It is hard to get infected. The immune system is robust and has a multitude of interlinking defenses that are extremely efficient in beating off most pathogens. Most of the time.

Fortunately, it is a minority of microbes that have evolved to be virulent in humans. Bacteremia is common with our own microbiome. When you brush or floss, bacteria leak into the blood stream:

We identified oral bacterial species in blood cultures following single-tooth extraction and tooth brushing. Sequence analysis of 16S rRNA genes identified 98 different bacterial species recovered from 151 bacteremic subjects. Of interest, 48 of the isolates represented 19 novel species of Prevotella, Fusobacterium, Streptococcus, Actinomyces, Capnocytophaga, Selenomonas, and Veillonella.

but with a good immune system, low virulence bacteria and no place to go, unfortunately the bacteria rarely cause infections.

Even heroin users rarely get infection. Heroin is a rich melange of  with bacteria and, on occasion, yeasts (I hate to say contaminated, since avoiding microbes is hardly a worry of heroin manufacturers), and the water used for injection is rarely sterile, yet infections are relatively rare despite the filth in which many heroin users exist.

I used to be somewhat fatalistic about hospital acquired infections. However, as the institutions in which I have worked have proven, almost all infections in the hospital are preventable if the institutions aggressively pursue high standards of care.

There are many systems in place in society to prevent infections: flush toilets, good nutrition, public health, vaccines, antibiotics, good hygiene, and an understanding of disease epidemiology, and I suspect people forget there are bugs out there that are pathogenic, just waiting to sicken and kill us. At least a couple of times a year I see patients come into the hospital, previously healthy, who rapidly die of acute infections.  But for most people, most of the time,  it takes a lot of effort to get an infection.

From my perspective we are Charlie Chaplain on skates , mostly unaware of the infections that awaits us if we do something silly, or even when we act with the best intentions to avoid illness. The odds are small we will get a life threatening or serious infection in the US, just as the odds are small we will drown or be killed in a car accident. The germs are there, waiting, and in the end, no matter what we do, we will be consumed by the microbial world.

It is that perspective that leads to a lack of understanding as to why some people seem to love tipping the odds in favor of the bacteria. Avoiding vaccines is perhaps the most popular method for getting infections that could otherwise be avoided, but dietary habits are an curious way to acquire preventable infections.

Humans and cows have a long history of sharing infectious diseases. Measles is either a variant of rinderpest, a cattle illness, or they share a common ancestor. On the beneficial side of the relationship was cowpox, which lead to the small pox vaccination.

While I am a bit of a foodie (for example, while I do not remember by first kiss, I remember the epiphany of my first gourmet restaurant meal), I cannot grok (see how old I am) people who either think a specific food is to be avoided at all costs or is the panacea for preventing illness. Like cows milk.

There is school of thought that cows milk should be never be consumed: it is filled with pus, blood, hormones, foreign protein and antibiotics.  And not only does milk not build strong bones, it leads to cancer. And if you can’t trust a kinesologist, who can you trust?

It’s not natural for humans to drink cow’s milk. Humans milk is for humans. Cow’s milk is for calves.

Sounds like a metaphorical argument for cannibalism to me.

And, as the anti-cows milk proponents note,  milk has infectious diseases swimming in the white murk. A cesspool of bovine feces and bacteria that should be avoided, although how you can eat a homemade chocolate chip cookie without it, I cannot imagine.

So milk is one of the bad foods and should be avoided. Except when you shouldn’t. Newtons Law states that for every SCAM, there is an equal and opposite SCAM. Milk is dangerous, except when it is a panacea, when the milk should be raw milk, fresh from the organic, happy, contented cow.

Why raw milk? Pasteurization and homogenization rids the milk of the beneficial components: white cells, proteins, lactoferrin, immunoglobulins, fats, cholesterol and bacteria, curiously all the substances that the anti-milk faction says are the root of milky evil. I suppose that, for a raw milk aficionado, there would be no greater dietary sin than a warm glass of milk at bed time or a cup of hot chocolate after skiing.

The truth? I do not doubt that flash heating (usually to 165 degrees for 15 seconds) is going to have some nutritional effects on the milk and, if my diet consisted entirely of milk, it would be a concern. However, what small decrements in nutritional value occur would, and should, be made up with a varied diet. Milk is not, unless turned into Baskin Robbins Chocolate Chip ice cream, a miracle food. I also have no reason to doubt that there is a subset of people who have allergic issues with cows milk. Not everyone can drink bovine proteins with impunity.

Taste, of course, is a personal matter, and I cannot gainsay those who say raw milk tastes better. In my family everyone is picky about their milk; it cannot come in plastic and has to be a specific brand, Dairygold. My wife insists Oregon milk is inferior in flavor to Minnesota milk. French milk tasted weird, and I though everything else tasted better in France. Pasteurization has mild effects on the nutritional components of milk, and perhaps the taste.

But what raw milk is, above all,  a source for infection. There have been outbreaks with Campylobacter, Salmonella, E. coli associated with raw milk and other organisms can be found in raw milk, some not common in the US, including  Brucella, Listeria, Mycobacterium bovis (a cause of tuberculosis), Salmonella, Shigella, Yersinia, Giardia, and norovirus. Some are found in cows milk, and some, such as Brucella, more common from goat’s milk. These outbreaks have lead to hospitalizations and a few deaths.

Warm liquid filled with protein, fat and sugars. A good growth media for a bacteria, if they can gain access to the milk. Impossible. Proponents of raw milk point to the clean cows and clean environments that produce raw milk, but you cannot deny both microbiology and gravity. The colons of cows are frequently colonized with the aforementioned potential pathogens and the udder sits below, waiting to be splashed with cow pie. MMMMmmmmmm. Milk and pie. Seriously. Would you lick any cow udder, no matter how clean?

Still, people want their raw milk for the taste and health benefits. Some obtain raw milk illegally at milk speakeasies where I bet the password is Swordfish. You can time share a cow and get the milk straight from the source, although you have to see a presentation on time sharing cows to get the free weekend on the farm. This is good news for me. Since we have instituted aggressive infection control at my hospitals nosocomial infections have plummeted. Once upon a time milk was associated with 25% of infection outbreaks; in part due to pasteurization those rates fell to 1%. Thanks to the raw milk advocates, infections are looking up. The sad thing is parents will feed their children milk supplemented with cow poo. Adults have the right to be stupid; it is what makes America great. But it is a shame that children should suffer as a result of their parents goofy idée fixe.

There is a tendency for humans to have the oddest dietary obsessions, both for and against.

God told Moses certain animals were “clean” to eat — those with cloven hoofs which chewed the cud such as cattle, goats, sheep, deer, and so forth. All fish with fins and scales, and insects of the locust family were also “clean.” The pig and the camel, however, were “unclean” and were not to be eaten. All carnivorous birds, sea creatures without fins and scales, most insects, rodents, reptiles, and so forth were “unclean.

Milk is not on the list. Milk can be an enjoyable part of a diverse diet for most people, but like most foods it should not be filled with live organisms. Pasteurization is a good thing. Except for Hefeweizen. Give me my raw beer.

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An Embarrassment of Riches?

Much has been written here about the dietary supplement business, a multibillion dollar industry with powerful political connections, and about the woeful inadequacy of regulation which allows widespread marketing of supplements without a solid basis in science or scientific evidence. 

The veterinary supplement market is a pittance compared to the human market, but still a billion-dollar pittance that is growing rapidly. Unfortunately, the resources available for good quality research in veterinary healthcare are also a pittance, and it is not at all unusual for our pets to suffer, or even be euthanized, as a result of treatable diseases for want of money to pay for needed care. So $1 billion a year spent on nutritional supplements may not be such a good deal if these products don’t effectively prevent or treat disease. 

The variety of supplements available is staggering. Many proprietary concoctions of vitamins, minerals, herbs, and other ingredients are marketed for health maintenance, “boosting the immune system,” retarding aging, or treating specific diseases. A comprehensive review of this multitude of moving targets is impossible. But the lion’s share of the pet supplement market goes to a few specific compounds, so I will focus on these. Most of these ingredients are also among the most popular supplements for humans, so there will be substantial overlap with previous discussions of the plausibility and evidence for many of these substances. 

1. Glucosamine

The biggest name in the veterinary supplement world by a large margin is glucosamine. It is sold alone or in combination with chondroitin, MSM, green-lipped mussle extract, and a zillion other ingredients. It is sold over-the-counter and through veterinarians and as an additive in commercial pet foods, and it is ubiquitous. It is also widely believed by pet owners and veterinarians to be an effective treatment for osteoarthritis. 

Glucosamine for arthritis in humans has been discussed at length here before. There is some reasonable plausibility to the underlying theory, but decades of clinical trials have failed to find any consistent benefit, and the balance of the evidence strongly suggests it is no better than a placebo in treating arthritis in humans. Given the subjective nature of pain and the multitude of ways biologically inert interventions can influence people’s perceptions of their own discomfort, this placebo effect might be of marginal value in humans, but the same kind of psychology does not apply to dogs and cats, though it certainly does apply to their owners.

There is very little clinical research on glucosamine as a treatment for arthritis in dogs and cats. In preparing a recent brief literature review, I found only two clinical trials in dogs. One found no benefit for glucosamine and the other, which had a weaker design, showed little benefit. Both showed far greater and more predictable benefit to non-steroidal anti-inflammatory (NSAID) therapy, which is a consistent feature of clinical research on glucosamine.

Because cats are poorly tolerant of NSAIDs, there is particularly great interest in glucosamine and other nutraceutical therapies for osteoarthritis in this species. Nevertheless, I have found no published clinical trials studying this supplement in arthritis cats. The closest is a study of a diet containing glucosamine, chondroitin, and a number of other supplements purported to have benefits in managing arthritis. I have addressed this study in detail elsewhere, but in brief there were not consistent differences between the experimental diet and the control diet even on subjective measures of comfort and no differences at all on objective measures of activity. And, of course, the role of glucosamine, if any, in any effect that might have been seen would not be demonstrable in a study of a diet with many other ingredients.

Glucosamine is also marketed for treatment of feline interstitial cystitis, an uncomfortable and potentially very serious chronic inflammatory disease of the urinary bladder. However, the only clinical trial to investigate this use did not find any evidence of benefit.

2. Fish Oil

After glucosamine, one of the most popular supplements for pets is fish oil. In humans, the most common use of this supplement is for lowering blood lipid levels and prevention of cardiovascular disease. There is some controversy about exactly how much of which components is useful for which specific conditions, and whether eating fish is better than taking fish oil supplements, but in general there is good evidence for some benefit in cardiovascular disease prevention.

Cats and dogs don’t have the problems humans do with atherosclerosis and cardiovascular disease, so this is not a reason for use of fish oils. Instead, this supplement is most commonly used in the treatment of skin allergies. A 2010 narrative review of the evidence for various approaches to treating canine skin allergies concluded that there was some evidence that fish oil supplements can improve coat quality and reduce the dosage of steroid medications needed to control itching, but that these effects are small and not great enough to substitute for other therapies. There is also not evidence to support the use of any particular source, dosage, or formulation of fish oil over any other. 

The other common use of fish oils in pets is for treatment of arthritis. There is weak evidence in humans for the use of fish oil supplements as an adjunctive treatment in patients with rheumatoid arthritis, but in general this is not a well-supported intervention for degenerative osteoarthritis in people. There have been several studies of fish oil as a therapy for osteoarthritis in dogs, which I have reviewed in detail (here and here). These are pretty well-designed studies, all by the same group of investigators, and as is common for studies of dietary supplements, they report mostly negative results but then focus on the few statistically significant findings, generally with subjective measures, to conclude the studies are proof of a benefit. The idea that fish oil supplements might have some small benefit for arthritis in dogs and cats is not out of the question, but so far the evidence is not encouraging.

3. Probiotics

Mark Crislip has eloquently addressed the theory and science of probiotics for humans, and the bottom line for pets appears to be much the same. We understand very little about the important and complex ecology of the gastrointestinal tract, about what bugs are there and what they do for or to us. So while the idea of influencing this flora to restore or maintain health makes some sense, adding a few Lactobacillus to the mix and expecting it to have a major effect seems a bit like tossing a few grass seeds into the Amazon rain forest and expecting a golf course to grow there (thanks Mark!). 

Clinical studies in humans support some benefits for some conditions, particularly antibiotic-associated diarrhea, but many of the claims made for probiotic products, especially for health maintenance or “boosting the immune system” are unsupported. There is less research on probiotics for dogs and cats, but there are some encouraging studies which show a likely benefit of some products for acute idiopathic diarrhea in dogs (e.g. here and here, analyzed in detail here). There are also serious problems with the quality control of largely unregulated veterinary probiotics. A recent study found the majority of products tested had inaccurate labels, with many not containing the amount or species of organisms claimed on the label. There are also many products marketed with ridiculous and completely unsupported claims. 

So overall, the idea of probiotics as a therapy for gastrointestinal disease seems promising, and there are some early suggestions that some products may be useful for some conditions. But this optimism must be tempered by the very limited, preliminary understanding we have of gut ecology and how to manipulate it, the minimal reliable clinical trial evidence to support probiotic use, and the concerns about poor quality control and exaggerated, unscientific claims for probiotic products.

4. Multivitamins

Multivitamins are widely touted as a preventative health measure or as “insurance” for a nutritionally imperfect diet. As Harriet Hall has discussed previously, taking a multivitamin is more a form of self-administered psychotherapy than a preventative health practice. A 2006 review of the available evidence, as well as more recent studies, do not support claims of health benefits in humans from vitamin supplementation in the absence of confirmed deficiencies. And there are circumstances in which vitamin supplementation can be harmful (for example raising cancer risk, interfering with cancer therapy, or even increasing mortality). 

As usual, there is virtually no research on the subject in dogs and cats. Commercial pet diets are nutritionally balanced in a way that the rather haphazard eating habits of most humans is not, so there is even less reason to think a multivitamin would be necessary in dogs and cats eating such a diet. In fact, such supplementation could very well lead to excessive, even toxic levels of fat soluble vitamins or some minerals. Homemade and raw food pet diets, however, are more likely to be nutritionally inadequate, so multivitamin supplementation might be more appropriate when feeding such diets. However, the bottom line is there is no good quality epidemiological or experimental research to suggest that dietary deficiencies are common or that non-targeted vitamin supplementation of apparently healthy pets eating a balanced diet has any value. And there is some evidence that supplementation under certain circumstances can be harmful (for example, calcium in growing large-breed dogs). 

The lack of evidence may preclude a definitive statement that such supplements are unnecessary or harmful, but it also makes the confident, sweeping claims of supplement marketers entirely unjustified. 

5. Lysine

Lysine is an amino acid which is hypothesized to be useful in the prevention and treatment of Feline Herpesvirus (FHV-1) infections. This virus is extremely common, and many cats will be exposed and become infected as kittens. Clinical symptoms include sneezing, nasal congestion, and conjunctivitis, and they range from mild and self-limiting to very severe. Most cats will get over the initial infection, but many remain chronically infected. With suppression of immune function from stress, medication, or disease, the virus can re-emerge and cause symptoms again. A small subset of cats may develop chronic, ongoing symptoms associated with this infection. Vaccination reduces the severity of symptoms but does not prevent infection. 

Lysine is proposed to interfere with the replication of FHV-1 by blocking the uptake of another amino acid, arginine. There are theoretical concerns that lysine supplementation could make cats arginine deficient, but experimental studies suggest this is unlikely in practice. So it appears to be safe, but does it work?

Well, maybe. For once, numerous studies have been done, but there is no clear, consistent pattern of results. Some show that oral supplementation is ineffective and might even make infection worse (Drazenovich, 2009; Rees, 2008; Maggs, 2007). Others do seem to demonstrate some benefit (Maggs, 2003; Stiles, 2002). So while lysine supplementation appears to be safe and there is a plausible rationale for its use, no definitive conclusion about its efficacy is justified.

6. Milk Thistle

Milk thistle is an herbal product that is widely recommended and used. Like glucosamine, it is a supplement which has leapt over the gap between alternative and conventional medicine. The active ingredient is a cluster of compounds called silymarin. There has been extensive in vitro research on silymarin, and it has a wide range of potentially useful effects. It appears to interfere with pro-inflammatory chemicals, functions as an anti-oxidant, and may interfere with the metabolism of some chemicals into toxic compounds in the liver. It also has some activity which could be potentially harmful, including interfering with the metabolism of a number of drugs and stimulating the effects of hormones like estrogen.

The primary uses of silymarin in humans are to protect or treat liver damage from toxins and infectious diseases, to improve the condition of diabetics, and to protect the kidneys from toxins. In dogs and cats the primary use of for non-specific “support” of the liver regardless of the specific disease. 

In humans, clinical trial evidence is mixed. A couple of studies have suggested it reduces insulin resistance in diabetic and may lower blood lipid levels. A Cochrane review of 13 studies including 915 people “could not demonstrate significant effects of milk thistle on mortality or complications of liver disease in patients with alcoholic and/or hepatitis B or C liver disease.” High quality trials were negative, and low quality trials suggested a benefit. 

Very little research exists in dogs and cats. A small study of 20 cats given acetaminophen, a known liver toxin, found that those given a single oral dose of silymarin did not show the elevation of liver enzyme levels seen in those not given the compound. A similar study in dogs found some differences in elevations of kidney values between those that got silymarin and those that didn’t following exposure to a kidney toxin, though there was not a completely consistent pattern.

A study done in 1978 showed that dogs given a toxic mushroom compound orally and then given silymarin intravenously did not show the increase in liver enzymes that was seen in control dogs. Another in 1984 found that 30% of the control dogs died whereas none of the dogs given IV silymarin along with the mushroom toxin died, and the livers from the treated dogs did not appear damaged by the toxin. What relevance this has for the value of oral supplementation isn’t clear.

As far as risks, there appear to be few. Nausea, diarrhea, and other gastrointestinal effects are sometimes seen in humans and animals, and allergic reactions have been reported in humans.

So overall, the in vitro and laboratory animal evidence indicates it is plausible that milk thistle extract might have beneficial effects, though harmful effects in some situations could be possible as well. In humans, the clinical trials show weak evidence for benefit in some conditions and no evidence of benefit in others. Very little experimental, and apparently no high quality or controlled clinical research exists in dogs and cats. So once again, harm seems unlikely and a benefit is possible for some dose and some form of silymarin in some conditions, but we lack the information to use the compound rationally or to know for certain if it is even useful in most cases.

7. S-adenosyl methionine (SAM-e)

SAM-e is a chemical which occurs throughout the body and has a fascinating array of in vivo functions and in vitro effects. In humans, it is marketed for use in depression and arthritis, and a variety of other conditions. The clinical trial evidence is mixed and not generally high quality (for example, Cochrane Reviews for arthritis and alcoholic liver disease, Mayo Clinic summary for various conditions). 

In pets it is primarily promoted as protecting the liver from damage due to disease of toxins, often in combination with Milk Thistle, though its use for arthritis and other conditions is also sometimes recommended. While the theoretical arguments for these uses, especially in the case of liver disease, are plausible, there is virtually no clinical research that the compound actually benefits patients when given as an oral supplement. There is one study which found no significant benefit in preventing liver changes associated with steroid use, one case report claiming some possible benefit in a dog with acetaminophen toxicosis, and one clinical study that suggest some possible value in treating age-related cognitive dysfunction in dogs. And despite how widely used this supplement is, and how sweeping the claims made for it often are, that’s about it.

8. Digestive Enzymes

The claims made for digestive enzyme supplements are often sweeping and dramatic, and they can make you wonder how anyone ever digests their food without them. The usual arguments are that these enzymes exist in raw foods but are destroyed in the production of commercial pet foods, so if you are so foolish as to feed a nutritionally balanced commercial diet, you’d better give your pet these supplements, or else! These exaggerated, unsupported, sometimes outright mythical claims for raw food diets in humans and dogs have been discussed here before. They are based on fundamental misconceptions about digestive physiology and nutrition, and they hold no water.

Healthy humans and dogs have all the enzymes they need to effectively digest foods. The organs that produce such enzymes do not become stressed or fatigued by doing what is, after all, their normal function. Commercial diets and their constituent ingredients are extensively tested for digestibility, and there is no evidence that any deficiency of enzymes in these foods creates nutritional deficiencies or any specific health problem. 

In addition to use in healthy individuals, enzymes are also recommended for cancer treatment, anti-inflammatory effects, and treatment of many other disease conditions. Though the occasional study is published to support these recommendations, often in “integrative medicine” journals, there is no consistent, high-quality clinical evidence in humans that digestive enzymes are effective therapy for any condition other than true pancreatic enzyme deficiency. And there is evidence that this approach may be ineffective or even harmful. 

There is, surprise surprise, no clinical research at all on the subject in cats and dogs. Apart from pancreatic insufficiency, in which enzyme supplementation is often effective, the claims made for the use of enzyme supplements are based solely on anecdote, theory, or extrapolation from in vitro research. 

9. Coenzyme Q10

Like most dietary supplements, coenzyme Q10, also known as ubiquinone, is recommended for a wide range of apparently unrelated conditions. It is recommended in humans for cardiovascular disease, Alzheimer’s disease, migraines, diabetes, and many others, as well as a general tonic and, of course, the inevitable “boosting” of the immune system. In dogs and cats it has primarily been recommended for treatment or prevention of heart disease and age-related cognitive dysfunction. 

There is controversy about many of the recommended uses in humans, with mixed and generally low-quality clinical trial evidence for most uses. And, as you will no doubt have anticipated by now, there is virtually no reliable research on its use in pets. One small experimental study failed to find evidence of decreased Coenzyme Q10 levels in dogs with congestive heart failure. There appear to be no clinical trials for any specific indication, and the recommendations for this supplement are again based entirely on theory, anecdote, and pre-clinical research or clinical research conducted in humans.

10. Azodyl

Azodyl is a proprietary mixture of probiotic organisms and prebiotics (substances intended to promote the growth of supposedly beneficial gastrointestinal bacteria) that is marketed for the treatment of kidney failure in dogs and cats. The theoretical argument advanced to support its use is “enteric dialysis,” the idea that populating the gastrointestinal tract with bacteria that breakdown some of the nitrogenous wastes the kidneys normally remove from the body can lower the levels of these substances and improve clinical symptoms of renal failure. While this idea is not inherently unreasonable, it does suffer from the weakness of other probiotic therapies in that it requires relatively small additional to the gastrointestinal flora to have significant systemic physiologic effects, which may or may not actually be possible. In any case, it is not a concept that has been validated in practice.

A single pilot clinical trial of the product in humans, sponsored by the manufacturer, has been published. This identified statistically significant changes in one out of three laboratory measures and in a subjective assessment of clinical symptoms. An unblinded, uncontrolled case series in 7 cats reported small changes in laboratory values in 6 of the subjects. And similar small studies in vitro and in rats and miniature pigs, again all supported by the manufacturer, have reported some positive changes in some measures of kidney disease.

Overall, the theory is possible but of uncertain plausibility in the real world, and the clinical evidence is limited and highly vulnerable to bias in terms of methods and funding source.

Bottom Line

So to answer the original question, do these popular supplements work? Well, glucosamine almost certainly does not, and the case for multivitamins and digestive enzymes are extremely weak. Fish oil likely does have small benefit for allergies, and no definitive conclusion can be made concerning arthritis, though the early veterinary trials haven’t been promising. Probiotics are a promising avenue for research, and there is reasonable evidence for some benefit in acute idiopathic diarrhea, but overall they are really not ready for prime time. Lysine, SAM-e, Milk Thistle, and Coenzyme Q10 all have reasonable theoretical foundations based on preclinical research, and none have adequate clinical evidence to draw any firm conclusions.

So should veterinarians and pet owners use these products? The decision whether or not to employ a particular medical intervention is always a matter of balancing the urgency of acting with the risks and benefits of the therapy, and always in the context of the limitations on the available information. In cases where the therapy is very unlikely to provide a benefit, such as glucosamine, there is really no rational argument for its use even if it is harmless, and the resources wasted on such treatments could better be spent on more plausible therapies or research to find better treatments.

In cases where there is a plausible theoretical rationale but inadequate clinical evidence to make a firm conclusion, I am personally reluctant to recommend using such supplements because in the face of such uncertainty we are as likely to do harm as good. For example, Milk Thistle and the combination SAM-e and Milk Thistle products seem to induce loss of appetite in cats and dogs fairly frequently in my experience, and they are usually given to patients who are pretty sick and already taking many other medications. So in the absence of stronger evidence of benefit it seems imprudent to use them routinely. However, in urgent cases where there is no validated therapy and the clinical circumstances are dire, I can’t fault anyone for grasping at straws, and I have certainly done so myself. 

And, of course, if there is a sound theoretical rational and some reasonable clinical evidence, as in the case of fish oils for allergies and probiotics for acute uncomplicated diarrhea, use of such supplements seems perfectly reasonable. We must be careful not to let the perfect become the enemy of the good, and in veterinary medicine where the quantity and quality of the research evidence will always be less than optimal, we are justified in trying out things that are reasonable but unproven if the clinical circumstances warrant it. 

Of course, the marketing used to promote these supplements goes well beyond anything justified by real scientific evidence and is almost universally untrustworthy. Likewise, the testimonials and anecdotes about their effects, whether from patients, pet owners, veterinarians, or Nobel Laureates, are all just stories with almost no probative value. And since most good ideas in medicine ultimately fail to become real, effective clinical therapies, it is likely that many even of the more plausible of these products will turn out not to be useful or to have unknown risks. Without adequate supporting evidence and without effective quality control, regulation, and post-market surveillance, we can never be sure we are helping and not harming our patients by using them. 

However, it is also possible that some of these products will survive the rigors of real scientific investigation, if they are ever subjected to them, and will turn out to be truly useful therapies. And in the meantime, it may be reasonable to use some of them if the existing evidence and clinical need of the particular case are sufficient to justify doing so.

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A new study looks into the disorder known as delusional parasitosis, which many dermatologists believe is the true diagnosis behind the controversial disorder called Morgellon’s disease. Morgellons is a controversial disorder because many patients with symptoms believe they are being infected by an unusual organism, causing excessive itching, but no offending organism has been found. Some patients claim they have strange fibers exuding from the sores in their skin.

The term “Morgellons” was coined in 2002 by Mary Leitao, who was trying to find a diagnosis for her son who was suffering from skin lesions. Since then it has become a grassroots diagnosis – used by some patients to describe themselves but not accepted by the medical community.

Most dermatologists, rather, feel that the disorder is actually a manifestation of delusional parasitosis – a mental disorder. This has set up an unnecessarily confrontational situation. And of course, some charlatans are exploiting the situation by taking the side of the patients and offering them their nostrums as a cure.

These situations are always helped, but rarely resolved, by better information. It is in this context that Hylwa et al performed a retrospective analysis of patients diagnosed with delusional parasitosis at the Mayo dermatology clinic. They analyzed records from 108 patients who had either a skin biopsy (80 patients) or presented their own sample (a patient-provided specimen – also 80 patient), or both (52 patients).

They found that in all 108 cases no evidence of infection or infestation was found.

They did find, however, that 48% of biopsies showed dermatitis – inflammation of the skin. This finding has two plausible interpretations. The first is that in some patients with delusional parasitosis, they may have an underlying skin condition that causes non-specific dermatitis (an allergy, for example) and the symptoms of this dermatitis triggers the psychological reaction that results in the belief that they are infested with something foreign. In this case they could be simply misinterpreted their skin sensations. Further the chronic symptoms can cause stress and lack of sleep and result in the anxiety and depression that often accompanies this disorder.

The other plausible interpretation is that the dermatitis is secondary to scratching and perhaps treating the skin with irritating substances intended to treat the problem. The current study is not capable of distinguishing between these two possibilities.

The authors acknowledge the limitations of this study – mainly that it was retrospective. It also needs to be considered that their search criteria was for patients diagnosed with delusional parasitosis – not all patients with unknown or mysterious skin lesions. In that respect the results are not surprising – the diagnosis may result from a negative biopsy or sample analysis, and so of course patients with that diagnosis will have had a negative biopsy.

The authors do not even address the controversy surrounding Morgellons. Rather they are asking if skin biopsy is useful in patients presenting clinically with delusional parasitosis. Again – given the retrospective nature of this study I don’t think it answers that question.

This study does, however, review a large series of cases demonstrating a lack of biopsy or sample analysis findings in patients who fit within the clinical syndrome that is labeled as either Morgellons or delusional parasitosis. It should further be noted that those who claim that Morgellons is a distinct disease caused by a skin infestation cannot point to any objective evidence of an actual infestation to support that claim.

What proponents do have are mysterious fibers sometimes found in the skin lesions of people with this syndrome. The fibers often cannot be specifically identified, or they are identified as foreign fibers consistent with clothing. They usually do not appear to be of organic origin. At best the fibers represent an anomaly, and are not specific evidence of any underlying cause.

What is especially disturbing about the Morgellons phenomenon is the tone of the discussion, the extent to which the controversy has been politicized. Often irrelevant issues are brought to the forefront, such as patient empowerment or medical authority. Not that these issues are not important – they are just not relevant to the real question of what, exactly, is the underlying cause of what is referred to as Morgellons.

Patients who suffer from this syndrome are best served by bringing objective scientific evidence to bear to discover exactly what the cause(s) and best treatments for their symptoms are. But this issue is often derailed by accusations that the medical community is dismissing them and their claims. By grabbing the reigns of diagnosis and treatment such patients are given a false sense of empowerment, but are likely just cutting short earnest attempts to understand and treat their condition.

And of course, good science has to follow the evidence wherever it leads, even if the answer is not what is hoped. The truth does not care what people need or want – it is what it is.

Conclusion

This latest study will likely not change the debate about Morgellons vs delusional parasitosis. Although it should be kept in mind that delusional parasitosis (DP) is a disorder in its own right, and pre-existed any notion of Morgellons. Morgellons is likely just a recent manifestation of DP – a cultural entity spreading mainly on the internet. It should also be noted that DP likely contains two or more subgroups that have distinct causes – such as the two causes of dermatitis I discussed above.

At present there is no compelling evidence that Morgellons exists as a discrete entity separate from DP. The CDC is currently studying the condition (which they are calling unexplained dermopathy) but has not yet made any report of their findings.

My review of the evidence is that it best supports the conclusion that Morgellons is a mostly a psychocultural condition (it may be triggered in cases by an underlying skin condition). It is a combination of a cultural phenomenon spreading mostly online, giving specific manifestation to an underlying psychological condition. I am willing to be convinced that there is a biological process going on, but so far no compelling evidence to support this hypothesis has been put forward.

I also think that specific harm can be done to individuals with this syndrome by the spread of false information. Sufferers can easily be made to settle prematurely on a false conclusion, and in fact can reinforce their delusions if that is ultimate cause of their symptoms. They can be lured away from practical interventions and the medical community to dubious treatments that are, if nothing else, a waste of their resources.

The situation represents a challenge to the medical community. Perhaps the only solution is to explain and promote the scientific approach to diagnosis and treatment.

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Explanatory studies are done under controlled conditions to determine whether a treatment has any efficacy compared to a placebo. Pragmatic studies are designed to assess how the intervention performs in everyday real world practice. Pragmatic studies measure practical success but don’t determine actual efficacy: that requires a proper randomized controlled trial (RCT) with an appropriate control. Pragmatic studies have their place, but they can sometimes make an ineffective treatment look good: a phenomenon I have christened Cinderella Medicine.

Research studies don’t always predict how a treatment will perform post-marketing. A study might be done on men aged 30 to 70 with no other illnesses. Once the drug is out on the market, it will probably be taken by women, by people who are under 30 or over 70, and by those who have concurrent diseases like diabetes or atherosclerosis or are taking a lot of other medications; and the dose or frequency may vary from the study protocol.

A good example is the clot-busting drug t-PA. In clinical trials, it clearly improved the outcome of stroke patients, but in actual use in community ERs the death rate was almost twice as high in patients who received it as in patients who did not. There are many possible explanations: perhaps it was offered to patients with more severe strokes, perhaps the protocol wasn’t followed as carefully, perhaps some patients were mis-diagnosed, perhaps they had confounding factors that were not present in the research studies.

Pragmatic studies are useful for the questions they are designed to answer: how a treatment performs outside the limited environment of a research study, which of two treatments should be preferred by doctors, patients, and policymakers, deciding how limited resources can be best utilized. They are an integral part of comparative effectiveness research.

But they have limitations. They are unblinded and the patients are generally self-selected. Larger studies are needed to compare two active treatments than to compare an active treatment to a placebo. Lack of compliance and a high drop-out rate can skew results. Patient self-assessments of subjective outcomes are not as reliable as objectively measurable outcomes.

Pragmatic trials can’t determine which components of a “package” of care are essential, and they can’t assess the contributions of the therapeutic relationship. When used for studying a treatment with a strong placebo effect, they may make an ineffective treatment look better than an effective one. CAM proponents like pragmatic studies because they are often the only studies that seem to support them. They are attempting to bypass good science by showing that, in practice, their methods seem to work.

Cinderella didn’t look very pretty in her rags and ashes. Imagine that her Ugly Stepsister had a complete makeover, with hair styling, expertly applied cosmetics, jewels, and a beautiful designer dress. Maybe tooth whitening or even orthodontia, charm school, modeling classes, and elocution lessons. If you entered her in a beauty contest along with the unadorned, dirty Cinderella in her original rags, the Ugly Stepsister might win hands down. But it wouldn’t be a fair beauty contest unless both were in their original unenhanced state or unless you compared the makeover-enhanced stepsister to the Fairy-Godmother-enhanced Cinderella. (Or if, for a really well-controlled study, you managed to persuade the FG to do her magic on both of them.)

Acupuncture’s makeover

Studies comparing acupuncture to standard treatment have shown that acupuncture works better. Standard treatment is like the original Cinderella in her rags: plain and unenhanced in any way. The doctor may only see the patient for one visit and tell him “You have a common garden variety backache; we don’t know why people get these, but they usually resolve spontaneously in a few weeks; while it is going away on its own, I could offer you a prescription for pain pills or a referral to physical therapy.” He doesn’t spend much time with the patient and may seem bored and unsympathetic.

Acupuncture is like the Ugly Stepsister after her complete makeover. The treatment itself (insertion of needles) is like the Ugly Stepsister before her makeover. It doesn’t have any specific effects (it is no more effective than touching the skin with a toothpick). But the acupuncturist surrounds the treatment with all kinds of enhancements that produce “nonspecific effects” that are not due to the treatment itself, but rather to the interaction with the provider.

• The acupuncturist assures the patient that he knows how to relieve the back pain, and he provides a complicated explanation with all kinds of impressive, esoteric oriental terminology.
• He explains that his system is derived from ancient Chinese wisdom and that his needles will adjust the flow of qi through the patient’s meridians to restore health.
• He takes the patient into a quiet back room, has him lie down and relax, and spends half an hour or more doing up-close-and-personal hands-on treatment.
• He is charismatic, shows great interest in the patient, asks a lot of questions, and may uncover another unrelated problem that needs treatment.
• After treatment, he prompts “You feel better now, don’t you?” and the patient feels a social pressure to agree.
• Instead of dismissing the patient with a prescription, he asks him to return over and over, maybe 3 times a week for several weeks; and when the initial course of treatment is finished, he may want the patient to keep seeing him for treatments to maintain health and prevent future problems. He develops a strong, caring doctor-patient relationship.

The plain needle insertion has been given the Cinderella treatment and transformed into an enhanced package of suggestion, expectation, relaxation, ancillary psychological effects, personal interactions, etc. Acupuncture treatment is ready to go to the ball and wow the prince. It is the ideal placebo package; it’s hard to imagine how anything could be devised that would be better at eliciting placebo responses.

So acupuncture, with no specific effects but many nonspecific treatment effects, will appear to outperform a standard treatment that offers some small specific effects but little in the way of nonspecific enhancements.

The common argument is that it doesn’t matter how a treatment succeeds: it should be used because patients report feeling better faster than with standard care, that it is more effective in a practical sense. But fooling patients with nonsense about imaginary meridians, qi, and acupuncture points amounts to lying. Using placebos and offering fantastic explanations undermine the doctor-patient relationship; and this kind of thing leads people to think non-critically, to accept other kinds of pseudoscience, and to reject science-based treatments that might help them objectively or even save their life in the future.

Cinderella treatments: beautified and dressed up with added enhancements. Why not add as many as possible of these Cinderella enhancements to standard, science-based treatments? Without lying or misrepresenting our knowledge? These pragmatic trials don’t show that acupuncture works; they show that the way standard treatments are offered provides fewer nonspecific effects and could stand a bit of a makeover. That should be our goal.

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Dr. Andrew Weil is a rock star in the “complementary and alternative medicine” (CAM) and “integrative medicine” (IM) movement. Indeed, it can be persuasively argued that he is one of its founders, at least a founder of the its most modern iteration, and I am hard-pressed to think of anyone who did more in the early days of the CAM/IM movement, back before it ever managed to achieve a modicum of unearned respectability, to popularize CAM. In fact, no physician that I can think of has over the course of his lifetime done more to promote the rise of quackademic medicine than Dr. Weil. The only forces greater than Dr. Weil in promoting the infiltration of pseudoscience into academic medicine have been the Bravewell Collaborative and the National Center for Complementary and Alternative Medicine (NCCAM). Before there was Dr. Mehmet Oz, Dr. Dean Ornish, Dr. Mark Hyman, or any of the other promoters of IM, there was Dr. Weil.

And why not? Dr. Weil looks like an aging 1960s rock star, and, operating from his redoubt at the University of Arizona, is quite charismatic. For all the world he has the appearance of a kindly, benevolent Arizona desert Santa Claus, an ex-hippie turned respectable dispensing advice about “natural” medicines, writing books, and making himself ubiquitous on television and radio whenever the topic of alternative medicine comes up. Before Dr. Oz told Steve Novella that “Western” science and medicine can’t study woo like acupuncture, Dr. Weil was there, paving the way for such arguments, previously considered ludicrous, to achieve a patina of respectability.

In fact, he’s still at it, doing it far better and far more subtly than the ham-handed Dr. Oz. Unfortunately, it’s the same anti-science message and the same appeal to other ways of knowing built upon tearing down straw men versions of evidence-based medicine (EBM) with gusto. This was brought home last week when Dr. Weil co-authored an opinion piece with Drs. Scott Shannon and Bonnie J. Kaplan for the journal Alternative and Complementary Therapies entitled Safety and Patient Preferences, Not Just Effectiveness, Should Guide Medical Treatment Decisions, an article that was noted at the blog Booster Shots in a credulous, fawning post entitled Dr. Weil says there’s a better approach to evaluating clinical drug trials. In contast, Steve Novella put it far more succinctly (and accurately) in the title of his post: Andrew Weil Attacks EBM. That’s exactly what Weil and company did in this article.

While Steve is absolutely correct, I also see it more as Dr. Weil demonstrating once again that, upstarts like Dr. Oz aside, he is still the master of CAM/IM apologia, much as, even though both were Sith Lords, Emperor Palpatine remained master over Darth Vader until just before the end. You’ll see why in terms of the arguments, both subtle and not-so-subtle, that Dr. Weil and his acolytes make. Moreover, even though his disciple Shannon is granted the coveted first author position, the arguments presented leave little doubt that it’s Weil who’s driving the bus.

Efficacy, effectiveness, and safety, oh, my!

Shannon et al begin by emphasizing that there is a difference between “efficacy” and “effectiveness,” and from the very beginning take pains to separate their definitions of the two, pointing out that they will not use the terms interchangeably. Specifically, they refer to the definition of “efficacy” as “demonstration of benefit under ideal conditions, typically in randomized controlled trials” and “effectiveness” as “demonstration of benefit in real-life conditions.” These are relatively new concepts, comparatively speaking. Even so, they are nothing “alternative,” being instead firmly within the bailiwick of EBM. This doesn’t stop Shannon et al from presenting these concepts as though EBM and science-based medicine (SBM) don’t consider questions of whether treatments work under real-life conditions. As you will see, it is also the opening volley in a rather complex set of fallacious arguments designed to support the watering down of scientific rigor in order to allow CAM/IM modalities that can’t stand up under close scientific investigations to be labeled as “effective” (or at least acceptable).

First of all, let’s see a bit more what Weil and company are up to when they compare “effectiveness” with “efficacy.” Mostly, it’s meant to attack the reliance of EBM randomized clinical trials (RCTs) in order to set the stage for proposing something else more to their liking:

The value of efficacy lies mainly in its ability to indicate potential for effectiveness accurately. Sadly, in the drive to emphasize the importance of delineating clearly sound measures of clinical effectiveness, modern medicine has come to equate RCTs as the final arbitrators of clinical decision making. As discussed below, RCTs are but one tool to sort out these complex questions. In integrative medicine (IM), particularly, with its emphasis on patient variables and practitioner participation, evaluation of efficacy is not sufficient.

I agree that one major value of efficacy in RCTs is that it indicates the potential for effectiveness in the real world. I also even partially agree that EBM overemphasizes RCTs as the final arbiters of clinical decision-making, although, I note, not for the same reason as Weil and his acolytes. We at SBM frequently make the argument that plausibility based on science should be a much more important consideration in evaluating treatments than it is in EBM. Indeed, this is a major reason that the term science-based medicine, as opposed to evidence-based medicine, was coined in the first place. EBM emphasizes RCTs without considerations of prior plausibility, relegating basic science considerations that conclusively demonstrate CAM/IM modalities like homeopathy to be so implausible as to be not worth studying in humans to its lowest rung in its scale of evidence. So, while we agree somewhat that EBM overemphasizes RCTs, we most definitely do not agree with Dr. Weil about how it does so. Whereas Dr. Weil seems to think that RCTs are overemphasized because they are too standardized and do not adequately take into account real-world conditions, he most definitely would not like SBM’s plea to EBM to consider scientific plausibility, because doing so would relegate modalities like energy healing, homeopathy, and acupuncture to the hopelessly implausible.

Dr. Weil also does a very clever thing with his argument. While he correctly points out that evaluation of efficacy is not sufficient to determine whether a treatment is effective, as Steve Novella pointed out, Dr. Weil conveniently neglects to acknowledge that it is at the very least necessary. If RCTs indicate that a therapy is not detectably more efficacious than a placebo, which is the case for the vast majority of CAM/IM modalities, then there is no point in doing trials in “real world” conditions because there is no reason to expect the to be effective. Basically, RCTs serve as a screening test to identify promising therapies that are likely to be effective in real world use. In essence, Dr. Weil is echoing the same two-pronged attack that CAM/IM advocates make against RCTs, the first being the claim that “Western science” can’t study his woo, which is the same fallacious argument that Dr. Oz made regarding acupuncture. The second prong of the attack is to point to what Weil calls “alternative sources of valid information” as demonstrating that his woo works when RCTs do not support its efficacy. Although Dr. Weil is careful never to state this explicitly or even use the term “pragmatic trial,” his emphasis on “effectiveness” over “efficacy” is in essence a plea for relying much more heavily on observational trials, in particular pragmatic trials.

But what are “pragmatic” trials? They are trials that seek to determine if a treatment is effective outside the confines of an RCT, in other words, out there in the “real world.” RCTs, because they seek to determine efficacy, need to control for as many potentially confounding factors as possible, which makes them inherently artificial to one extent or another. Once efficacy is established under controlled conditions, it is sometimes then useful to determine whether this efficacious treatment is effective under usual circumstances in the “real world,” where patient compliance might be poor, either due to side effects, cost, or difficulty in adhering to the therapy; where complicated protocols might be more problematic to follow compared to academic medical centers; and where use of the treatment will inevitably be expanded to patient populations not represented in the RCTs used to approve the drug.

Pragmatic trials can go one of two ways. In the case of treatments demonstrated efficacious in RCTs, most commonly pragmatic trials demonstrate a lower level of effectiveness than the efficacy measured in RCTs might indicate. As Harriet Hall discussed a couple of years ago, a classic example of a treatment that was shown to be efficacious in RCTs but potentially more dangerous in pragmatic studies of actual use in community hospitals was the clot-busting drug t-PA, which was effective for ischemic strokes in RCTs but resulted in a higher death rate. For efficacious interventions, the “real world” is almost always less hospitable than the “ideal world” of RCTs. There is one case, however, where the “real world” can make a treatment seem more effective than it is by any objective measure, and that’s for treatments that are essentially placebos. Outside of the rigorous, carefully controlled world of RCTs, placebo medicine can seem to have effectiveness, which is exactly why proponents of pseudoscientific medicine love pragmatic trials. The populations aren’t as well-defined; often there is no placebo control; and they are almost always unblinded. There is a good reason why, after well-designed RCTs have demonstrated acupuncture to be no more efficacious than placebo or sham acupuncture, acupuncturists have returned to pragmatic studies, as, I will note in a shameless plug, Harriet Hall will discuss tomorrow. The hospitableness of pragmatic trials to placebo medicine is also behind much of the attack on RCTs by advocates of pseudoscience, and Shannon et al certainly engage in such attacks with gusto:

RCTs have dominated decision making about efficacy in health care for almost 50 years. Many researchers have explored the difficulty of subjecting IM treatment approaches to RCTs. There are some characteristics of IM interventions that make RCTs particularly difficult to carry out, and perhaps even less relevant, than for conventional allopathic medicine. As Fønnebø pointed out, the gap between published studies of integrative approaches on the one hand, and the clinical reports by practitioners on the other hand, may partially result from the fact that placebo-controlled RCTs are designed to evaluate pharmaceutical interventions.

Or, more likely, they result from the biases and lack of adequate controls for placebo effects inherent in “clinical reports” by practitioners. Also note the Oz-like argument that RCTs can’t evaluate Weil’s favored woo.

Granted, uncontrolled clinical reports from practitioners can, if carefully documented, represent one form of pragmatic trials; more often they are at best preliminary data and at worst nothing more than anecdotes. To support their attack, Shannon et al cite a prominent New England Journal of Medicine study, namely Concato et al, which found that well-designed observational studies often produce the same results as RCTs, meaning that placing observational studies lower on the rung of the EBM hierarchy might not be justified. Unfortunately, the authors failed to note that Concato et al only looked at studies of clinical questions with objective outcomes, including the Bacille Calmette-Guérin vaccine and tuberculosis, mammography and mortality from breast cancer, cholesterol levels and death due to trauma, treatment of hypertension and stroke, and treatment of hypertension and coronary heart disease. Moreover, Concato et al have been criticized for cherry picking their examples. In contrast, most CAM modalities are designed to treat symptoms with a major subjective component. Also going against Weil’s argument that, because RCTs are designed for pharmaceutical treatments, they might not be so good evaluating non-pharmaceutical treatments is a more recent study comparing effects in RCTs versus observational studies in digestive surgery, which found that a quarter of observational studies gave different results than randomized trials and that between-study heterogeneity was more common in observational studies. If this study holds up, it would appear that RCTs work just fine (and better than observational studies) for surgical interventions.

The merits and flaws of Concato et al aside, it is a false dichotomy that we must choose either controlled RCTs or or less rigorously controlled observational studies. EBM and SBM encompass them all; they simply disagree on how much relative weight to give each type of evidence. Fortunately, Weil doesn’t make the argument that we must favor one or the other. Unfortunately, he’s more subtle than that. What he does instead is to argue for decreased influence of RCTs by arguing that they should be only one part of the picture, an argument he makes by bringing up the Bradford-Hill criteria.

Trying to shrink the importance of the RCT

The heart of the argument in this paper is that RCTs should be only one (presumably of many) factors that determine whether medicine considers and intervention to be effective or not. As the title suggests, safety and patient preferences play a prominent role in Weil’s argument, but first Weil yokes poor Sir Austin Bradford-Hill, FRS, a pioneering early to mid-20th century epidemiologist best known for his work linking smoking to lung cancer and pioneering the RCT, into his service. Bradford-Hill proposed a set of criteria for drawing causality about disease etiology, but his nine criteria are sometimes used in considering the effectiveness of treatments.

Shannon et al set the stage:

As he [Bradford-Hill] pointed out, not all criteria are appropriate for all issues being analyzed, but he listed nine in total from which appropriate ones should be selected for any given situation:

1. Strength—referring to the robustness of the association between the causative agent and the outcome
2. Consistency—meaning being able to obtain similar results across different research sites and methodologies (i.e., replication)
3. Specificity—by which Bradford-Hill meant one disease having one specific outcome, which may not be relevant to complex disorders (e.g., psychiatric problems)
4. Temporality—referring to the commonsense notion that the cause always precedes the outcome
5. Biologic gradient—which is best described as a dose– response curve: increased treatment would presumably result in a proportionate increase in the effect (again, not relevant in all disorders)
6. Plausibility—referring to whether the results are biologically sound
7. Coherence—which refers to the agreement of a study’s findings with what is already known (hence, not relevant in situations of truly novel interventions)
8. Experiment—the situation in which randomly introducing the causative agent results in the outcome
9. Analogy—which is the idea that a similar cause results in a similar outcome.

It is particularly interesting to note that the Bradford-Hill criteria, specified by the individual who influenced the methodology we now accept for RCTs massively, lists experiment with randomization methods as only one of nine criteria for establishing causality.

See, you nasty, reductionist scientists? RCTs are only one criteria! They’re not the be-all and end-all of clinical evidence! I can’t help but point out that there is an implicit straw man here in that embedded in many of the Bradford-Hill criteria are the same sorts of arguments we make at SBM, particularly criteria numbers 1, 2, 5, 6, and 7. In particular, we at SBM like criteria numbers 6 and 7. Key to the very concept of SBM is that interventions should have biological plausibility. They should also be congruent with what is known about the disease or, if not congruent, the evidence supporting an intervention must be sufficiently compelling that it justifies overthrowing the existing paradigm (for example, in the case of the discovery that H. pylori causes peptic ulcers). I also can’t help but point out that most CAM/IM treatments still fail most of Bradford-Hill’s criteria. In particular, CAM/IM treatments almost always run afoul of all of Bradford-Hill’s criteria other than #4, and, quite frankly, sometimes the wackier ones even seems as though they could run afoul of #4 as well.

Perhaps realizing this, Weil says nothing more about Bernard-Hill criteria other than to mention them again briefly in his conclusion. Instead, he and his merry trio of woo-apologists move on, Gish gallop-like, to other deficiencies in the “Western, reductionistic” model.

Use and abuse of systems biology and “holistic” methods

Unable to abuse poor Bradford-Hill anymore, Weil moves on to list “unique” features of CAM/IM research that—surprise!—turn out to be not-so-unique and not nearly as difficult to take into account in SBM (or even in EBM) as he implies:

For instance, the healing relationship of a doctor and patient is generally excluded or “controlled for” in conventional RCTs, whereas some researchers would argue that unconditional positive regard forms the underpinnings of the healing relationship between two people.

The enhanced focus on the healing relationship is thus another factor delineating IM from conventional health care models. A second example is the concept of individualized care, which is rarely included in RCTs (perhaps the MTA study in childhood ADHD is a notable exception). The notion that each patient is unique and quite different permeates IM.

I like the admission that most CAM/IM is placebo medicine, though. Oh, you didn’t see that? The emphasis on the “healing relationship” between practitioner and patient tells you that what Weil is talking about is placebo medicine. After all, that relationship is very important to placebo effects.

Be that as it may, I’ve discussed the so-called “individualization” of CAM treatments before, as well as the difference between the “personalized medicine” when practitioners of SBM use the term versus when CAM/IM advocates use the term. For the full discussion click on the links; the CliffsNotes version follows. Basically, the notion that each patient is unique is a notion that is recognized in EBM and SBM. It’s also utterly facile and obvious, given that no two people are alike. What EBM and SBM try to do is to classify and stratify patients based on science-based characteristics that can be objectively related to disease severity, etiology, and response to therapy. As genomic medicine, systems biology, proteomics, and metabolomics become more sophisticated, it has become possible to make finer and finer distinctions between patients based on biology. The hope is that ultimately knowing these fine distinctions will allow us to “personalize” therapies to individual patients, thus ushering in an era of truly personalized medicine.

In contrast, in CAM/IM the idea of “individualization” and “personalized” medicine most frequently boils down to making it up as the practitioner goes along and doing whatever the practitioner feels like, all without a basis in sound science and evidence. In fact, Weil appeals to just such “personalization” or “individualization” based on magic and fairy dust as being a problem with applying RCTs to CAM/IM:

However, classic RCT research design requires patients to be broken out into groups with a similar diagnosis, which impairs the ability to evaluate an individualized treatment system, such as classical homeopathy, Traditional Chinese Medicine, or Ayurveda. In each of these systems, the patient must be individualized into a quite unique pattern that does not lend itself to a more broad disease generalization such as that found in conventional allopathic medicine. Curiously, the cutting edge of modern medicine anticipates that customized and individualized care looms as a result of advances in single nucleotide polymorphisms (SNPs) and the ability to create a specific genetic fingerprint for each individual.

Imagine that! Using groups that are based on diagnosis and actual disease biology, rather than based on prescientific vitalistic thinking! The nerve of those reductionistic “Western” physicians!

Here’s a hint: Genome variations, as demonstrated by SNPs, are not an example of the sorts of classifications one finds in homeopathy, traditional Chinese medicine, or Ayurveda, although I am impressed at the attempt to liken CAM classifications to “cutting edge” genomic variations and science-based classification systems. Sadly, though, leaving aside the utter ridiculousness of the analogy, Weil appears to be behind the times when it comes to personalized medicine and genomics. Ask any systems biologist or geneticist. SNPs aren’t even really “cutting edge” anymore. Maybe they were ten years ago (possibly even five years ago), but other methods and markers are rapidly supplanting SNPs, in particular direct sequencing of relevant parts of the genome, a technique made practical by next generation sequencing technologies and the concomitant exponential plummeting of the cost of such analyses. Also, as Harriet Hall has pointed out, the claim to “personalization” is a sham; many CAM/IM therapies ultimately appeal to one of many examples of the “One True Cause of Disease” fallacy.

Speaking of shams, so is Dr. Weil’s claim of being “holistic”:

A third methodological issue that distinguishes IM from the environment of pharmaceutical RCTs involves systems thinking. With its roots in holistic, natural, and aboriginal medicine, IM has always embraced a more systems-based orientation to patient care than conventional care. It should come as no surprise that a narrow modality for evaluating treatment effectiveness would become increasingly limiting to IM research. The movement toward increasingly narrow scientific evaluations may create an artificial and arbitrary view of human health, medicine, and treatment effectiveness. Fritjof Capra, PhD, the well-known physicist, indicated that the great surprise of twentieth century science was that complex systems cannot be understood by analysis. Ecology and epigenetics are examples of the strong movement toward systems thinking in modern biology.

This is, of course, utter nonsense. “Holistic,” “natural,” and aboriginal medicine relied upon a prescientific, not a “holistic,” understanding of biology and patient care. Appealing to “systems” thinking based on prescientific or outright religious systems, such as homeopathic provings, traditional Chinese medicine, Ayurveda, and “energy healing,” is meaningless when the systems being invoked are without a grounding in science—or even reality. The rise of systems theory in biology and elsewhere has nothing to do with the sort of false “holistic” thinking invoked by Weil and his ilk. Rather, it has to do with the increasing ability to analyze more than one aspect of a complex system at once. For example, in my field (cancer), thirty years ago it was only possible to analyze one gene or perhaps handful of genes at a time. Then, beginning in the late 1990s, the development of cDNA microarray chips made it possible to analyze hundreds, then thousands of genes simultaneously—then every gene in the genome. As technology and computing power increased and scientists and mathematicians developed techniques to analyze ever larger datasets, it became possible to take the data from these sorts of experiments and begin to understand the complex networks inherent in the expression of the thousands of genes that are produced in human cells. Today, it is becoming increasingly possible to integrate massive quantities of data from various sources, including genomics, proteomics, and metabolomics and begin to understand the vastly complex networks that they form, how they resist perturbation, and how they can be restored when they are perturbed.

That is real holism. Not homeopathy. Not traditional Chinese medicine. Not Ayurveda. What Weil represents as “holism” is in reality a series of pretenders to “holistic” understanding that substitute non-evidence-based prescientific belief systems for science, gussying them up in “science-y”-sounding language that co-opts new science the way CAM/IM co-opts science-based modalities like diet and exercise as being somehow “alternative.”

The rest of the rest

Those who have actually read Dr. Weil’s article will note that I have not yet mentioned one point that Weil hammered on relentlessly, apparently thinking himself Maxwell bringing his silver hammer down upon the heads of those who think scientifically, the better to knock the propensity towards SBM (or even EBM) out of them. That issue is safety. Weil goes on and on about patient safety, even going so far as to propose a ranking system for patient safety. This part of his article is, quite frankly, an insult to physicians’ intelligence. Physicians practicing EBM already weigh efficacy/effectiveness versus safety; all Weil is doing is to rename and rebrand something that EBM does already. To a small extent he has a point that EBM does not yet have a as rigorous “hierarchy” of risk or harm to evaluate treatments as it does levels of evidence for efficacy, but even if we did have such a rigorous hierarchy, risk-benefit estimates still require weighing benefit versus risk. If the expected benefit is zero, or near zero, then even a tiny risk can quickly become unacceptable. To take one example, in the case of acupuncture, where the benefit is not distinguishable from that of placebo, then even a tiny risk of, say, a pneumothorax from a needle stuck too deep becomes very problematic. In other words, Weil’s classification system is unlikely to make CAM seem as attractive as he seems to think it will, although no doubt his intent is to make that evil “reductionistic” allopathic medicine seem more dangerous by comparison.

In addition, Weil makes a big show of complaining about commercial influence, in essence using a weaker form of the “pharma shill” gambit to dismiss pharma-funded RCTs whose conclusions he does not like. This serves, more than anything else, as a ploy to imply guilt by association, given that virtually all pharmaceuticals are manufactured for profit. As we have written about here on numerous occasions, commercial influence is a problem that is recognized in EBM (and SBM). It is increasingly appreciated as an issue, and practitioners of EBM do consider funding sources when considering clinical trial results. Indeed, one can’t help but wonder why Dr. Weil’s concern about pharma influence is so conveniently limited. Does he complain about the influence of supplement manufacturers (which, by the way, are increasingly owned by various pharmaceutical companies and wield a great deal of clout in Congress)? If he does, I haven’t seen evidence of it. Steve was right; this part is just window-dressing, as is Weil’s proposal for a different five-level hierarchy of evidence that not-so-subtly tilts the playing field so that some observational studies and other studies that can’t be considered RCTs could be considered Level One evidence.

What’s truly ironic is that Weil would never admit that there are few, if any, CAM modalities that can meet the criteria of level one evidence even under his own proposed system! In fact, most of the very best-supported CAM modalities would fall either into level four (“Weak indicators of uncertain value: poorly designed studies without strong support from the Hill criteria; small observational studies”) to level five (“Very weak indicators of efficacy or effectiveness: expert opinion of effectiveness; case series; multiple anecdotal reports”). That’s why it’s tempting simply to grant Weil his new system and then challenge him to show more than a pitiful handful of CAM modalities that have evidence to support them stronger than level four.

Finally, two of the more pernicious proposals in Weil’s paper are related. First, he repeats his explicit argument for favoring placebo medicine:

Given the history and philosophical preferences of allopathic medicine, it should come as no surprise that the factors defining the healing response become minimized or ignored in current practice. This failing must be remedied, as these factors account for a huge component of how humans heal and recover. The healing relationship has taken a much larger role in IM as practitioners in nearly all CAM modalities place a much higher emphasis on it. The importance of these issues can be demonstrated most clearly in psychiatry research, where the placebo response plays a huge role accounting for as much as 40%–90%+ of the total response.²⁶

Significant placebo and expectancy responses inhabit other areas of medical practice, such as dealing with pain and even life expectancy in patients with terminal cancer. Clearly, patient factors must compose a significant part of all treatment selection processes. Ideally, every treatment should be matched to the individual’s belief system to reach the highest level of response possible.

Aside from stating, “CAM is placebo medicine, and we should use placebo medicine when it fits in with patient beliefs,” a more explicit admission that what is being proposed in this opinion piece is placebo medicine I cannot imagine. Worse, it’s based on misinformation, the most egregious of which is Weil’s claim that placebo and expectancy effects can increase life expectancy in patients with terminal cancer. Would that it were true, but unfortunately it’s not, either in late stage cancer or early stage cancer. Nor is there any evidence that it has an effect on recurrence. This is where Weil’s second, related thrust occurs. Using this assumption that placebo medicine “works” better if its tenets match the patient’s belief system, he proposes turning the entire concept of informed consent on its head with respect to medical decision-making (MDM):

The ideal process in MDM would remodel the process of informed consent. The actively engaged patient would be offered a quick overview of appropriate treatments (both CAM and conventional) with an unbiased reflection of both safety and effectiveness. The patient would then declare a preference for one over the other(s). Once a practitioner ascertains the basic worldview of a patient (natural versus conventional; safety versus effectiveness) many simple elements of MDM would flow quickly in the future.

This is a process that to which I’ve referred in the context of two other discussions, vaccines and supplements. In essence, what Dr. Weil is proposing is an ideology-based version of misinformed consent. Although Dr. Weil would not doubt strenuously object to my comparison, when you boil it all down, what he is doing, although more subtle, is not materially different than what anti-vaccine groups do when they grossly exaggerate the risks of vaccination and downplay its benefits or what “health freedom” groups do when they exaggerate the benefits (and the scientific evidence for such benefits) of supplements. What these groups each do is to give patients a skewed view of the risks and benefits of an intervention, intentionally making it more likely that patients will choose the “alternative” option. Weil is doing the same thing by trying to confuse the issue of efficacy/effectiveness by throwing in the issue of “patient belief” and placebo medicine. As is the case with anti-vaccine activists and supplement hawkers, the purpose is, having failed to win on “conventional science,” to find a way to tilt the playing field back towards the “alternative” using other means.

Conclusion

The proposals in Shannon et al are nothing original, although I must grudgingly tip my hat to Weil and his acolytes for having repackaged old ideas in a very attractive, slick new package. In essence, they boil down to a massive appeal to other ways of knowing, hence the attack on RCTs in which they point out deficiencies that those of us advocating SBM and EBM have recognized for decades; the emphasis on effectiveness over efficacy that ignores the fact that it’s necessary to have good evidence of efficacy before even considering effectiveness in the “real world”; the tarting up of safety considerations as though EBM doesn’t take safety into account; and a direct appeal to placebo medicine via the methodology of misinformed consent. All of these strategies are clearly designed to try to give CAM/IM a leg up on science that it can’t achieve through science alone. Unfortunately, although such strategies are transparent to SBM bloggers (and, I daresay, many of our readers), to others they are not so obvious, even to proponents of EBM. I also can’t help but think: If Dr. Weil detests EBM so much, he’s really not going to like SBM at all. Not one bit.

Perhaps the most ironic part of all of this is that many of us at SBM actually agree with the contention that EBM relies on RCTs too much. Many of us would even agree with several of the Bradford-Hill criteria as considerations that are worthy of more emphasis in EBM. Where we differ is in how to do this. Most importantly, we emphasize much more strongly scientific/biological plausibility. Prior probability appears to be anathema to Weil, given that he mentions it as part of the Bradford-Hill criteria and then completely ignores it thereafter. No doubt, he knows how scientifically implausible many CAM/IM modalities are. Instead, Dr. Weil Gish gallops off to emphasize, as he does in the title of his article, patient preferences and safety, in essence using these issues to bolster an explicit plea for placebo medicine. Rather than accepting that rigorous scientific examination of his favorite CAM/IM modalities fails to find any benefit over placebo, Dr. Weil cleverly embraces placebo medicine and argues for lower scientific standards to permit pseudoscientific and unscientific medicine to appear to be co-equal with EBM.

Unfortunately, such are the arguments that have been the wedge used to insert quackademic medicine into medical academia. Even more unfortunately, they are working.

REFERENCE:

Shannon, S., Weil, A., & Kaplan, B. (2011). Medical Decision Making in Integrative Medicine: Safety, Efficacy, and Patient Preference Alternative and Complementary Therapies, 17 (2), 84-91 DOI: 10.1089/act.2011.17210

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