A systematic review about nothing

There’s dubious content in PubMed that you won’t find unless you look for it, or stumble across it inadvertently. It’s the entire field of alternative medicine which is abstrated and complied along with the actual medical literature. In this world, the impossible is accepted as fact, and journal articles focus on the medical equivalent of counting angels on pinheads. I’ve been trying to avoid blogging about alternative medicine practices like homeopathy lately because the practice itself is a scientific dead end. There is no emerging evidence or interesting research to describe, because there is no science to build on. But research on homeopathy is interesting if one wants to understand how placebo effects can appear to be real. Importantly, research and clinical trials of homeopathy allow us to see the underlying (baseline) challenges, flaws and biases in evaluating real medicine more clearly. Today I want to review a newly published systematic review of adverse effects attributed to homeopathy. The casual reader might not see the the multiple problems with this type of research. But once you understand the basis of homeopathy, the conclusion that one can draw is quite different that the authors’ conclusions. And if inert sugar pills can appear to have medicinal effects, and even adverse effects, then we can better adjust for these biases when we’re studying actual medicine. 

Homeopathy: the voodoo doll of medicine

Among all the forms of alternative medicine, homeopathy is the most implausible of them all.  Homeopathy is based on the idea that “like cures like”,  in that a small dose of what causes a symptom can actually cure that symptom. Like-cures-like is simply sympathetic magic,  a per-scientific belief that was first described by anthropologist Sir James George Frazer in his 1890 book, The Golden Bough. In the book, Fraser outlines the two components of sympathetic magic:

If we analyse the principles of thought on which magic is based, they will probably be found to resolve themselves into two: first, that like produces like, or that an effect resembles its cause; and, second, that things which have once been in contact with each other continue to act on each other at a distance after the physical contact has been severed. The former principle may be called the Law of Similarity, the latter the Law of Contact or Contagion.

I’ve discussed the “Law of Contagion” before, which underlies our current preoccupations with pseudoscientific ideas such as “detox” and “eating clean“. Sympathetic magic is the entire basis for the homeopathic belief system:

• Like-cures-Like: a substance that causes a symptom is diluted to treat that same symptom. Any substance is thought to be an effective remedy if it’s diluted enough: cancer, boar testicles, crude oil, oxygen, skim milk even  vacuum cleaner dust or moonlight. Deciding which substances will cure which symptoms is determined by a process called a “proving” which is equally without any scientific basis. (Here are homeopathic provings for the Berlin Wall remedy and also sunlight reflected off the planet Saturn, to give you an example of the science underlying this practice.
• Water has a memory: the more you dilute the substance, the more powerful its effect, even when there mathematically won’t be one molecule remaining. And when I say dilute, I mean dilute. The 30C “potency” is common – that’s a dilution of 10^-60.  You would have to give two billion doses of homeopathy per second, to six billion people, for 4 billion years, to deliver a single molecule of the original material. The result is that most homeopathic remedies are completely inert. Whether bottled as a liquid or dripped onto lactose tablets, they are a pure placebo.

The Growth of Homeopathy: Dilutions of Grandeur

Samuel Hahnemann invented the practice of  homeopathy in the early 1800’s. Hahnemann attempted to position homeopathy as a separate and more effective form of medicine compared to conventional medical practices. Given homeopathy is an elaborate placebo system, homeopathy probably was safer than medical practice at the time, which was still based around the idea of the four humors. Eventually, germ theory emerged, ideas of humors disappeared, as did the elements of vitalism and magic, and medicine slowly turned towards a scientific model based on objective observations. Alternative medicine practices like homeopathy have never progressed or evolved from their vitalistic roots. And how could they? They are not based on a scientific standard, so actual scientific evidence has no bearing on the belief in its efficacy.

Despite the implausibility of homeopathy, it has enjoyed modest popularity since its invention, with a resurgence in the past few decades as an “alternative” medicine system that is marketed and “gentle” and “more holistic” that evil Big Pharma with its harsh chemicals. It goes without saying that if homeopathy works in the way envisioned by Hahnemann and homeopaths believe, than the rest of medicine cannot. And that’s exactly what the evidence shows. Rigorous clinical trials confirm what basic science predicts: homeopathy’s effects are placebo effects. While there are plenty of clinical trials that show homeopathy is associated with positive clinical effects, they are always small, poorly controlled, and often biased. The two most comprehensive reviews of the evidence are the 2010 Evidence Check from the United Kingdom’s House of Commons Science and Technology Committee and the 2014 Australian National Health and Medical Research Council review, the latter of which made the following conclusion:

Based on the assessment of the evidence of effectiveness of homeopathy, NHMRC concludes that there are no health conditions for which there is reliable evidence that homeopathy is effective.
Homeopathy should not be used to treat health conditions that are chronic, serious, or could become serious. People who choose homeopathy may put their health at risk if they reject or delay treatments for which there is good evidence for safety and effectiveness. People who are considering whether to use homeopathy should first get advice from a registered health practitioner. Those who use homeopathy should tell their health practitioner and should keep taking any prescribed treatments. The National Health and Medical Research Council expects that the Australian public will be offered treatments and therapies based on the best available evidence.

Adverse Effects from Sugar Pills?

Accepting that sugar pills have no medicinal effects, you might understandably be curious how there could possibly be adverse effects from homeopathy. But homeopathy can harm in different ways:

• Through insufficient dilution of the base substance. The “homeopathic” cold remedy Zicam was found to cause permanent loss of smell because it contained zinc and was insufficiently diluted to reduce the toxic effects when applied directly on nasal passages. It wasn’t “homeopathic” at all.
• Through contamination introduced in the manufacturing process, deliberate or otherwise. Homeopathic “alternatives” to antibiotics have been recalled because they contained, yep, antibiotics. Even low-level exposure to antibiotics can cause allergic reactions in people with anaphylactic allergies. Sloppy manufacturing practices have been identified with other manufacturers of homeopathic remedies, raising questions about the quality and safety of these products.
• Finally, homeopathy can indirectly harm through the substitution of homeopathy for more effective treatment. One need only recall the tragedy of the Calgary, Alberta child who died of strep throat because his mother chose homeopathy over medicine. Or the death of infant Gloria Thomas in Australia who died of eczema (eczema!), simply because her parents refused medication, and relied on homeopathy. Her father, a homeopath, and her mother, were eventually convicted of manslaughter.

It’s the last category where most of harms occur from homeopathy. Edzard Ernt, discussing his systematic review of the risks of homeopathy noted:

So, how can a therapy that usually relies on nothing more than placebos cause harm? Many of the patients that experienced harm did so because the use of homeopathy meant that effective treatments were given too late or not at all. In our book TRICK OR TREATMENT, we describe the case of a homeopath who collaborated with my research team while conducting a clinical trial of homeopathy; before the trial had been completed, she died of cancer simply because she self-treated it with homeopathy and thus lost valuable time for proper therapy which might have saved her life. I have said it often and I say it again: if used as an alternative to an effective cure, even the most “harmless” treatment can become life-threatening.

In other cases, adverse effects can occur when remedies are not highly diluted. Most but not all homeopathic remedies are devoid of active molecules. Homeopaths prescribe treatments like arsenic and other highly poisonous substances; if such a remedy is not administered in a much diluted form, it can easily kill whoever is unfortunate enough to take it.

How sugar pills can appear to help (or harm)

Homeopathy can also appear to cause harms which are not due to the remedy itself. Homeopaths have noted that patients may do worse before they appear to improve after starting homeopathic remedies. This is termed an “aggravation” and homeopaths assure us it is normal. From one homeopath’s website,

An aggravation is the temporary appearance of new symptoms, or a temporary intensification of existing symptoms, following a dose of a homeopathic remedy. Aggravations are harmless, usually mild, and short-lived. They sometimes occur following the first dose of a remedy as part of the initial rebalancing effect, or when the remedy has been taken more often than needed, or if the person is unusually sensitive to that particular remedy.

But there is a much simpler and obvious explanation for the homeopathic aggravation. Consider an example of a someone that wants something to help with mild but chronic pain, like osteoarthritis.  In the diagram below I’ve illustrated how someone might report pain on a visual analog score over time. You can see that there’s always some pain, but its intensity changes day-to-day.

Imagine the patient has a surge of pain at t1 and then decided to take a homeopathic remedy. Suddenly the pain appears have been alleviated. This might be attributed to the homeopathy. But what if the patient had waited until t2 to start the homeopathy? There were two pain episodes in the period that follows, though not as bad as the period around t1. This might be described as a “homeopathic aggravation”, as the symptoms appeared to worsen. What the patient doesn’t know is if the homeopathic remedy had any effect at all on the natural fluctuation in the pain. The only way to understand if homeopathy has an effect would be to compare it to placebo in a randomized controlled trial.

There’s also the potential for any intervention to induce nocebo effect, where a substance with no biological effect appears to cause negative effects. Commonly observed in randomized controlled trials with real drugs, it’s only differences from the placebo arm that are considered to be meaningful adverse effects. Yet it can be remarkable how many adverse effects (some of which may be felt to be serious) might be observed in the placebo arm.

What do we know about homeopathy? We know enough

With all this background in mind, let’s now look at the paper, entitled, Adverse effects of homeopathy, what do we know? A systematic review and meta-analysis of randomized controlled trials. Its author is Trine Stub, and the paper is published in the CAM journal Complementary Therapies in Medicine. The objective of the paper was to investigate how adverse effects and aggravations from homeopathy were reported in the literature, to classify the reports according to commonly-accepted criteria, and finally, to compare the risks for patients compared to controls.

1129 RCTs were initially identified. After screening and filtering, 41 RCTs with 6,055 patients were included. Of the 41 trials, only 68% reported adverse effects. More than two third of these events was classified as “minor” and one third as moderate and severe/significant. Adverse effects were physician or patient-reported and in 3 trials, causality was discussed. Five RCTs specifically reported “aggravations”. As per the paper,

Homeopathic aggravations were reported as worsening of the patients’ symptoms, such as exacerbation of allergy, asthma, eczema, headache and hot flushes.

In terms of frequency of adverse effects and aggravations, the following was noted:

• Homeopathy versus overall control : An overall comparison was made between homeopathy and control. Thirty-nine trials (5.902 participants) made this comparison and no significant difference was found between
  homeopathy and control (426/2947 versus 264/2955), with OR 0.99, 95% CI 0.86 to 1.14
• Homeopathy versus placebo: A comparison was made between homeopathy and placebo. Thirty-one trials (4,836 participants) made this comparison and no significant difference was found between homeopathy and placebo.
• Homeopathy versus conventional medicine: There was no significant difference between homeopathy and conventional medicine in a meta-analysis of five trials (43/355 versus 71/401), with OR 0.82, 95% CI 0.56 to 0.1.21.

Conclusion: Placebo versus Placebo?

The authors of they systematic review conclude:

Adverse effects including the concept of homeopathic aggravations are commonly reported in trials. The meta-analysis demonstrated that the proportion of patients experiencing adverse effects to be similar for patients randomized to homeopathic treatment compared to patients randomized to placebo and conventional medicine.

The question they has a much more obvious answer. Sugar pills are going to be associated with adverse events because of the natural history of any condition, and the tendency to given credit for improvement (or blame for negative effects) to the treatment chosen. The review’s findings are exactly what we would expect if we were giving patients sugar pills. There is no such thing as a “homeopathic aggravation” any more than homeopathy can induce a real adverse effect. This systematic review confirms that homeopathy holds the dubious position as the air guitar of medicine.

Homeopathy photo via flickr user Angel Torres used under a CC licence.

from Science-Based Medicine http://ift.tt/2973Xy3