Another Study Shows CAM Use Harms Cancer Patients

A recent study of cancer patients provides yet another addition to my list of examples of how complementary and alternative medicine (CAM) can do harm.

Yun YH, Lee MK, Park SM, Kim YA, Lee WJ, Lee KS, Choi JS, Jung KH, Do YR, Kim SY, Heo DS, Kim HT, Park SR. Effect of complementary and alternative medicine on the survival and health-related quality of life among terminally ill cancer patients: a prospective cohort study.Ann Oncol. 2012 Oct 30. [Epub ahead of print]

This study was a prospective cohort study which followed 481 terminally ill cancer patients in Korea. The authors compared the use of any alternative therapy with the use of no such therapies, so obviously the study does not evaluate the effectiveness of individual treatments. Its purpose was to see if overall the use of CAM had a measurable effect of survival or quality of life for cancer patients. The essential findings were these:

  1. There was no overall difference in survival between patients who used CAM and patients who didn’t.
  2. Overall, CAM users exhibited poorer cognitive function and more fatigue than non-users.
  3. A series of subgroup analyses (always to be viewed skeptically) identified a number of poorer quality of life scores among CAM users and a poorer survival among those who used prayer as a healing intervention.

This is certainly not the definitive word on CAM in general, nor a clear disproof of the value of any particular CAM practice. What it is, is a sound rebuttal to the unsubstantiated claims that CAM use improves the survival or well-being of cancer patients. It also provides yet another stone in the avalanche of evidence that the blithe assumption that even if CAM doesn’t help it can’t hurt. Previous studies of both general CAM use and specific CAM practices, have found not only no benefit but a significant decrease in the survival and the quality of life of cancer patients using CAM.

All therapies need to be rigorously evaluated scientifically, beginning with the establishment of a plausible theoretical principle, progressing to proof of concept in animal model and in vitro studies and, if this information warrants it, ultimately being subjected to clinical trial evaluation to prove real safety and efficacy. The assumption of either efficacy or safety based on tradition, intuition, theoretical reasoning, or low-level preclinical evidence not only wastes resources on useless therapies but harms patients.

Additional Examples
Kurian Joseph, Sebastian Vrouwe, Anmmd Kamruzzaman, Ali Balbaid, David Fenton, Richard Berendt, Edward Yu and Patricia Tai. Outcome analysis of breast cancer patients who declined evidence-based treatment.World Journal of Surgical Oncology 2012, 10:118.

Lim A, Cranswick N, South M. Adverse events associated with the use of complementary and alternative medicine in children. Arch Dis Child. 2010 Dec 22. [Epub ahead of print]

Chang EY, Glissmeyer M, Tonnes S, Hudson T, Johnson N. Outcomes of breast cancer in patients who use alternative therapies as primary treatment.Am J Surg. 2006 Oct;192(4):471-3.

Bostrom, H. Rostrom, S. Quality of alternative medicine–complications and avoidable deaths.

Han E, Johnson N, Delamelena T, Glissmeyer M, Steinbock K. Alternative therapy used as primary treatment for breast cancer negatively impacts outcomes. Ann Surg Oncol 2011;Jan 12 [Epub ahead of print

The Danger of Choosing Alternative Therapies Over Conventional Care

Posted in General | 4 Comments

Caregiver Placebo Effects: New Study Shows that Owners and Vets Often Believe an Ineffective Therapy is Working When it Isn’t

The placebo effect is a critically important, and much misunderstood phenomenon which can mislead us greatly when we are trying to decide if a medical therapy is or is not effective. While most people understand the placebo effect to mean a patient feels better because they think they are getting a real therapy, when actually they are getting a fake therapy, this is only one kind of error included under this label.

Belief and expectation can certainly cause people to imagine an improvement in their condition even when they aren’t getting a real treatment, and even when objectively their disease is unchanged or getting worse. One relatively recent example is a study of placebo treatments, including acupuncture, for asthma.  In this study, fake therapies frequently made people feel their asthma symptoms were reduced, but objective measures of lung function didn’t change. This sort of result indicates pretty clearly that even if people report feeling better, it is not a good idea to rely on placebo effects alone because they don’t actually improve the condition being treated. There may be some value to improvements in subjective symptoms like pain even if they aren’t real, but we cannot ignore the fact that these improvements can occur even when the people feeling better are actually getting sicker.

There are many other sources of error in scientific studies of medical treatments that can lead to a false impression of improvement even if a therapy doesn’t work. Regression to the mean, the Hawthorne Effect, the natural course of disease, and many other similar phenomena can fool us into thinking a therapy is working when it isn’t, or lead us to believe the effect of a treatment is stronger than it really is. These are often called placebo effects because they can be controlled for in experimental studies by having a placebo treatment group, but they don’t involve belief or expectation on the part of the patient. Many of these effects occur in animals just as they occur in humans, even though animal patients likely do not have beliefs or expectations about their health. Even with a problem as apparently objective and straightforward as epileptic seizures, significant placebo effects have been seen in dogs.

One source of error seen in studies of medical therapies in humans, and which likely also operates in veterinary medicine, is the placebo effect by proxy (e.g. 1, 2). This is where the beliefs and expectations of someone caring for a patient (often a parent) influence the apparent effect of a medical treatment because the parent either reports on the effect of therapy or behaves differently in other ways related to the treatment being tested. Often, this effect makes it look like patients are improving by the subjective measure of caregiver evaluation even if objective measures show the patient actually is not getting better.

I have long argued that this form of placebo effect is a serious problem in veterinary medicine, where subjective measures of response based on owner or veterinarian opinion are often used to evaluate the effect of therapies for veterinary patients. Inconsistent and usually positive subjective evaluations of response to treatment show up in almost every veterinary clinical trial, and without adequate controls for placebo effects, these can lead to false impressions of a benefit. This is especially a concern with therapies shown in humans to operate mostly or entirely by placebo effects.

One area in which this problem appears to be significant is the treatment of arthritis in veterinary patients. Many therapies are used which have not yet been demonstrated to be effective through high-quality clinical trials (such as stem cell therapies) or which have been shown in humans to operate mostly as placebos (such as glucosamine, acupuncture, and others), are tested in dogs and cats using only subjective assessment by owners or vets to determine if they are effective. A new study specifically evaluating the impact of caregiver placebo effects on evaluation of arthritis treatments illustrates why studies that don’t use objective measures or control for placebo effects are very likely to be misleading.

Conzemius MG. Evans RB. Caregiver placebo effect for dogs with lameness from osteoarthritis. Journal of the American Veterinary Medical Association. 2012;241(10):1314-1319. 

This study looked at the assessment of lameness in 58 dogs who were in the placebo arm of a clinical trial evaluating a non-steroidal anti-inflammatory medication for arthritis treatment. The authors compared owner and veterinarian assessments of patient lameness with the results of an objective measurement tool that evaluated the amount of weight the dogs actually put on their arthritic legs. There were several important results that illustrate the importance of proxy placebo effects:

  1. Objective measures were consistent throughout the study, while subjective evaluations were inconsistent and tended to show progressive improvement as the study progressed, even in dogs who were not actually improving.
  2. A placebo effect in the owner evaluations occurred 56.9% of the time.
  3. A placebo effect in veterinarian evaluations occurred between 40% and 45% of the time, depending on which specific method of evaluation was being used.
  4. These placebo effects were highly significant at every point at which the dogs were evaluated (P<0.001).
  5. Changes in lameness of </= 5% measured objectively were not unusual, but changes >/= 10% were rare, suggesting that small changes may occur naturally and can interfere with accurate evaluation of a therapy. Higher effect sizes should be seen if we are to have confidence that a therapy is truly working. 

These placebo effects, seen in dogs not actually receiving any therapy for their arthritis, were highly significant and easily large enough to make an ineffective therapy appear effective without an objective measure of response. This illustrates quite clearly how important it is that we not accept only subjective assessments of arthritis treatments as proof that they work. We have to remember that the caregiver placebo effect means that the owner or veterinarian judge the patient to be improved, but actually the patient is likely in as much or more pain as they were without the treatment. Trusting in our uncontrolled observations to judge the value of treatments for arthritis pain very likely guarantees uncontrolled suffering for our pets and our patients.

Posted in General, Science-Based Veterinary Medicine | 12 Comments

HopeScience Vet’s EFAC for Periodontal Disease and Arthritis

My attention was recently drawn to another dietary supplement product with pretty dramatic claims, this time for treating both oral disease (gingivitis and periodontal disease) and joint disease (osteoarthritis). As usual, the company web site and promotional materials are unequivocal about the benefits you can expect.

Comprehensive oral health care is now a reality!

Safe, No Side Effects…Only Side Benefits

A truly major advancement…

Far more effective and much faster acting than current natural joint products

Of course, there is the usual disclaimer, which one presumes is present because the company has not met the FDA requirements for making health claims:

This information is presented for informational purposes only and is not intended as an endorsement of any product. The information is not intended to be a substitute for visits to your local veterinarian. Rather, these testimonials / research pages and/or case studies offer the reader information written by pet owners and/or veterinarians concerning animal health and products that have shown results.

It is hard to imagine anyone actually claiming this information is “not intended as an endorsement of any product” given that the context is entirely product advertising, but that’s a relatively minor example of the weird things that happen when one tries to advertise a health care product not approved by the FDA as a health care product.

Several of the warning signs of bogus claims are present, including:

Claims of a major scientific breakthrough, initiated by a hunch or guess and an uncontrolled personal experience

Support for these claims primarily through testimonial and anecdote

Reference to scientific proof with few details

Claims of great benefits with absolutely no side effects

A money back guarantee

And while science is often used as a marketing point, this company goes farther, making several references to evidence-based medicine and making a number of statements about  the need for meaningful scientific evidence with which I agree completely:

[this product is] not just another one of the multitude of unproven joint products, as it is also evidence-based. This is an often used term and at the same time an often abused term. As an example, we often see “contains clinically proven ingredients” In reality this usually implies that the actual product was in fact never tested clinically.

Esterified oils are the only evidence-based product for gum or periodontal health.

There is scientific support for natural approaches, but at the same time there are a lot of half truths and at times totally misleading statements made in order to sell products. We will let the science speak for itself.

The company also aggressively challenges the usefulness of what they appear to see as their major competition for the arthritis supplement market, glucosamine products. And here again, they make a case I am in complete agreement with about the lack of clinically meaningful, proven benefits for glucosamine supplements*:

It is quite amazing that so many people, including physicians just assume that glucosamine is effective. This is understandable when we consider how much joint health advertising that takes place. The sad reality is that in well controlled clinical trials that the placebo pills produced just as good effects as glucosamine.

Advertisers have frequently referred to GAIT and the 72 patient’s that seem to benefit, but they fail to mention the other 95% of trial participants or the fact that this 72 patient group went on to experience more cartilage loss than placebo.

So let’s take a look at this “evidence-based” product, what it is and what the evidence says about it.

What Is It?

The exact active ingredient in the product is listed as a “proprietary blend” of an “esterified fatty acid complex” from “beef tallow”. Esterified fatty acids are similar to other fatty acids, such as fish oils, with some chemical modifications. The other ingredients are a variety of vehicles and some compounds with Vitamin E activity, which are commonly included with fatty acid supplements since these tend to reduce Vitamin E activity in people or animals taking them.

Does It Work?

Given the heavy promotion of this as an “evidence-based” product, is there strong evidence to support the strong claims made for it? Well, not really.

The company claims, “EFAC has been studied with seventeen (17) animal and clinical studies, with six (6) studies presented at scientific meetings and six (6) published in pre-eminent scientific journals.” Of these, they provide links to 5 papers and once conference presentation, however all but one of the links are currently broken. It’s not clear what other studies they are referring to.

In terms of the use of esterified fatty acids in general (not this product specifically) for osteoarthritis, there are a few clinical trials that suggest some improvement in human patients with osteoarthritis. (1-3) These are the sort of small, early trials which can suggest a potential effect is worth investigating further, but the results often are not supported in larger, better controlled, and independently funded research. In fact, the clinical trial evidence supporting glucosamine as an arthritis treatment is far greater, and yet the largest and highest quality trials have turned out to show, as this company points out on their site, that there is not a real benefit. It seems a bit self-serving to correctly identify the weakness in the evidence for glucosamine and yet to aggressively promote their own product as “evidence-based” on the strength of far weaker clinical trial evidence.

As for the use of this product to prevent or treat gingivitis and periodontal disease, I have only found one related published paper, a report of a study involving the topical application of esterified fatty acids to the gums of 18 rabbits in which periodontal disease was artificially induced.(4) This is the sort of animal model study that is useful for providing proof of concept, but it is not appropriate to justify widespread clinical use in dogs and cats based on one laboratory study in rabbits. The company also claims a trial has been done in cats, and provides a testimonial from a veterinary dentist supporting the product, but apparently that study has not yet been published

The company also promotes the fact that they have been granted a patent for their product. This does not, however, have anything to do with whether or not it is effective. Evidence of clinical safety and efficacy is not required for a patent application, and patents have been granted for a wide range of bizarre and useless inventions.

Is It Safe?

A few safety studies in laboratory animals have been done and did not identify any hazards. I am also not aware of any reported side effects in humans or other species taking these supplements, though there does not appear to be any formal surveillance or reporting mechanism in place.

Bottom Line

It is certainly possible that esterified fatty acids could have clinically meaningful benefits. There is no clearly established physiologic mechanism by which this would occur, but there are a few small clinical studies in humans suggesting a benefit for osteoarthritis and at least one animal model study suggesting some benefit for periodontal disease. There is no evidence of any risk at this time.

At this level of evidence, the proper assessment is that benefits are possible but unproven. Use of the product would certainly be appropriate in controlled research studies and situations in which established therapies are not available or tolerated. Substituting these products for established therapies is not appropriate. And, unfortunately, despite all the talk of being scientifically validated and “evidence-based,” the claims made for these products go well beyond anything justified by published scientific evidence. Such language indicates only a recognition of the marketing value of science and the term “evidence-based medicine,” not any qualitative difference between the level of evidence behind claims for these products and that supporting similar claims by other nutritional supplements marketed to treat or prevent disease.

*Articles I have written about glucosamine for arthritis

 Veterinary Glucosamine and Chondroitin

Growing skepticism about glucosamine for arthritis in dogs and cats

Is recommending glucosamine for arthritis evidence based medicine or wishful thinking?

Nope, glucosamine and chondroitin still don’t work in humans

Cognitive dissonance in action: Glucosamine no matter what!

 

References

  1. Kraemer WJ, Ratamess NA, Anderson JM, et al. Effect of a cetylated fatty acid topical cream on functional mobility and quality of life of patients with osteoarthritis. J Rheumatol. 2004;31:767–74.
  2. Kraemer WJ, Ratamess NA, Maresh CM, et al. Effects of treatment with a cetylated fatty acid topical cream on static postural stability and plantar pressure distribution in patients with knee osteoarthritis. J Strength Cond Res . 2005;19:115–121.
  3. Hesslink R Jr, Armstrong D, Nagendran MV, et al. Cetylated fatty acids improve knee function in patients with osteoarthritis. J Rheumatol . 2002;29:1708–12.
  4. Hasturk H, Goguet-Surmenian E, Blackwood A, Andry C, Kantarci A. 1-Tetradecanol complex: therapeutic actions in experimental periodontitis.J Periodontol. 2009 Jul;80(7):1103-13.

 

 

Posted in Herbs and Supplements | 24 Comments

Cranberry Products for Prevention of Urinary Tract Infections: An Update of the Evidence

I have written previously about the rationale and evidence concerning the use of cranberry products to prevent or treat urinary tract infections. In my summary, I concluded:

There is weak theoretical justification for using cranberry products for urinary tract infections (UTI), though none of the supporting preclinical evidence involves dogs or cats. There is conflicting clinical trial evidence in humans, and no clinical studies in dogs and cats.  

A recent Cochrane review concerning the use of cranberry products to prevent UTIs in humans further undermines the already weak argument for the value of these products. This update of the previous review in 2008 includes an additional 14 clinical trials in a meta-analysis. The conclusion was that there is no evidence cranberry products are effective for preventing UTIs:

Data included in the meta-analyses showed that, compared with placebo, water or not [sic] treatment, cranberry products did not significantly reduce the occurrence of symptomatic UTI overall (RR 0.86, 95% CI 0.71 to 1.04) or for any the subgroups: women with recurrent UTIs (RR 0.74, 95% CI 0.42 to 1.31); older people (RR 0.75, 95% CI 0.39 to 1.44); pregnant women (RR 1.04, 95% CI 0.97 to 1.17); children with recurrent UTI (RR 0.48, 95% CI 0.19 to 1.22); cancer patients (RR 1.15 95% CI 0.75 to 1.77); or people with neuropathic bladder or spinal injury (RR 0.95, 95% CI: 0.75 to 1.20).

Prior to the current update it appeared there was some evidence that cranberry juice may decrease the number of symptomatic UTIs over a 12 month period, particularly for women with recurrent UTIs. The addition of 14 further studies suggests that cranberry juice is less effective than previously indicated….Given the large number of dropouts/withdrawals from studies (mainly attributed to the acceptability of consuming cranberry products particularly juice, over long periods), and the evidence that the benefit for preventing UTI is small, cranberry juice cannot currently be recommended for the prevention of UTIs. Other preparations (such as powders) need to be quantified using standardised [sic] methods to ensure the potency, and contain enough of the ‘active’ ingredient, before being evaluated in clinical studies or recommended for use.

Cranberry juice does not appear to have a significant benefit in preventing UTIs and may be unacceptable to consume in the long term. Cranberry products (such as tablets or capsules) were also ineffective (although had the same effect as taking antibiotics), possibly due to lack of potency of the ‘active ingredient’.

This review indicates pretty clearly that overall, cranberry juice is not effective in preventing UTIs despite theoretical reasons why it might be. This illustrates, yet again, why we cannot rely on extrapolation from pre-clinical or in vitro studies to tell us what will work in actual patients.

As always, one cannot completely rule out a subset of patients for whom these products might have benefits, but quite a variety of patient populations and different forms of cranberry have been investigated so far without any convincing evidence of value. And, of course, there is no clinical research at all in veterinary species to support using cranberry products to treat or prevent UTIs.

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Storyteller’s Creed–How do you feel about this?

There’s a pretty good argument to be made that a lot of the differences between people’s opinions on controversial issues have more to do with differences in temperament and its influence on world view than with the facts or arguments related to specific conflicts. Journalist Chris Mooney has made a compelling case, based on extensive research in psychology, that our political opinions, for example, are shaped more by our temperament than our experiences. And that temperament is determined largely (perhaps 70%) by our genes.

Such a theory certainly seems to explain some of the ideological divisions in the U.S. today, and the intense and reason-proof arguments often seen around so-called “culture war” issues. It would also explain why facts and rational arguments are of so little value in challenging faith-based beliefs, both those pertaining to alternative medicine and those in other domains. Ultimately, a clash of philosophies, built largely on a clash of personalities, may underlie arguments that seem like differences of opinion about factual matters but which seem insoluble and intransigent no matter how much data is available.

Of course, this is a simple theory about a complex subject, human belief and behavior, and it may very well not be correct. Certainly, it can’t be said to be established beyond any reasonable doubt. Still, I find it intriguing and perhaps enlightening.

I ran across the credo below at an art fair last week. My own reaction to it was that it represented the kind of thinking that is behind many of the worst choices and arguments people make. Willful denial of reality in favor of what we wish were true can’t be a sound basis for decisions, in medicine, politics, or any other area involve the world outside our own minds.

I would never deny the importance and power of imagination, hope, love, or other core human feelings. Anyone who knows me will attest I am nothing if not intense in my feelings. Still, I find this set of statements naïve at best and perhaps even a little offensive. Obviously, others see it in a much more positive light. I suspect, though I can’t see any way to prove, that how one reacts to this credo might very well be predictive, to some extent, of how one views religion, alternative medicine, and other areas of conflict between reason and emotion, skepticism and faith. 

I’d be interested in any thoughts or reactions to the series of principles that inspired it.

 

 

The Storyteller’s Creed

 

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Zoopharmacognosy–Do Animals Self-Medicate?

Before becoming a veterinarian, I did a master’s degree in animal behavior, working primarily with chimpanzees. These are fascinating creatures, with many of the cognitive abilities of a young human child (and with a similar emotional temperament as well, which can be a problem in an animal far stronger than any human and equipped with large canine teeth!). One of the most interesting observations about chimpanzees in the wild is that they are sometimes seen eating plants, dirt, or other substances not part of their normal diet, substances which are thought to have possible therapeutic values in preventing or treating parasitic infestations, infections, and other medical problems. Other mammals, birds, and even insects have been seen engaging in similar behaviors, and the suggestion has been made that these creatures are, in some sense, deliberately medicating themselves, a phenomenon labeled zoopharmacognosy.

This is, not surprisingly, a popular idea among proponents of herbal medicine and other medical approaches that claim natural remedies and intuitive knowledge are central to health. However, as a skeptic I am well aware of how easily anecdotes, and elaborate theories built on them, can turn out to be descriptions of what we hope or wish to be true rather than of the world as it actually is. Humans are masters of seeing what we want to see and ignoring things that contradict our beliefs. So do animals self-medicate? 

How Can We Find Out?
The first question to ask in order to explore this subject is how would we demonstrate self-medication and distinguish it from other behaviors? A variety of criteria have been suggested for identifying self-medication in wild animals. And as always in science a consistent pattern that holds up even when attempts are made to explain it with alternative hypotheses is necessary for a reliable conclusion.

Ideally, animals should be seen to seek out and ingest plants or other substances that are not part of their normal diet. They should do so only when they have some objectively identifiable marker of a specific illness. There should be some plausible explanation for why the substance ingested could potentially affect the illness the animal has (e.g. laboratory evidence that a chemical consistently found in a plant can reduce the levels of a GI parasite; NOT simply an unproven folk belief in the medicinal value of the plant). The marker of illness should consistently resolve after the animal has ingested the substance thought to be therapeutic.

Of course, all of these steps could be present and still not definitively prove self-medication, especially given that most behavior of wild animals isn’t observed, and there are many ways in which observers can skew results be selectively attending to or noting some behaviors more than others. Controlled experimentation would also be needed to rule out other explanations. This is, of course, rarely possible with great apes or other wild mammals, though some work has been done with laboratory animals and insects.

Another question to consider is what mechanism might explain self-medicating behavior if it were observed. Do animals have theories of disease, as humans do, that lead them to select specific therapies based on predictions from these theories? Do they remember or communicate to others the particular remedies for particular illnesses? Such deliberative thinking seems pretty unlikely, and there is no reliable evidence of it, despite extensive research, even in the most cognitively advanced species such as the great apes.

More likely, self-medicating behavior would be, like all other behaviors, a product of natural selection operating on underlying variation between individuals. The tendency to seek out certain tastes or smells, for example, when experiencing certain symptoms could easily be fixed by selection if doing so improved the reproductive success of individuals with genes prompting this behavior over that of individuals without such genes. Of course, such adaptive explanations can easily be manufactured for every behavior, and they need to be demonstrated experimentally when possible to be truly believable.

What’s the Evidence?

Wild Animals
In any case, what is the evidence for self medication? In wild animals, it consists largely of uncontrolled observations with a significant risk of bias or misinterpretation. Anecdotes abound, but rigorous, repeatable patterns with solid links between symptoms, behavior, and outcome have not been demonstrated. It is common to note the consumption of an unusual substance and begin looking for evidence of a medical problem to explain it, but instances of that same problem or consumption of that same substance that are not related are overlooked. This is a form of recall or confirmation bias that makes all anecdotes unreliable as evidence for a particular theory.

The medicinal value of plant ingested in such cases is often assumed based on local folk medicine practices or the presence of certain chemicals in the plant which have in vitro effects that might be relevant. The same sources of evidence are often used to validate all kinds of claims about the medicinal value of herbal remedies, and the reality often turns out to be that there is no such value. These kinds of evidence can only suggest possible relationships, not prove them.

And we have to remember that animals also frequently ingest substances that are actively harmful to them. I pull a surprising variety of potentially deadly objects out of the gastrointestinal tract of dogs and cats on a regular basis. And both domestic and wild animals have been seen to succumb to ingestion of poisons as well as indigestible foreign objects. So any theory about intentional self-medication has to also explain this self-injurious behavior. Are these animals committing suicide? Or, as seems more likely, are they mistaking harmful and inedible substances for food or exploring the world through taste and ingestion without a consistent regard for the likely benefit or harm?

There is, of course, little question that animals seek out specific tastes, smells, and colors in their food that are associated with relevant nutrients. It is reasonable, then, to suppose they might similarly seek out such cues in medicinal substances. And the distinction between food and medicine can be unclear when both are made up of substances found in nature and not processed in any significant way. So, all the anecdotes about self-medication behavior may represent an evolved behavior that reduces the burden of disease and parasitism in some individuals, conferring a selective advantage. As of now, however, this is still simply a hypothesis that has not been rigorously demonstrated.

Laboratory Experiments
More convincing evidence of self-medication is available from experimental studies in insects and laboratory animals. One such study, looking at Monarch butterflies, elegantly shows a facultative change in food source associated with parasitism.

These butterflies normally lay their eggs on milkweed. The larvae ingest the plant and incorporate toxins called pyrrolizidine alkaloids into their tissues. These act as a defense mechanism. Predators eating the distinctively colored butterflies will be nauseated by the toxins and will avoid similarly colored butterflies in the future. This doesn’t, of course, help the individual the predators eat, but it can help related individuals who carry similar genes. This is itself a fascinating and amazing example of natural selection in action.

The research study showed that butterflies affected by a certain parasite preferentially lay their eggs on a variety of milkweed which they do not ordinarily use as a food source. This variety contains a higher level of pyrrolizidine alkaloids than the one they usually lay eggs on. Larvae which hatch out on the more toxic variety and ingest its toxins have lower rates of parasitic infestation and a greater reproductive success than parasitized larvae feeding on regular milkweed.

Interestingly, there is a cost to this behavior. Unparasitized larvae that hatch on the more toxin milkweed actually have a reduced survival, so the behavior is only advantageous in the face of parasitism, otherwise it’s a bad choice for the female butterfly. This is also a nice illustration of the fact that all medical therapies, whether “natural” or not, involve balancing risks and benefits in specific circumstances.

This model shows how behavior that can be called self-medicating can evolve in the same way that food preferences evolve. It also shows that the development of such behavior doesn’t require advanced mental abilities or any mystical intuition about the healing value of plants. The trial-and-error processes of natural selection operating over long periods of time are capable of leading to behaviors that appear purposeful even though they are not.

Bottom Line
So do animals self-medicate? Iwould say the answer is a qualified “yes.”

There is good evidence that some animals have evolved adaptive behaviors which include selecting certain food sources preferentially when the individual has a medical problem that that food source can ameliorate. There is considerably less evidence that animals consistently make accurate choice about ingesting specific substances to treat or prevent specific medical conditions. The numerous anecdotes of behaviors which appear to suggest this could easily be matched by anecdotes of behaviors which are clearly self-injurious or neutral with respect to health, so any theory about self-medication has to account for both kinds of behavior.

The theory that most effectively does so is the same general theory of how natural selection shapes food preferences and other complex behaviors over time, through differential reproductive success among individuals with genes predisposing to different behavior patterns selecting for the most adaptive pattern for the current environment. Many such variations are expressed. Some are harmful or maladaptive and eventually die out, but they can be seen at any given “moment” in evolutionary time and mistaken for something that is adaptive. Some variations may hit upon a truly beneficial behavior and, over time, the genes underlying these behaviors will become more frequent in the population, as wil the behavior.

It is important to point out also that this has nothing to do with the complex theories and mythologies used to justify herbal folk medical practices. People may or may not have gotten the idea of using certain plants for treating disease from watching wild animals. Whether or not this is true doesn’t mean those plants are actually effective as medical therapies, in humans or in animals. That has to be proven in the usual rigorous, controlled, scientific way.

And there is no need to imagine a mystical intuition about the healing power of plants to explain self-medication. Butterflies can be manipulated to show such behavior under controlled conditions, and this can be easily explained by established mechanisms of natural selection, without any need for recourse to mystical explanations. Likewise, the medicinal use of natural substances by animals doesn’t suggest this is a highly effective or desirable form of medicine for modern humans. Evolved self-medication and folk medical practices were part of human behavior for millions of years with little improvement in our overall health and longevity. We are fortunate to have stumbled across methods of identifying cases, treatments, and preventive measures for disease that are far more effective even if not “natural” in any atavistic sense.

There is also ample evidence that animals, including humans, make maladaptive choices about food and medicinal substances. Animals ingest poisons and inedible foreign objects readily. And while humans have a clearly adaptive drive to seek certain nutrients which were scarce in the environment in which we evolved (like sugar, salt, and the ample calories in fat), our inability to curb our desire for these substances now that most of us have an abundance of them is the source of the most serious disease afflicting the developed world. The mechanisms of food selection and self-medication which may be beneficial in one environment, can just as easily be harmful in another. They are not drives towards health and well-being; they are specific behaviors generated by natural selection to better adapt our ancestors to a particular environment.

 

 

 

Posted in General, Herbs and Supplements | 11 Comments

The American Holistic Veterinary Medical Foundation: Science or Salesmanship?

One of the biggest problems with alternative veterinary medicine is the promotion of specific therapies or practices without reasonable scientific evidence that these are safe or effective. Sometimes, the evidence is actually clear that a specific approach is not effective, and yet advocates refuse to acknowledge this and abandon the practice. They often defend such practice on the basis of anecdotal experiences suggesting an effect while ignoring all the reasons uncontrolled observations are often wrong and why miracle stories and other testimonials can’t be trusted. However, sometimes scientific research is used to defend a practice even when the research doesn’t truly validate it.

There are several ways to use science to support a therapy that doesn’t actually work.

1. Extrapolation from tangentially related theories:
Proponents of an untested or demonstrably ineffective method will refer to scientific ideas in unrelated areas to suggest their theories must be true. Quantum physics is commonly relied on in this way since it is complex and not really comprehensible to most of us without facility with advanced mathematics. Homeopaths, have made much of the phenomenon of hormesis to suggest that it validates the ultradilution of homeopathic remedies, though it clearly does not.

The problem with this time of defense is it creates the appearance of scientific legitimacy without actually saying anything substantive about the method being defended.

 2. Extrapolation from pre-clinical research:
In vitro or animal model studies can be very useful in demonstrating a basic concept or in screening for possible safety concerns or other biological effects from a therapy. But what happens in a test tube or a lab mouse is not a reliable guide to what happens when an actual patient, often of a different species, with naturally occurring disease. Such research can generate hypotheses and provide support for them, but it cannot be the primary validation for medical therapies.

Again, the problem is that such research is real, legitimate science used illegitimately to imply that we know more about the effects of a medical therapy than we really do.

3. Low-quality, poorly controlled clinical research:
For some CAM therapies, such as homeopathy and acupuncture, there is an enormous body of clinical research in humans. You would think this would make a decision about whether these therapies work easier, but that isn’t always the case. It has been persuasively argued that most published research is wrong, in conventional as well as alternative medicine. It is very easy to set up an experiment to confirm what you already believe. Even with reasonably good controls, single studies often generate unreliable, usually positive results.

The Decline Effect is a well-known phenomenon in which small, early tests of a hypothesis generate positive results, but as independent investigators get involved and potential sources of error are better understood, the effect of the intervention get smaller and sometimes evaporate altogether. This is how science is supposed to work, but it leads to trouble when early, small, low-quality studies without confirmation by replication are cited as evidence to support a therapy.

The National Center for Complementary and Alternative Medicine (NCCAM) was set up specifically to investigate therapies which had committed believers but had little in the way of plausible theories or preliminary research evidence to suggest they were worth subjecting to clinical trial analysis. Its parent was politics, not science, and after more than 10 years and $1.4 billion, the results have been largely negative and have had little impact on the popularity of CAM therapies, even those shown to be useless. The political figure most responsible for this organization, Senator Tom Harkin, reacted to the negative scientific findings with disappointment and a clear lack of understanding of the purpose and methods of science:

One of the purposes of this center was to investigate and validate alternative approaches. Quite frankly, I must say publicly that it has fallen short. It think quite frankly that in this center and in the office previously before it, most of its focus has been on disproving things rather than seeking out and approving.

Of course, real science doesn’t set out to prove what one already believes but to find out what is true.

Which makes me ambivalent about an initiative by the American Holistic Veterinary Medical Association (AHVMA) to generate funding for alternative veterinary medicine research through the American Holistic Veterinary Medical Foundation (AHVMF).

There are certainly some CAVM therapies which deserve rigorous scientific investigation, particularly in the area of herbal medicine. There are also some that we would be better off without, and if clear scientific evidence that these are useless would lead to their decline in popularity, this too would be a good thing. However, based on both human nature and the example of NCCAM, I am suspicious that the AHVMA efforts are more likely to lead to the promotion of alternative therapies without strong, robust scientific evidence that they are worthwhile.

What is the AHVMF, and what is its purpose? Here’s what the AHVMF web site says:

The Foundation was established to receive and administer funds for research and education in all aspects of integrative medicine, especially as it pertains to that part which is called variously, holistic, alternative, or complementary veterinary medicine, or CAVM. The Foundation concentrates on 3 aspects: scholarships for veterinary students who are interested in this branch of veterinary medicine, research in this aspect of veterinary medicine, and support for the use of and education in this branch in veterinary schools.

So from the beginning, the purpose seems largely about promotion of alternative therapies. Research to investigate objectively the potential value of some specific therapies is certainly appropriate. Supporting students who wish to study these therapies seems a bit premature given the lack of evidence that the therapies themselves have value and deserve to be taught. Likewise, supporting the teaching of CAVM in veterinary schools presumes the value of the methods to be taught. So it is difficult to imagine the AHVMA supporting truly rigorous and impartial research given it seems to be focused primarily on promoting therapies that have yet to demonstrate their worth through such research.

Obviously the AHVMF is an offshoot of the AHVMA, sharing office space and many individuals in leadership positions. The AHVMA is a professional association and lobby for CAVM practitioners, so again this suggests that the AHVMF has been formed as a promotional organization rather than to sponsor truly independent research.

This is further supported by the AHVMF statement specifically about the research aspect of their activities:

Holistic medicine often has answers to chronic disease that use methods with few to no side effects. It may have an answer that is non-existent in conventional medicine. But this type of research is always under-funded and overlooked. The AHVMA Foundation is the best way to bring these modalities into the consciousness of mainstream medical thinking and practice.

Clearly, the starting point for AHVMF-funded research is the proposition that CAVM methods work and research is a useful tool for convincing others of this. This does not suggest a truly critical, open-minded approach to the subject. And if there were any doubt about this, it should be eliminated by the fact that the AHVMF has a page specifically devoted to testimonials for the miraculous benefits of CAVM therapies.

Inspiring stories about patients who have been helped by Integrative Medicine. If you have a story, please send it to us, along with a picture and the name of your veterinarian.

Inspiring stories about the success of specific therapies are not typically found on the web sites of organizations supporting research aimed at finding new or better therapies, such as the American Heart Association, American Lung Association, the National Multiple sclerosis Society, and such. Testimonials are he tool of organizations selling something even if, as in his case, it is not a product but a point of view being marketed.

Organizations like the Bravewell Collaboration and others have been very successful at promoting the integration of unproven or disproven therapies into mainstream medical schools and hospitals by providing financial incentives to hop on the bandwagon. Little good-quality science has resulted, and as mentioned earlier what research has been done hasn’t served to effectively validate much CAM or to discourage the use of methods shown not to be effective.

Obviously, it is impossible and inappropriate to judge in advance the quality of the research the AHVMF claims to be raising money to sponsor. The foundation has already raised over $400,000, a not inconsiderable sum in veterinary medicine, and is aiming for $20 million. I hope these resources lead to good-quality, rigorous studies that will let evidence-based medicine advocates like me accept and begin using new, effective therapies and that will convince CAVM advocates to abandon practices which are shown to be effective despite their a priori beliefs. Perhaps the involvement of veterinary schools will ensure the marketing and promotion activities of the AHVMF don’t damage the integrity of the research it funds. I am skeptical that this will be the case, but I will certainly be watching closely and hoping for the best.

Posted in General | 9 Comments

The Problem with Systematic Reviews of Acupuncture in China

One of the highest levels of evidence in the system of evidence-based medicine is the systematic review. Unlike narrative reviews, in which an author selects those studies they consider relevant and then summarizes what they think the studies mean, which is a process subject to a high risk of bias, a systematic review identifies randomized controlled clinical trials according to an explicit and objective set of criteria established ahead of time. Criteria are also used to grade the studies evaluated by quality so any relationship between how well studies are conducted and the results can be identified. Done well, a systematic review gives a good sense of the balance of the evidence for a specific medical question.

Unfortunately, done badly systematic reviews can create an inaccurate impression that there is high-level, high-quality evidence in favor of a hypothesis when there really isn’t. Reviews of acupuncture research illustrate this quite well.

Acupuncture is one of the most studied CAM practices, and this means there is a large volume of research to evaluate. While one might expect this to be a good thing, making it easier to tell whether acupuncture is effective for any specific medical problem, the amount of research studies actually makes for muddy waters in which the truth about the clinical efficacy of acupuncture is difficult to discern. The more studies there are, the greater the chance of getting positive results even for an ineffective therapy. If the quality or methodology of the studies is poor, the results will be unreliable. And if numerous studies of questionable quality exist, it becomes easier to generate systematic reviews which appear to provide high-level supporting evidence that doesn’t actually mean what it looks like it means.

For example, a recent systematic review of the use of acupuncture for pain following stroke appeared in the Journal of Alternative and Complementary Medicine.

Jung Ah Lee, Si-Woon Park, Pil Woo Hwang, Sung Min Lim, Sejeong Kook, Kyung In Choi, and Kyoung Sook Kang. Acupuncture for Shoulder Pain After Stroke: A Systematic. Review The Journal of Alternative and Complementary Medicine. September 2012, 18(9): 818-823.

The conclusion seems quite promising; “It is concluded from this systematic review that acupuncture combined with exercise is effective for shoulder pain after stroke.” Given that a systematic review is high-level evidence, this ought to provide us with a fair degree of confidence that acupuncture is useful for this problem.

But a more detailed look casts a bit of doubt on this conclusion. For one thing, 453 studies were identified and only 7 met the quality criteria for inclusion. This suggests that, even in the eyes of acupuncture researchers, most acupuncture research is lousy. And the 7 studies that were evaluated were all conducted and published in China and all showed positive results. This may have as much to do with how research is conducted and published in China as with the efficacy of acupuncture for this problem.

While there is no question that great scientific research is done in China, there is evidence for a systematic problem with the conduct and publication of alternative medicine studies there. Studies reported as randomized are most often not actually properly randomized. And one review in 1998 found that no negative study of acupuncture had ever been published in China. This strongly suggests that the acupuncture literature coming from China is unreliable due to poor methodological quality and a high risk of publication bias.

A review of systematic reviews published in the same journal as the review of acupuncture for shoulder pain also supports a skeptical interpretation of the first paper.

Bin Ma, Guo-qing Qi, Xiao-ting Lin, Ting Wang, Zhi-min Chen, and Ke-hu Yang. Epidemiology, Quality, and Reporting Characteristics of Systematic Reviews of Acupuncture Interventions Published in Chinese Journals.  The Journal of Alternative and Complementary Medicine. September 2012, 18(9): 813-817.

These authors identified and evaluated systematic reviews of acupuncture research published in China and these were their findings:

Results: A total of 88 SRs were identified; none of the reviews had been updated. Less than one third (27.3%) were written by clinicians and one third (35.2%) were reported in specialty journals. The impact factor of 53.4% of the journals published was 0. Information retrieval was not comprehensive in more than half (59.1%) of the reviews. Less than half (36.4%) reported assessing for publication bias. Though 97.7% of the reviews used the term “systematic review” or “meta-analysis” in the title, no reviews reported a protocol and none were updated even after they had been published after 2 or more years.

Conclusions: Although many SRs of acupuncture interventions have been published in Chinese journals, the reporting quality is troubling. Thus, the most urgent strategy is to focus on increasing the standard of SRs of acupuncture interventions, rather than continuing to publish them in great quantity.

This suggest that most systematic reviews of acupuncture published in China don’t search the literature thoroughly and don’t evaluate it properly. Given existing evidence that much of the research being reviewed is itself questionable, there is ample reason to be suspicious of the conclusions of such systematic reviews.

What this means is that when supporters of acupuncture who claim to follow the principles of evidence-based medicine cite systematic reviews, there is a strong possibility that these reviews don’t actually fairly present the balance of the evidence. If they are poor quality reviews based on a biased sample of questionable studies, then they can only serve to create an inaccurate impression of the efficacy of acupuncture.

And there are systematic reviews of the systematic reviews for acupuncture which have found that the balance of the evidence does not suggest a benefit from acupuncture: “In conclusion, numerous systematic reviews have generated little truly convincing evidence that acupuncture is effective in reducing pain.” A large number of studies makes it possible to generate high-level evidence both for and against a hypothesis, in this case concluding both that acupuncture does and does not relieve pain. That only further clouds the issue since naturally everyone cites those reviews which support their a priori position on acupuncture.

Another way of evaluating the state of the evidence on a given intervention is to compare the quality of studies with the likelihood of positive results. Dr. R. Barker Bausell has reviewed the acupuncture this way in his book Snake Oil Science. As it turns out, the highest-quality studies of acupuncture consistently find acupuncture works no better than placebo and that using fake needles and even jabbing the skin in random places with toothpicks work just as well as “real” acupuncture. Lower quality studies are more likely to be positive. This too sheds doubt on the reliability of positive clinical trials

As supporters of acupuncture will undoubtedly point out, this doesn’t prove acupuncture doesn’t work in those conditions for which systematic reviews have stated it does work. It does show, however, that a lot of time, energy, and money has been spent on acupuncture research without generating a consistent body of evidence to support it, which does not justify great confidence.

Which raises the issue of prior plausibility. In theory, I do not object to clinical trial testing of interventions without well-established theoretical foundations. As Sir Austin Bradford Hill, one of the early luminaries of clinical epidemiology, put it, “What is biologically plausible depends upon the biological knowledge of the day.” And as CAM proponents delight in pointing out, sometimes wacky ideas prove true.

What they often fail to acknowledge, though, is that science does a pretty good job of accommodating such things if they can prove themselves through rigorous testing. The theory that Helicobacter could cause duodenal ulcers was considered implausible when proposed in 1982, and it won a Nobel prize for the proponents of the idea in 2005. That’s a pretty quick acceptance of an initially controversial idea, not consistent with the caricature of mainstream science as closed-minded and dogmatic.

In the real world, however, crazy ideas are far more likely to turn out to be wrong than revolutionary. Dr. Sanden’s Electric Belt was at least as wacky as the idea that bacteria cause ulcers, but it has faded into history without any recognition from the Nobel committee. When time, money, and talent are limited (and they always are), spending them on ideas unlikely to bear fruit is hard to justify.

And while a perfect world might allow for thorough, methodical testing of every possible practice, in the real world we owe it to our patients to focus our energies on those ideas most likely to result in real help for them, those ideas which build on established knowledge rather than asking us to ignore or overturn it.

Finally, some sort of reasonable limit on the time and resources committed to investigating an idea is needed. When adequate effort has been made and a strong, consistent body of evidence has failed to emerge, it is time to move on.

In the case of acupuncture, the original theoretical mechanisms invoked to explain why it should help (Ch’i, meridians, and so on) are vitalistic and inconsistent with established science. Attempts to find alternative mechanisms have yielded some interesting information about physiology and the mediation of pain sensation, but they have not turned up a coherent, unified theory of action supported by good evidence. And enormous numbers of clinical trials have been done over decades, again without yielding a consistent body of evidence supporting a specific therapeutic effect for acupuncture beyond the placebo effects of the therapeutic ritual.  

So determining the truth about acupuncture requires more than simply looking for published systematic reviews. The quality of these reviews, and the studies they evaluate, must be critically appraised. And the evidence at all levels, not simply clinical trials, must be considered. Finally, the proposed mechanisms by which acupuncture might work must also be critically evaluated to see if they are supported by good evidence and consistent with established scientific knowledge. It is a misuse of evidence-based medicine to simply conduct poor quality systematic reviews on poor quality trials with a high risk of bias and then take the conclusion of these reviews at face value. A more comprehensive look at the question and the evidence at all levels is required.

 

 

Posted in Acupuncture | 3 Comments

Magic Mushrooms–Can a mushroom-derived compound slow the progression of cancer in dogs?

There is a recent study out which looks at the potential for a chemical derived from mushrooms to slow the progression of one type of cancer in dogs. It has both strengths and weaknesses, and it is a nice example of both good preliminary, exploratory research and why we shouldn’t put too much confidence in the findings of such research.

Dorothy Cimino Brown and Jennifer Reetz. Single Agent Polysaccharopeptide DelaysMetastases and Improves Survival in Naturally Occurring Hemangiosarcoma. Evidence-Based Complementary and Alternative Medicine. Volume 2012, Article ID 384301, 8 pages. doi:10.1155/2012/384301

The goal of the study was to see if a Chinese herbal medicine product, ImYunity, containing a standardized amount of a chemical called polysaccharopeptide (PSP), had an effect on the progression of the malignant blood vessel cancer hemangiosarcoma (HSA) in dogs. The dogs were those diagnosed with HSA after having surgery to remove their spleens, which were bleeding due to the presence of HSA. Typically, dogs with HSA who have a splenectomy and no other treatment only live a couple of months, though of course there is enough variation that the life expectancy of any individual patient cannot be accurately predicted. Given chemotherapy, these patients tend to live quite a bit longer, however most still do not survive to a year, and all will eventually die from metastatic HSA. Given this poor prognosis even with standard therapy, it is certainly reasonable to investigate alternative approaches.

PSP is believed to be the active compound in some mushrooms used for medicinal purposes, and there is a moderate amount of in vitro and laboratory animal research to suggest the compound may have some effects on the immune system and on cancer cells. I agree with the authors of this paper point out, however, when they say that “as with all other preclinical data, whether these reported findings of suppression of cell proliferation and induction of apoptosis in malignant cells from murine models have relevance in patient care is uncertain.”

Methodologically, the study was of mixed quality. There were only 15 subjects, which is a very small number, and this can lead to random individual variations having a significant effect on any differences seen between groups of subjects. The dogs were selected on the basis of having been diagnosed with HSA and having had their spleens removed. Some had metastases elsewhere in their abdomen at the time of diagnosis and others did not. The dogs were randomly assigned to three different dosage levels of PSP. The investigators and owners were blinded to which dose each dog was getting. However, there was no control group receiving either a placebo or standard therapy.

The two main outcomes studied were time to progression of metastatic disease in the abdomen and survival. While survival is a fairly clear outcome, it is influenced by factors other than the just the progression of the disease since most dogs with cancer are euthanized at their owners’ request. The factors that lead an owner to be ready to do this are many and varied, and not all hinge on the stage of disease in the pet. Still, this is a useful measure in the real world since presumably an effective therapy which slows the progress of disease will be an important factor in determining how long it is before an owner feels it is time to let the pet go.

The second outcome measure is a little less clearly described. An abdominal ultrasound was done on all patients at the time of their enrollment in the study and them monthly thereafter. It isn’t perfectly clear from the report, but it appears that the radiologists performing these examinations were unaware of the treatment each dog was receiving. According to the paper, “Based on this comparison, the board certified radiologist made the determination of progression of metastatic disease.” It’s also not entirely clear what criteria were used to determine progression. How many new lesions or how much growth in established lesions counted as “progression,” and how standardized and consistent was this determination between different radiologists? Such a subjective measure can complicate interpretation of the effect of a therapy.

The results were relatively unimpressive, though some could be consistent with a therapeutic benefit. There was no difference in the median survival among the three groups. However, dogs in the middle and high dose groups lived longer than has previously been reported for dogs with HAS treated only with surgery. This could be consistent with the theory that PSP had some effect on survival.

However, in the absence of an untreated control group, it is at least as likely that this group of dogs differed from those for which survival has previously been reported in some way other than the use of PSP. For example, dogs treated with surgery and not chemotherapy are typically not given any other treatment, and they are certainly not extensively evaluated monthly at a university veterinary hospital. Perhaps the owners who were willing to be a part of this trial were likely to take longer to choose euthanasia than those owners not interested in having their dogs take part for psychological reasons. Or perhaps they generally took better care of their dogs than owners not interested in participating. And it is well know that, for a variety of reasons, people who participate in a research study have better outcomes than those who don’t even if the participants are only getting a placebo, for a variety of reasons. So this result cannot reliable establish that the PSP had any effect on how long these dogs lived.

The other outcome measure, time to progression of abdominal metastases, only showed a statistically significant difference between the high-dose group and the low-dose group. There was no detectable difference between the middle group and either of the others. And the p-value, which establishes how likely this difference was to be due to chance (though not that the difference was due to the treatment), was 0.046. The usual cutoff value for significance is 0.05, so this value was only marginally significant. The difference might be due to an effect of treatment, but it might also be due to chance, especially given the small number of dogs in the trial and the lack of any control groups.

A reasonable interpretation of these results is that this small pilot study found a marginal difference between progression in the high dose group and the low dose, and this could suggest an effect of the drug or could be due to chance, measurement variability, bias, or some other factor. And the survival of the high dose group, which was roughly 6 ½ months compared to the previously reported 3 months for dogs treated with surgery alone (and 6-9 months with chemotherapy), could represent a small benefit from the PSP. Or it could simply be due to random variation or some other, undetected difference between this group of dogs and those studied previously.

Not surprisingly, the authors take a somewhat more positive position on the significance of the results.

While it is necessary to now document more robust and statistically significant differences in an appropriately powered definitive placebo controlled study, it is encouraging that clear patterns and an obvious dose choice emerged from the pilot program.

Based on this data, one could hypothesize that PSP has the potential to have effects on survival similar to that which is seen with standard of care chemotherapy.

Proving, in a biologically aggressive animal model, that PSP delivers antitumor and survival effects in a magnitude similar to that which is seen in standard chemotherapy could have significant implications for shifts in standard of care from current cytotoxic therapies to complementary compounds, such as PSP, that have little to no negative documented effects on normal cells. Most importantly, for those cancer patients throughout the world for whom advanced treatments and cytotoxic therapies are not accessible, CAM, such as PSP as a single agent, could offer benefits to survival and quality of life that are not yet imagined for those populations.

One could hypothesize that PSP is as good as standard chemotherapy for this disease, but that’s only a guess, and this study does little to support that hypothesis. The authors are correct to acknowledge that additional work is needed to demonstrate this is actually true, but they strike a tone that is just a touch more optimistic than these data would seem to justify. Such is inevitable when a researcher has a lot invested in their hypothesis, and it is understandable that the authors would try to put as positive a spin on the results as possible.

However, the suggestion that this therapy, or other alternative therapies, might potentially replace chemotherapy for cancer care is thoroughly unwarranted. For one thing, it has been shown repeatedly than avoiding conventional care in favor of alternative therapies, or even adding these therapies to conventional care, more commonly worsens outcome and quality of life. (see the studies below for a few examples). So it would take a much stronger result than that shown in this paper to even begin to justify the suggestion that alternative therapies could ever be considered a replacement for conventional care.

And the authors also seem to suggest one advantage of PSP as a cancer therapy is the absence of any side effects. No truly effective therapy for a serious disease has ever been found that is free of side effects, so this is an extraordinary hypothesis, which will require extraordinary evidence to prove. Given how unlikely the idea is, it deserves great skepticism and it is ethically questionable to put it forward as an appropriate expectation.

Finally, the authors justify their study partly on the principle that many people cannot afford conventional cancer therapy and that cheaper, possibly safer alternatives should be sought.

A large percentage of [cancer patients] will live in countries that lack the resources for cancer control. The dramatic technological changes that will continue in surgery, radiotherapy, and chemotherapy will lead to increased cure rates; however, these anticipated advances come at a price usually beyond the means of most cancer patients. It is imperative that affordable complementary and alternative treatment strategies, that could considerably reduce the global disease burden at manageable costs, are developed.

There is clear evidence that health and longevity have improved since the advent of a science-based approach to health, and that the benefits of scientific medicine have been greatest in countries which are affluent enough for people to have access to this kind of care (Fig. 1). In poorer countries, people often are forced to rely on traditional folk medicine practices that have not been scientifically validated, and they frequently have poorer health. So there is no question that there is a need to provide better healthcare to people in these countries. There is not, however, any justification for suggesting that alternative medicine, even if rigorously investigated scientifically, will meet this need.

 

This figure shows how life expectancy, one measure of health, has increased as the scientific approac to health has replaced traditional medicine, and how lack of access to scientific medicine is associated with lower life expectancy.

 

For one thing, the reason conventional care is so expensive is largely because tremendous resources are needed to properly develop and research therapies to ensure they are safe and effective. Alternative therapies are largely cheaper because this rigorous scientific study has not been carried out and such therapies are not subject to meaningful regulation requiring evidence of safety and efficacy or verifiable quality control in production and distribution. There is no reason to suppose that if alternative therapies were subject to the same standards of evidence and the same regulatory oversight as conventional medicine that they would be any cheaper.

And it strikes me as ethically questionable to suggest that the proper answer to the healthcare needs of people without access to the best scientific medicine available should be met by putting resources into developing alternative medical therapies for them. These resources would likely be better spent reducing the cost and increasing the availability of therapies already established to be effective. It is perfectly fine to look for additional or better treatments in alternative medicine (subject to reasonable use of plausibility and pre-clinical research to target limited resources efficiently), but the suggestion that such therapies can or should replace conventional care for economically disadvantaged people is not reasonable. There is no good evidence these therapies will be as safe or effective as conventional care or cheaper, so this is a weak justification for research efforts directed at alternative interventions.

Bottom Line
This paper provides an intriguing suggestion that there might be benefit to mushroom-derived PSP for patients with hemangiosarcoma. It is by no means adequate in size or design to demonstrate this to be true, and the results are actually quite weak and as likely to be due to chance or bias as to an actual effect of PSP on this cancer. However, further research into this therapy is certainly justified.

The suggestion that alternative medicine is likely to provide therapies that are as effective as conventional therapy with no side effects is implausible and contradicted by existing evidence. The idea that the proper response to the inadequate availability of proven cancer therapies for economically disadvantaged people is to put resources into investigating alternative medicine and developing a separate set of therapies for these people is an ethically dubious proposition. While investigating such therapies may be appropriate given sufficient evidence to suggest they will prove useful, it would be more appropriate to address healthcare inequities directly rather than justifying such investigation with the goal of developing separate treatments for people with different socioeconomic status.

 

  1. Han E, Johnson N, Delamelena T, Glissmeyer M, Steinbock K. Alternative therapy used as primary treatment for breast cancer negatively impacts outcomes. Ann Surg Oncol 2011;Jan 12 [Epub ahead of print].
  2. John A. Chabot, Wei-Yann Tsai, Robert L. Fine, Chunxia Chen, Carolyn K. Kumah, Karen A. Antman, and Victor R. Grann. Pancreatic Proteolytic Enzyme Therapy Compared with Gemcitabbine-based Chemotherapy for the Treatment of Pancreatic Cancer. Journal of Clinical Oncology. 2010;28(12):2058-63.
  3. Kurian Joseph, Sebastian Vrouwe, Anmmd Kamruzzaman, Ali Balbaid, David Fenton, Richard Berendt, Edward Yu and Patricia Tai. Outcome analysis of breast cancer patients who declined evidence-based treatment.World Journal of Surgical Oncology 2012, 10:118.
  4. Risberg T, Vickers A, Bremnes RM, Wist EA, Kaasa S, Cassileth BR. Does use of alternative medicine predict survival from cancer? Eur J Cancer. 2003 Feb;39(3):372-7.

 

Posted in Herbs and Supplements | 7 Comments

Is Big Pharma Trying to Make CAM More Science-Based or Just Get a Piece of the Action?

There have been a number of mentions in the media lately of an initiative by GlaxoSmithKline (GSK), one of the biggest of Big Pharma companies, setting up a division in China to study Traditional Chinese Medicine (TCM). Here’s one report quoting a company representative:

Pharmaceutical company GlaxoSmithKline will open a new research unit in China to look at traditional Chinese medicine.

According to the company, Innovative TCM will be one of GSK’s R&D programs in China, aiming to transform TCM from an experience-based practice to evidence-based medicines through innovation and differentiation.

“Traditional chinese medicine is a well-established system of medical practice developed through thousands of years of empirical testing and refinement of herbal mixtures, and relies generally on clinical experience,” said Zang Jingwu, senior vice president and head of R&D China.

“Western medicines, on the other hand, are generally target-based small molecules or biologics, and their approvals for clinical use are based on clinical evidence of safety and efficacy by staged clinical trials,” he said.

He said the newly formed unit is working with academic TCM experts in China to develop new TCM products for the benefits of patients in China and the rest of the world.

The strategy is to integrate the existing TCM knowledge of diseases with modern drug discovery technology and clinical trial methodology.

“We are developing novel therapeutic TCM mixtures as prescription medicines through innovative extraction methods and combinations, and we use clinical data/evidence to differentiate from existing TCM products on the market,” he said.

I have to admit a bit I’m not quite sure how to think about the prospect of this integration of an idiosyncratic and unscientific approach to healthcare with a profit-driven, corporate research and marketing machine. I can spot a few potential problems, though the possibility that something good might come of it is there too.

To begin with, it’s important to remember what TCM is. It is a complex system of looking at health and disease that is vitalistic (based on manipulating spiritual energies not detectable by scientific means), idiosyncratic (not really traditional at all but a set of principles cobbled together in the 20th century from a variety of sources and traditions with some modern innovations tacked on), and, as the GSK representative says, founded on trial and error and individual experiences rather than systematic scientific research. (1, 2, 3, 4) Ultimately, the modern incarnation of TCM as a coherent and comprehensive system of healthcare founded in a philosophical and spiritual world view is fundamentally incompatible with science, which is acknowledged by some practitioners of TCM as well as skeptics. (5)

That doesn’t mean, of course, that some TCM remedies might not be effective. Many of the remedies used are combinations of herbal ingredients, and these unquestionably contain active chemicals that have physiologic effects. The problem is that without controlled research, whether these effects are clinically meaningful, and whether they are beneficial or harmful, isn’t known.

The theoretical system of diagnosis and selection of therapies in TCM is not validated by anything other than anecdote and personal faith, and it contradicts established science, so it is highly unlikely to be accurate or worth investigating. And so far extensive scientific evaluation of acupuncture has failed to find a consistent, meaningful benefit beyond placebo effects. (6, 7). However, rigorous evaluation of the ingredients and combinations of herbal preparations used in TCM might turn up some useful compounds. Certainly, this has been the case for many other drugs derived from plants, though the ultimate use of the drug often bears little relationship to the pre-scientific use of the plant.

There are, of course, some problems even with scientific evaluation of herbal remedies employed in TCM. There is little consistency in the ingredients of particular remedies, with undisclosed substitutions being common, and there is a significant problem with contamination of TCM remedies with parts from endangered plants and animals, toxic metals and even pharmaceuticals (8, 9). So to study such products scientifically, one would first have to clear the hurdle of deciding what the accepted constituents for every given remedy tested really are, and one would have to be very conscious of quality control and not extrapolating results for the product tested to variants identified as the same but not scrupulously evaluated to ensure they actually are the same. Quite a challenge, but perhaps ultimately worth pursuing if the resources and the will are available to do the job properly.

On the other hand, it is important to remember what GSK is. It is a multinational private corporation with enormous financial resources and concomitant influence over governments and the media. It unquestionably produces life-saving medical therapies, but its primary purpose is to make money, and there is no shortage of examples in the pharmaceutical industry of how this can distort the ostensibly humanitarian project of developing medicines.

Perhaps GSK intends to make money by identifying, through rigorous and properly conducted scientific investigation, safe and effective therapies amidst the mélange of remedies currently used according to largely mystical principles in TCM. Or, perhaps GSK intends to cash in on the mystique of TCM, the growing popularity of alternative medicine, and the notoriously weak and ineffectual regulation of the herbal supplement industry to produce products it can sell despite inadequate information about safety and efficacy.

The track record of pharmaceutical companies, and of Chinese food and medicine exporters, in safeguarding the public health is not encouraging. It would be wonderful to see the incredible resources of a company like GSK targeted and a truly scientific evaluation of the potential medicines lurking in TCM remedies. However, just as faith and ideology can distort even honest attempts by alternative medicine proponents to bring scientific scrutiny to their practices, so the potential for profit can distort the efforts of corporations to produce safe and effective medical therapies. There is some evidence that the herbal medicine industry is even less trustworthy than the pharmaceutical industry (10), though I suspect the difference is more that herb and supplement manufacturers are not regulated and watched as closely, not that there is any fundamental difference in the motives, cultures, or practices of large corporations in these two similar industries.

So I will be interested to see whether the growing involvement of conventional pharmaceutical and healthcare companies in the domain of alternative medicine brings more reliable, scientific approach to evaluating TCM remedies (with the necessary rejection of those that fail to prove safe and effective), or if it simply leads to bigger, more aggressive marketing of inadequately evaluated therapies.

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