 years or so, fewer and fewer of these have been done, thanks to better CT imaging and evolving practice in which more and more Hodgkin’s lymphoma patients receive chemotherapy. Indeed, during my residency I can only recall doing one or two staging laparotomies.

While CT imaging has revolutionized surgery and medicine, it is not entirely benign. Often, it requires the injection of intravenous contrast agents that can damage the kidneys and cause allergic reactions, occasionally life-threatening. Pretty much every physician is aware of these risks. Less acknowledged is the risk from the ionizing radiation from such tests, and physicians tend to downplay the risks from radiation. One exception is pediatrics, because it’s long been known that children are more sensitive to the effects of radiation than adults are, and they have much more time left in their lives for potential radiation-induced cancers to make themselves known. That is why pediatricians tend to be more judicious about the use of CT scans. In any case, by and large, CT scans require far more radiation than other imaging modalities. This concern was again brought to the fore last week by two studies recently published in the Archives of Internal Medicine, along with an accompanying editorial^1,2,3. Together, these studies suggest that far more radiation is used in some CTs than is necessary and that there may be far more radiation-induced cancers due to medical tests than we would like to acknowledge. Taken together with another review article in the New England Journal of Medicine from a couple of years ago, they should make us as physicians think more carefully about how we use diagnostic imaging studies.

The NEJM review⁴ is useful because it gives the background in terms of typical doses of radiation for various imaging studies:

And for the huge increase in the number of CT scans being done in the U.S. every year:

That’s over 60 million CT scans performed in the U.S. in 2006. More recent data shows that 70 million scans were performed in 2007². and, for example, a typical CT scan of the chest results in an absorbed radiation dose 100-fold higher than a typical two-view PA and lateral chest X-ray. Moreover, as Smith-Bindman et al² point out:

Exposure to ionizing radiation is of concern because evidence has linked exposure to low-level ionizing radiation at doses used in medical imaging to the development of cancer. The National Academy of Sciences’ National Research Council comprehensively reviewed biological and epidemiological data related to health risks from exposure to ionizing radiation, recently published as the Biological Effects of Ionizing Radiation (BEIR) VII Phase 2 report.⁷ The epidemiologic data described atomic bomb survivors, populations who lived near nuclear facilities during accidental releases of radioactive materials such as Chernobyl, workers with occupational exposures, and populations who received exposures from diagnostic and therapeutic medical studies. Radiation doses associated with commonly used CT examinations resemble doses received by individuals in whom an increased risk of cancer was documented. For example, an increased risk of cancer has been identified among long-term survivors of the Hiroshima and Nagasaki atomic bombs, who received exposures of 10 to 100 milli-sieverts (mSv).^8-11 A single CT scan can deliver an equivalent radiation exposure,¹² and patients may receive multiple CT scans over time.¹³

They then observe that few studies have tried to quantify rigorously the typical real-world doses of radiation received in hospitals due to CT scanning. Most studies, other than for CT coronary angiography, have used phantoms rather than patients. So Smith-Bindman et al² looked at imaging studies in four San Francisco-area hospitals, one of which was at UCSF, and used a method called the “effective dose” to quantify radiation exposure in consecutive studies. What was most shocking is what they found regarding the variability in radiation exposures both within and between institutions even for the same test. Indeed, they noted a mean 13-fold variation between the highest and lowest radiation dose for each study type:

This particular plot type, known as box-and-whiskers, shows the 25^th to 75^th percentile range in the boxes, while the bars show the range between the highest and lowest values, with the median value being represented by the dots. The investigators then estimated the increased excess risk of cancer for these radiation doses and concluded:

Among 40-year-old women, 1 cancer would occur among 8105 patients who underwent a routine head CT scan (IQR, 1 in 6110 to 1 in 9500). For a 60-year-old woman, the risks were substantially lower and varied from approximately 1 in 420 examinations for CT coronary angiography (IQR, 1 in 370 to 1 in 640) to 1 in 12 250 examinations for a routine head CT scan (IQR, 1 in 9230 to 1 in 14 360). For a 20-year-old woman, the risks were substantially higher and varied from approximately 1 in 150 examinations for CT coronary angiography (IQR, 1 in 130 to 1 in 230) to 1 in 4360 examinations for a routine head CT scan (IQR, 1 in 3290 to 1 in 5110).

These are not insignificant risks. It should be noted, however, that this study has several weaknesses. The biggest weakness is that the cohort studied (1,119 patients) was not large enough to identify possible reasons why the dose of radiation varied so much for even the same tests, including experience of the technologist, physician availability to check the studies and determine the need for additional imaging, geographic variation, imaging algorithms available or used, and patient factors (such as weight). The authors point out that far more standardization is required and that studies are needed to figure out why there may be such variation in radiation dose.

The second study drives home the point that radiation from CT scans can increase cancer risk by using different methodology. Berrington et al¹ started with risk models based on National Research Council’s “Biological Effects of Ionizing Radiation” report and organ-specific radiation doses derived from a national survey were used to estimate age-specific cancer risks for each scan type and then combined these models with age- and sex-specific scan frequencies obtained from insurance claims data and surveys. Using a Monte Carlo simulation, they then estimated the number of excess cancers due to radiation from CT scanning. Their conclusions:

Overall, we estimated that approximately 29,000 (95% UL, 15 000-45 000) future cancers could be related to CT scans performed in the US in 2007. The largest contributions were from scans of the abdomen and pelvis (n = 14,000) (95% UL, 6,900-25,000), chest (n = 4100) (95% UL, 1,900-8,100), and head (n = 4000) (95% UL, 1,100-8,700), as well as from chest CT angiography (n = 2,700) (95% UL, 1,300-5,000). One-third of the projected cancers were due to scans performed at the ages of 35 to 54 years compared with 15% due to scans performed at ages younger than 18 years, and 66% were in females.

This graph tells the tale:

The black bars are for men; the white for women. Women tend to have a higher sensitivity to the effects of radiation in cancer production.

One thing that is very important is to put these figures in perspective. 29,000 is a huge number, but compared to the number of new cancer cases every year (estimated to be 1.5 million in 2009, down from earlier years). Indeed, Berrington et al¹ estimate that their study suggests that approximately 1% to 3% of cancers in any given year can be attributed to past CT use. Another thing that is very important is that these results are due to a simulation, which is very dependent on the values inputted and the assumptions made in constructing the simulation. The estimates of the number of CT scans. For example, for solid tumors the assumption was a five-year lag period and a linear dose-response model. I’m not sure how valid that assumption for lag time is, given that there are quite a few tumors with longer lag periods after radiation exposure. Still, overall, this study likely represents a fairly good estimate of how many additional cancers there are due to CT scanning, but it is just that, an estimate. It also does not provide any information to tell us which cancers were actually caused by radiation from a CT scan. Neither of these studies do; they’re both population-based and look at aggregate statistics. Even so, the possibility that as many as 3% of adult cancers might be due to radiation from medical imaging studies is a problem that should sober even the most gung ho advocate of using such studies, particularly considering that the risk tends to be higher in younger people.

All of this brings us back to what I started this post with: All of medicine is a balancing of risks versus benefits. One reason I was so disturbed by the proliferation of whole-body imaging studies being marketed by unscrupulous companies on a cash basis is because, in an asymptomatic patient, the risks from radiation from such studies on average probably outweigh any conceivable benefit, especially if we take the risks of false positives leading to invasive tests such as biopsies into account. Still, there is no doubt that CT scans are highly beneficial when it comes to diagnosing disease and, these days, to guiding physicians in doing less invasive needle biopsies for diagnosis where before a surgical biopsy might have been required. That leaves the question: What to do with these results?

One approach to reducing radiation exposure from medical imaging would be to be to try to standardize imaging studies more, so that the dose of radiation for each one varies less, and, even more importantly, to find ways to decrease the dose of radiation for each test without sacrificing image quality or diagnostic sensitivity or specificity. The authors of both studies agreed on these tactics. However, far more difficult will be tactics designed to change physician behavior.

Clearly, the first thing we as a profession should do is to make ourselves very aware that a CT scan (or any scan involving a significant radiation dose) is not an entirely benign thing. We sometimes do treat them that way, and this must stop. There are several strategies to reduce the risk from these imaging studies. One obvious one, of course, is to order fewer studies and to stop ordering them for questionable indications. Critical to this approach would be better data and studies that help us clearly define when such tests are appropriate and indicated; i.e., a more rigorous application of science-based medicine to medical imaging. Sadly, this is not as much the case now as it should be, as the author of the accompanying editorial³, Dr. Rita Redberg, points out:

In addition, it is certain that a significant number of CT scans are not appropriate. A recent Government Accountability Office report on medical imaging, for example, found an 8-fold variation between states on expenditures for in-office medical imaging; given the lack of data indicating that patients do better in states with more imaging and given the highly profitable nature of diagnostic imaging, the wide variation suggests that there may be significant overuse in parts of the country.⁴ For example, a pilot study found that only 66% of nuclear scans were appropriate using American College of Cardiology criteria—the remainder were inappropriate or uncertain.⁵

Indeed, medical imaging is highly profitable. Moreover, sometimes laziness rules. It is easier just to order a CT scan than to use more mundane methods of trying to figure out what’s wrong with a patient, and the current malpractice climate often leads to physicians practicing “defensive” medicine, part of which may involve, for example, ordering a CT scan for a patient with abdominal pain “just in case” even when it’s known that the diagnostic yield is likely to be very low. At the risk of getting myself in trouble, I’ll point out that patients, too, bear some of the blame, just as they do for the overuse of antibiotics that leads to resistant organisms. Some just won’t be reassured without an imaging study; although they might be if they were more carefully informed of the increased risk of cancer from medical imaging studies. In any case, all of these factors combine to drive the explosion in CT imaging, which has increased faster than evidence of its benefit.

Finally, it is critical to remember that, for individual patients, the risk of any single imaging study is pretty low, and the potential benefit, when the study is ordered appropriately according to science- and evidence-based guidelines, will almost certainly far outweigh the slightly increased risk of cancer. For example, if you’re in the emergency room with severe chest pain, the last thing you should be worrying about is the radiation you’ll receive from a cardiac catheterization and angioplasty. Even if your chance of developing cancer from the radiation is increased by 1 in 100, that pales in comparison to your chance of dying now if your blocked coronary artery isn’t identified and opened up. If you’ve been in a car crash and might have a lacerated spleen or liver that needs repair or might have a subdural hematoma that could squish your brain against the inside of your skull, the risk from the radiation due to the CT scans that would diagnose these problems is nothing compared to your risk of death or serious disability now.

The problem is that the indications for CT scans have expanded to the point where they are often done even when they don’t provide information that will change the course of management for a patient. For instance, it used to be that general surgeons (of which I still count myself one) could diagnose acute appendicitis in a young male (who doesn’t have female reproductive organs, disorders of which can be confused with appendicitis) by history and physical exam alone and be highly accurate doing so. Yet these days, even young men with right lower abdominal pain get a CT scan that tells the surgeon that, yes, they have acute appendicitis before going to the OR. Many patients with acute peritonitis don’t need a CT scan for a surgeon to know that they need an operation. A very ill-appearing febrile patient lying perfectly still because the slightest movement causes him intense abdominal pain doesn’t need a CT scan; most of the time, he needs a trip to the OR as soon as possible to fix whatever intraabdominal catastrophe is going on. (This reminds me of a surgical aphorism that some attendings used to use to tweak residents examining a patient with peritonitis, which went, “What are you waiting for? Even the janitor can see that this patient needs an operation!”) Unfortunately, these days it seems that virtually all patients presenting to the ER with abdominal pain get a CT scan. As Dr. Redberg points out, “more and more often patients go directly from the emergency department to the CT scanner even before they are seen by a physician or brought to their hospital room.” This approach is all too easy and seductive, and all too often even general surgeons have allowed it to become the rule rather than the exception because it’s far easier to wait for the CT scan than to get out of bed to determine if a patient really needs a CT scan. Indeed, back when I still did general surgery call and chastised an ER doc for ordering a CT scan that I didn’t consider indicated, the response was that all the surgeons there wanted a CT before he even called them about a patient with abdominal pain and would get irate if he didn’t have one. This happened over ten years ago.

The bottom line is that, when the test is indicated based on guidelines constructed using science and evidence, the benefits of doing a CT scan or other medical imaging procedures requiring similar amounts of radiation outweigh the benefits. The problem is that all too often these scans are not ordered using science-based guidelines and in all too many cases the evidence is not clear that doing a CT scan will improve patient outcomes. Clearly, we require more and better studies that define when the benefit of doing a CT scan outweighs the risk from the radiation. In the meantime, physicians and patients need to be aware of data like these regarding the risk of cancer due to radiation from CT scans, and physicians need to exercise some restraint and–dare I say?–clinical judgment when deciding to order these tests.

MORE INFORMATION:

The NCI Factsheet on Computed Tomography: Questions and Answers

REFERENCES:

1. Berrington de Gonzalez, A., Mahesh, M., Kim, K., Bhargavan, M., Lewis, R., Mettler, F., & Land, C. (2009). Projected Cancer Risks From Computed Tomographic Scans Performed in the United States in 2007 Archives of Internal Medicine, 169 (22), 2071-2077 DOI: 10.1001/archinternmed.2009.440
2. Smith-Bindman, R., Lipson, J., Marcus, R., Kim, K., Mahesh, M., Gould, R., Berrington de Gonzalez, A., & Miglioretti, D. (2009). Radiation Dose Associated With Common Computed Tomography Examinations and the Associated Lifetime Attributable Risk of Cancer Archives of Internal Medicine, 169 (22), 2078-2086 DOI: 10.1001/archinternmed.2009.427
3. Redberg RF (2009). Cancer risks and radiation exposure from computed tomographic scans: how can we be sure that the benefits outweigh the risks? Archives of internal medicine, 169 (22), 2049-50 PMID: 20008685
4. Brenner DJ, & Hall EJ (2007). Computed tomography–an increasing source of radiation exposure. The New England journal of medicine, 357 (22), 2277-84 PMID: 18046031

It looks like the H1N1 pandemic is fading fast. I am amazed at how lucky we were, at least in the hospitals where I work. A month ago all the ICU beds were full, most of the ventilators were in use and we were wondering how we were going to triage the next batch of patients who needed advanced life support and we had none to offer. Then, right as we reached maximum capacity and had no more wiggle room, the rates plummeted. We skated right up to the edge of the precipice, looked down, and did not have to jump.

The pandemic has not been as bad as expected, but it was still no walk in the park. Nationwide H1N1 killed maybe 10,000, with 1,100 in children and 7,500 among young adults (ref). Oregon has had 1200 hospitalizations and 68 deaths. We had about 8 deaths from H1N1 in my hospital system. We would have had twice that number, but one of our hospitals is a trauma center and offers ECMO (Extra Corporeal Membrane Oxygenation) and we managed to save a number of people who would have died if they had been in a lesser hospital. The national statistics mirror our experience. None of the deaths were in the elderly. Pity the vaccine was slow to be produced as it could have prevented the majority of those deaths.

Are we done with H1N1? Will it become part of seasonal flu? Will it have a third comeback, fueled by holiday travel? Will it mutate and increase virulence? Will it recombine with avian flu to generate a new strain? Is this THE pandemic that comes every 30 years or so, and we will not see another until after I am long dead?

How am I supposed to know? I can’t see the future. Or can I? Mr. Randi, listen up: I am thinking I will be eligible for that million dollar prize. I am receiving future information from the Large Hadron Collider, curiously delivered inside a baguette. I think I can predict the next infection to sweep the US.

Measles.

Easy call, huh?

I have seen a grand total of one case of measles in my career. It was in an unimmunized young male who picked up measles traveling to Africa. I had not expected to see another case thanks to immunization. I am no longer certain that will be the case.

Measles, due to the rubeola virus, is a typical virus, with the usual fever, cough, runny nose, red eyes and a generalized, maculopapular, erythematous rash. One of many childhood infections that have plagued mankind. Measles is very infectious, with 90% of household contacts exposed developing the disease. It is one of those infections that is easy to acquire in the waiting area of a doctors office.

Case fatality rates in the West are low, about 0.3%, while in the third world it kills up to a third of infected children. About one in a thousand get encephalitis.

In the old days, everyone developed measles with about 3 million cases a year, with relatively little, but devastating, morbidity and morality.

“Before measles vaccine, nearly all children got measles by the time they were 15 years of age. Each year in the United States about 450 people died because of measles, 48,000 were hospitalized, 7,000 had seizures, and about 1,000 suffered permanent brain damage or deafness.”

Much of this is preventable by the vaccine. No vaccine is perfect, and the measles vaccine is no different. Measles vaccine is about 90-97% effective in preventing infection, depending on the population studied. Or to think of it another way, 3 to 10% of the population would remain susceptible to the disease even if we had 100% of the population vaccinated.

Thanks to Dr. Andrew Wakefield, fear of MMR induced autism is highest in Great Britain and as a result measles vaccination rates have fallen. Perhaps it should now be Mediocre Britain, at least where vaccines are concerned.

Vaccination rates have fallen in England, and at one point 20% of children were susceptible to measles, mumps and rubella. Since the English refer to vaccination as ‘the jab’ I am surprised they get anyone to take the vaccine. It’s like referring to colonoscopy as riding the python. Who would want that?

“A particularly significant decline was observed between 2000 and 2004, which can arguably be attributed to deterioration in public confidence about the safety of the MMR (Reference).”

As a result, measles boomed.

All due to Dr. Wakefield’s report in the Lancet, which evidently should have been published as work of dark humor in Punch.

“More importantly, the controversy appeared to affect parental decision-making. Uptake rates for MMR in England fell from 87.4% in 2000-01 to 79.9% in 2003-04, the lowest figure at any time since the widespread introduction of the triple vaccine in 1990-91. The decrease was especially significant given that the single vaccines alternative was only available from private medical clinics, at a cost of around £200.

The Wakefield study has been widely discredited, and MMR uptake has recovered to an extent: in 2007 vaccination rates stood at 84.6%. Meanwhile, measles notifications in 2006 and 2007 were the highest for almost a decade. (Reference)”

I wonder, as an aside, about responsibility. One of the refrains of the antivax crowd is that big pharma is protected from any liability from vaccine injury. Big pharma cannot be held responsible. I wonder, when the causes of autism are finally elucidated and vaccines are definitely exonerated as we have the answers to the etiology of autism, if Dr. Wakefield, AoA and Ms. McCarthy will assume the responsibility and liability for all the morbidity and mortality their actions caused. I am sure they will happy to step up to the plate and offer restitution to the affected families.

There was, of course, another paper out of Poland, “Lack of Association Between Measles-Mumps-Rubella Vaccination and Autism in Children,” this month exonerating the MMR as a cause of autism. Poland has an interesting history with regards the measles vaccine:

“The MMR vaccine was introduced in Poland later than in most other European countries. For the past 10 years, the MMR vaccine has been gradually replacing the single-antigen measles variety. When it was first introduced, MMR was not covered by the national health service of Poland. Parents who wished to vaccinate their children with MMR, as opposed to the single mandatory measles vaccine, had to pay extra. For this reason, few children were immunized with MMR. The Polish mandatory vaccinations schedule did not include MMR for all children until 2004.”

As a result,

“Poland’s heterogeneous population (ie, vaccinated with MMR, vaccinated against measles only, nonvaccinated) serves as a unique sample group for studying the debated association of these vaccines with autism in children.”

In comparing the three groups they found no association between MMR and autism. None. In fact, they found “a lower risk of developing autism for children vaccinated against measles, with the lowest risk being found for children vaccinated with MMR.”

This finding is dismissed by the authors as perhaps

“the decreased risk of autism among vaccinated children may be due to some other confounding factors in their health status. For example, health care workers or parents may have noticed signs of developmental delay or disease before the actual autism diagnosis and for this reason have avoided vaccination.”

Dr. Gorski also thought the finding was a fluke. Part of the argument against MMR being protective being that having one child in the family with autism would make it unlikely for other children in the family to get the vaccine out of fear of the vaccine causing autism when, in fact, it is due to perhaps inherited causes. The lack of vaccination actually being a marker for families with other predispositions to developing autism.

I am not certain that is true. As the authors report:

“This serves as evidence that, despite extensive media coverage of the debated association between MMR and autism, public acceptance of this vaccine remains very high. The situation in Poland is different to that of many European countries, where MMR vaccinations by age 2 years fell more than 10% and were followed by measles outbreaks. In this time, Poland’s already high rate of measles immunization even slightly increased.”

Seems that the Poles were immune to the anti-MMR hysteria, although I cannot say with certainty. If so, then the finding of the protective effect of vaccination, given the study population, may be valid.

Me? I think everything is due to an infectious disease. Infections are the One True Cause of All Disease. While this is the first study to demonstrate the protective effect of the MMR, remember that measles, mumps and rubella area neurotropic viruses with encephalitis a known complication. There has long been a suspicion of viral infections altering the brain to unmask schizophrenia and there is an association between borna virus and OCD. Could a subtle neurologic infection exacerbate a predilection towards autism? I do not think it is out of the question. But that is my delusion.

Vaccination rates have fallen in some segments of the US population as well. In the US, low vaccination rates are found primarily in the children of the well-to-do and often are clustered in alternative schools. There are dozens of schools with vaccination rates under 80%, with some schools having vaccination rates of 5% (reference).

Well, fine, you may say to yourself: they can get the measles or other vaccine preventable diseases. At least it will stay in the those enclaves of unvaccinated children. My kids are vaccinated and in schools where vaccine rates are high. My kids are safe. I would have thought the same thing.

Herd immunity and the models that try and predict what levels of immunity are needed to protect a population are based on the assumption that unimmunized people are randomly distributed in a population, not clustered in alternative schools.

In the Journal of Infectious Diseases this month is a description of a measles outbreak in Canada where clusters of unvaccinated populations helped perpetuate a measles outbreak even though overall community vaccination rates were high (“Long-Lasting Measles Outbreak Affecting Several Unrelated Networks of Unvaccinated Persons”):

“Despite a population immunity level estimated at ?95%, an outbreak of measles responsible for 94 cases occurred in Quebec, Canada. Unlike previous outbreaks in which most unvaccinated children belonged to a single community, this outbreak had cases coming from several unrelated networks of unvaccinated persons dispersed in the population. No epidemiological link was found for about one-third of laboratory-confirmed cases. This outbreak demonstrated that minimal changes in the level of aggregation of unvaccinated individuals can lead to sustained transmission in highly vaccinated populations. Mathematical work is needed regarding the level of aggregation of unvaccinated individuals that would jeopardize elimination.”

The graphic shows how schools acted to magnify the epidemic:

The isolated measles virus was genotyped and almost all isolates were identical, demonstrating how infectious measles can be with what was presumptively minimal contact.

As the discussion said:

“An important assumption of mathematical models predicting elimination, however, is the random distribution of susceptible persons in the population. In reality, unvaccinated individuals are not distributed at random. Religious groups opposed to vaccination are often tightly knit communities. Our outbreak involving 2 unrelated alternative schools attended by children whose parents were resistant to vaccination on philosophical ground demonstrated that these persons also aggregate. The spontaneous interruption of this outbreak, despite the current level of aggregation in unvaccinated children, suggests that endemicity was not likely to be reestablished in this population. The continued propagation throughout many generations of cases, however, raised the possibility that a minimal change in the overall vaccine coverage in the population or in the level of aggregation of unvaccinated individuals can lead to sustained but protracted transmission despite an immunity level near 95%.”

Lest you think this outbreak epidemiology is limited to measles, the US northeast experienced a similar outbreak with mumps, where clusters of unvaccinated populations help magnify the spread of disease.

A child with mumps came to the US from, hey, I’ll be damned, England, thank you Dr. Wakefield, where, thanks to low uptake of the MMR (the second M standing for mumps) there is a mumps epidemic. The index case went to a religious camp and gave it to the other campers, who in turn went to other collections of unvaccinated people to start their own epidemic and so on. In this case there was little spread into the wider community that “might be attributable to generally high vaccination levels and little interaction between members of the affected religious community and persons in surrounding communities.”

It appears that collections of unvaccinated people may serve to magnify the ability of diseases to spread in a community. Those unvaccinated children in the alternative schools may be unlikely to keep their infections to themselves.

My million-dollar prediction? Measles will be imported into the US in a student from Mediocre Britain. That student will visit an alternative school and start an epidemic in the school. Measles will be spread from school to school and into the community and will be difficult to control.

It will occur in 2012. The Mayans, along with the other indigenous peoples in North and South America, were killed by the millions by vaccine preventable illnesses like measles, pertussis, mumps and smallpox. The real reason the Mayan calendar ends in 2012 is the end of the world will be due to the return of vaccine-preventable diseases.