Last month, PLOS One published a study which held significant interest for me; as a long time sufferer from acid reflux (which is currently reasonably controlled by regular use of a PPI – Proton-pump inhibitor – class of prescription antacid), I was curious to dive into this Randomized Controlled Trial (RCT) study from Beth Israel Deaconess in Boston, in which the investigators observed that Patient-Provider Interactions Affect Symptoms in Gastroesophageal Reflux Disease (GERD) as well as dyspepsia and other acid-reflux related issues, which affect 2-4 out of every 10 people in Western world (similar statistics were observed in the Northern part of India). The name of the study medication, Acidil, wasn’t immediately familiar to me, but it turned out to be a ‘homeopathic preparation’, which – along with the placebo-controlled designed – piqued my interest further. Although the severity of GERD symptoms may fluctuate due to different reasons, it is usually not one of those self-correcting conditions in which homeopaths often claim beneficial effect. So, sufficiently interested, I delved deeper.
The double-blind, placebo-controlled, randomized study – although short (only two weeks of observation) and small (only 24 subjects) – was otherwise reasonably well designed with the following arms and interventions:
|Standard Physician visit (Modeled on conventional Primary Care medical visit) – median length: 18 minutes
Asked questions about:
Acidil prescribed after brief physical exam.
Asked questions about:
Placebo prescribed after brief physical exam.
Expanded Physician visit (alloted extra time for ancillary questions) – median length: 42 minutes
Standard visit questions, plus:
Acidil prescribed after brief physical exam.
Standard visit questions, plus:
Placebo prescribed after brief physical exam.
The physician visit was single blinded, in that all subjects expected to be seen by the single study-physician, but they weren’t informed – prior to the end-of-study debriefing – that the physician-patient interaction was also being studied; both the physician and the patients were blinded (double-blind design) to the randomization to the acidil and placebo groups; subjects knew they’d get either “a natural supplement containing 4 plant-based ingredients in low dose” or a placebo, but had no way of knowing what they were taking, since both were tablets, looking and tasting similar, and identically packaged. The instructions for the usage of both were identical, and both groups were given mineral-salt-based, acid-neutralizing antacids for relief of severe breakthrough acid reflux symptoms, if necessary. All in all, a sound study design.
Study medicine ACIDIL: effective? “homeopathy”?
A few words about Acidil, the “natural supplement with plant-based ingredients”. According to the manufacturer, this tablet contains ingredients officially listed in HPUS, the Homeopathic Pharmacopeia of the United States, as plant-origin substances capable of relieving various acid reflux symptoms. What are these plants? First, Abies nigra, currently known taxonomically as Picea mariana, and commonly, Black Spruce, an evergreen conifer growing in colder climates of North America. The manufacturer claims this ingredient “Relieves stomach pain after eating“; however, searching PubMed for Abies Nigra (or Black Spruce) with GERD or acid reflux returns zero hits.
The next component is Carbo vegetabilis, credited with the ability to “relieve stomach bloating with gas“. This may be a claim that is the closest to being valid in part, since Carbo Veg (as it is popularly known) is not a plant, but basically activated charcoal – and activated charcoal is a highly porous material capable of non-specifically adsorbing liquids or gas. Charcoal is the black, carbon-containing, ashy residue left after animal or plant matter is slowly heated to high temperatures; further processing of charcoal using hot gases or chemical substances in presence of high heat increases its porosity significantly, creating activated charcoal, which has been used to trap certain chemicals as a treatment for poisonings, but the evidence of its efficacy is lowering flatulence is sketchy at best. Moreover, since the adsorptive function of activated charcoal is non-specific, therefore its co-administration with any other substance may have undesirable effects, and is contra-indicated in medication combinations.
Next we have is Robinia pseudoacacia, or Black Locust, a tree of the pea family found in temperate regions of most continents. According to the Acidil manufacturer, it is supposedly able to “relieve heartburn with acid indigestion“, of which there is no evidence in established medical literature. However, as a matter of fact, one variety of R. pseudoacacia produces a stilbene-like substance called amorphastilbol, which – like resveratrol found in red wine – modifies the expression of certain genes to improve glucose and lipid metabolism, similar in action to the anti-diabetic troglitazone, as seen in diabetic animal models. Research in this field is ongoing, and who knows – pharmacognostic studies may one-day produce another effective anti-diabetic in the same way the anti-malarial Artimesenin was discovered. But in the context, R. pseudoacacia extract or amorphastilbol doesn’t appear to have any GERD-specific effect.
And the final supposedly-active ingredient is a favorite of homeopaths all over the world, Nux Vomica, basically a formulation of the highly poisonous, bitter alkaloid strychnine, produced by the ‘poison nut tree’ Strychnos nux-vomica, native to India and other parts of Southeast Asia. Strychnine and other poisonous alkaloids are present in the seeds, blossoms and barks of the tree. According to the Acidil manufacturer, it “Relieves heartburn due to excessive eating and drinking“, a claim which doesn’t find wide support in established medical literature. However, strychnine is an antagonist for glycine receptors present in spinal neurons controling muscle contraction, and prevents binding of the neurotransmitter glycine to these receptors, causing a tonic contraction of certain muscles, including respiratory muscles – which can lead to death (depending upon the dosage); there is some evidence that strychnine, acting via a different mechanism, may prevent the relaxation of the circular muscle fibers of the lower esophageal sphincter at the junction of the stomach – thereby reducing acid reflux. It is important to note here that these studies were done ex vivo, using donated tissues; the dose of strychnine required to produce the reflux-reduction effect is likely to be deadly to the patient.
Then how are these substances used in the product Acidil? Starting with the plant (and charcoal) extracts, all these ingredients are diluted to 4C, which means a dilution of 1004 or 108, i.e. a final dilution of 1 part of the ingredient in 100 million parts of the solvent, or 10 ppb (parts per billion) – an extremely low concentration at which strychnine is unlikely to be toxic, which goes for other ingredients as well. What is not known is whether any of these ingredients will be active at that concentration. So, does Acidil work as claimed for the acid-reflux associated conditions it supposedly treats? The jury’s still out on that.
That brings me to a technical issue related to homeopathy as well. Even if by some magic, these ingredients manage to retain their biological activities at this low concentration, can this preparation be really called “homeopathic”? Classical homeopathy often prescribes doses that are serially diluted to the point where it is physico-chemically implausible for the dilution to contain even a single molecule of the original solute, such as 20C and 200X. This stems from the belief, unsubstantiated by any empirical evidence, the more dilute a substance is, the stronger its effect is – a process referred to as ‘Potentization’. This is one of the foundational principles of classical homeopathy as devised by Samuel Hahnemann. Therefore, can remedy formulations at 4C, where the molecules of the ingredients are still present in the solution, be truly considered homeopathic?
And now, back to the discussion of the main study:
The study protocol is not out of the ordinary for this type of study. The subjects were required to:
- Maintain a symptom diary, to be completed daily for 7 days before enrollment, and the duration of the two-week study.
- Record on a 5-point scale the severity of 9 different GERD and dyspepsia-associated symptoms, defined in the study as: daytime heartburn, nighttime heartburn, acid regurgitation, upper abdominal pain, fullness after eating, early satiety, flatulence, belching, and nausea. These scores were used to assess symptoms and treatment progress.
- Track their usage of study medication (acidil or placebo) and/or rescue antacid when needed.
What I found interesting was that subjects were asked to complete a questionnaire on patients’ beliefs associated with CIM (“Complementary and Integrative Medicine”; the currently-favored designation for alternative medicine); prima facie it makes no sense, since ordinarily the efficacy of pharmacological interventions on the physiological system is not a matter of ‘belief’. However, it has to be borne in mind that belief in the treatment and positive expectations of outcomes are two of the major players in the non-specific Placebo Effect which is known to influence treatment outcome. Therefore, making a baseline estimation of this variable in this study wasn’t logically unfounded. However, it also revealed that CIM beliefs of all participants, regardless of the assigned treatment groups, were rather high (see table 1), which likely made this group of participants the best-suited to estimate the efficacy of an alternative medicine modality – but, by the same token, subject to a lot of ill-defined variables that could confound analysis.
This under-powered study with small sample size (only 6 subjects per group) nevertheless provided a few major observation points, some of which, I find, have not been highlighted adequately in the discussion after the results.
- GERD symptom improvement from baseline to week 2: No significant difference between Acidil and Placebo group.
- Changes in symptoms of dyspepsia co-occurring with GERD: Again, no significant difference between Acidil and Placebo group.
I would like you, dear reader, to appreciate these observations maximally. Despite being a population with high inclinations to believe in the power of alternative medicine (high CAMBI scores), the subjects of this study showed NO DIFFERENCE in their physiological reactions to Acidil, a ‘homeopathic’ supplement, or placebo. This is not surprising to me; there is no evidence that any of the ingredients in this plant-based preparation actually works to alleviate the symptoms of GERD as claimed, and here is empirical evidence that such a preparation fared no better than medically-useless, inactive substance-laden, placebo.
To restate the obvious, then, homeopathic remedy, claimed to be effective in GERD, is found to be not, even though the authors take pains to point out in the discussion that this study should not be seen as a test of homeopathy especially because of shortcomings in the study design. To my mind, that protestation by the authors doesn’t quite wash, given that hypothesis (2b) mentioned in their study protocol (available as supplementary information) clearly mentions “homeopathic theory” – and they also mention the justifiably-debunked (see critique by Steven Novella) “Swiss Government study” which homeopathy aficionados tenaciously cling to, while ignoring both the 2010 British report and 2015 Australian report that found homeopathy effects are not more detectable over those of placebo. You know, exactly what the authors found out in this study.
So, what did work – in that some of the subjects reported a lessening of the GERD severity? Therein lies the interesting part of this study. Compared to subjects who had the regular physician visit, subjects who received the extended consultation from the physician reported significantly better improvement of GERD and/or dyspepsia symptoms (as well as less usage of rescue antacids) in two weeks after starting the treatment, regardless of whether they took Acidil or the placebo.
What the authors – a bit surprisingly – omitted to provide in the main paper (beyond sketchy mentions) is the data on usage of rescue medication, type and frequency, by the participants, which clearly can have an effect on the outcome. However, considering all the factors the authors could and could not determine, it appears that the inchoate, ill-defined, poorly-characterized variable of “patient-provider relationship” is of clinical significance when it comes to beneficial effects of otherwise implausible alternative-medicine modalities; aspects of the visit (not defined, but most likely anything contributing to the patients’ perception of the physician giving them better attention and/or empathy) appear to have had a positive effect.
In clinical medicine, this phenomenon is not unknown. For instance, in a study of over 700 patients, the perception of patients regarding empathy in a therapeutic encounter led to significant reduction in severity, duration, and objective measures of common cold, a viral illness. A widely-cited systematic review of RCTs published in the Lancet found that despite various inconsistencies in the outcome reports, one persistently observable effect was that warm, friendly physicians with a reassuring manner appeared to be more effective in terms of health outcomes. Ted Kaptchuk, one of the authors of this current study, has demonstrated the benefit from supportive patient-physician relationship in an acupuncture study with patients of irritable bowel syndrome (IBS). A more recent systematic review from the same institution as with the current study, looking at patient-physician relationship over a wide range of clinical situations, found a small but statistically significant effect of such a relationsip on the clinical outcomes, and went on to suggest that clinicians receiving interpersonal training as a part of their medical education may be beneficial. For sure, the psychobiological phenomena associated with the Placebo effect may be ill-defined, but their presence is observable in medicine associated with both physical and mental health, something I had commented upon several years ago.
Right here, then, is the main mode of action of homeopathy – or for that matter, most alternative medicine modalities – a sympathetic ear from the physician. The perception of empathy from the practitioner – a verbal ‘spoonful of sugar’, perhaps? – may sometimes make even implausible remedies have an effect. The question remains, is it ethical to base on this feel-good factor a therapeutic regimen for a patient in need of proper clinical attention? My answer would be a resounding ‘NO’.
Dossett, M., Mu, L., Davis, R., Bell, I., Lembo, A., Kaptchuk, T., & Yeh, G. (2015). Patient-Provider Interactions Affect Symptoms in Gastroesophageal Reflux Disease: A Pilot Randomized, Double-Blind, Placebo-Controlled Trial PLOS ONE, 10 (9) DOI: 10.1371/journal.pone.0136855