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Placebo effect and homœopathic effect
Placebo effect and homoeopathic effect A note on D r Davey'spaper in the M H R G Newsletter R. M. MORRIS-OWEN, BM, BCH
In this comment I am really only dotting a few i's in Dr Davey's paper, but I feel it worthwhile to try and focus from a slightly different viewpoint some of the questions he raises for us. Placebo response is for most of us a concept arising from observation in clinical trials, and implies that changes in a patient's condition have followed the administration of a "treatment" and are ostensibly consequences of the "treatment" although they cannot be direct biochemical or pharmacological consequences, because the material administered in the "treatment" is known to have been inert. Clinical trials are meant to guard us against all the possible sources of error which may distort impressions of the effectiveness of a treatment: fallacy of judgment, self-deception, and sheer coincidence. But it seems that there is also a quite objective process which may be initiated by the pure appearance of a treatment being given under certain conditions. From the point of view of someone organizing a trial to evaluate a drug or treatment, there is no need to distinguish these various kinds of irrelevant effect from each other; the sole purpose is to set their total against the total performance of the active treatment. So if we find that in a certain trial there was a placebo response rate of, say, 30%, we do not know just how much of this was what I would call "objective placebo response" in the sense above defined, and how much represented the operation of more superficial causes of misjudgment. The existence of this objective placebo effect was probably less present in the minds of those who originally designed clinical trials than other sources of error, such as coincidence and wishful thinking. But the emergence of placebo response as something distinct from, and subtler than, these superficial causes of false impression has not really been any great surprise. It merely has borne out what has been widely recognized in a general w a y - - t h a t a patient's attitude and expectations do play a part in determining the outcome of a treatment. But it has shown that this influence can in certain cases be very powerful, can operate in the absence of any specific treatment (provided the motions of giving treatment are gone through) and can have objectively demonstrable effects as well as merely subjective effects. While the results of few, if indeed any, trials have ever been analysed with the aim of distinguishing between "objective placebo effects" and the other types of event or influence that might contribute to a total score of results recorded in a group of patients on placebo, it seems pretty certain that these objective placebo effects can be exceedingly diverse. It would be rash to try and name any clinical 216
The British HomoeopathicJournal
situation in which they could not occur. Moreover there certainly can be such things as placebo reactions (if we distinguish as forms of placebo effect the "response" as a symptomatic improvement from the "reaction" as a symptomatic aggravation or a development of additional symptoms). Thus apparent sideeffects of a drug under trial may be recorded in patients who are in fact getting placebo, as may aggravations in trials of a treatment which could bring them about when the actual substance is given. I have had this very vividly presented to me in the results of a vaccine trial in patients with chronic vasomotor rhinitis, where it was recognized that the vaccine dose selected for use would be excessive for some individuals though suitable for others. It was expected that patients receiving vaccine would varyingly give reports of symptom remission or symptom aggravation, the purpose of the trial being simply to check the impression that a single dose of the vaccine would elicit some kind of symptomatic effect. It was a surprise to find as many instances of aggravation as of improvement among those who reported positive results on placebo. There were in fact even some instances of report of a biphasic effect, aggravation followed by improvement, a pattern which I had assumed would surely be limited to those who had actually had vaccine. The change of physiological behaviour elicited by a placebo in a suitably reactive subject is then capable of great variety and complexity and it is in some way orientated on the clinical situation and the nature of the treatment which has been imitated in administration of the placebo. It is far from being a simple wishful thinking effect, or a mere Coutistic self-suggestion o f " I ' m getting better". The problem of its mechanism breaks down into steps. The end-effect is physiological, observable in changed physiological parameters, or in clinical observation (e.g. of the nasal mucosa in the experiment I have referred to). But what initiates this effect is not a primarily physiological or pharmacological event. It appears to be a mental content of some sort. One thinks of it as an expectation or a pictured possible consequence in the patient's mind---except that there is not as a rule any such conscious content: some of my placebo reactors expressed surprise and it seemed quite genuine surprise; if they had had expectations, the event had been different from what they had been consciously expecting. In any case the basic determinant of what happens appears to be something psychological, rather than physiological, and how this acts is the "psycho-somatic" step in the mechanism. The prior step, which does not concern us at the moment, is how this "subconscious" picture or p r o g r a m m e is formed in a trial situation where treatment is given with a minimum of suggestive communication. Dr Davey's hypothesis deals with this psycho-somatic step. There must be a first step in the sequence of physiological changes that make up the whole effect. He proposes that we consider this to consist in the liberation of neuropeptides from various cells of origin in the central nervous system and the pituitary. In the case of placebo response in a trial of an analgesic the response might be mediated by activation of encephalins, solely or largely, whereas in other cases quite different peptide activations and liberations might be expected to occur, e.g. in initiating changes which end in improved functioning or aggravated dysfunctioning of the nasal mucosa. So we get the notion that a "programme", a psychic Volume 69, Number 4, October 1980
217
pattern developed by some obscure interaction of communication, imagination and speculation, is as it were projected in some way into a specific pattern of neuropeptide liberation. This presumably means a pattern of neuronal excitation. I am reminded of a declaration by Eccles (in a symposium in Studies on the philosophy of Biology, ed: Ayala and Dobzhansky 1974) "When thought leads to action, I am constrained, as a neurophysiologist, to postulate that, in some way completely beyond my understanding, my thinking changes the operant pattern of neuronal activities in my brain". Eccles was talking about the potential changes recorded from the cerebral cortex while a subject decided on and performed a simple voluntary movement. Perhaps we should think of the sort of process Eccles is envisaging transposed to neurosecretory areas or to the brain-stem. Anyhow the point is that we have in the placebo effect a clear-cut specimen case of changes in organic functioning initiated from a non-pharmacological origin. The response to homoeopathic potencies--the "hom~eopathic effect"mis likewise initiated by a stimulus which is "non-pharmacological", in the sense that the material administered introduces no molecule of active drug: the term pharmacology, I take it, is linked to the interaction of molecules with cells or with molecular systems in cell and body fluids. Dr Davey's original and far-reaching hypothesis i s - - i f I may phrase the matter a bit differently--that the physiological impact of potency action occurs at the same point as the physiological impact of placebo action, the action of what I have called the "programme" in the mind of the placebo-reactor, i.e. that as in the placebo effect we picture a mental "programme" projecting physiologically into a particular pattern of neurosecretory activation, so we could try to think of a "potency" similarly projecting into a specific pattern of neurosecretory activation in the hom0eopathic effect. This hypothetical identification of the point of impact and subsequent manner of sequential physiological action in the placebo effect and in the hom~eopathic effect stands on its own as a most important and far-reaching hypothesis even if the detailed development of it, locating this point of impact at the neurosecretory level, should not fully stand the test of time. This identification enables us to consider the distinction between placebo effect and hom~eopathic effect, and it is very important that we should do so. It must be kept very clear that we are not identifying homoeopathic effect and placebo effect entirely. It would be all too easy for superficial people to take away the notion that we are saying that hom0eopathic results are secured through placebo action. The distinction is clear enough in principle. We are postulating that a final common path of action is initiated either by a mental pattern or by a potency. So much of course is evident if the results are the same, but in this hypothesis we are specifically saying that the common path begins at the very first physiological effect, in that the mental programme projects or imprints a pattern on neurosecretory activity and so does the potency. But they will be different patterns and they arise from different kinds of active source. In particular the "programme" is some sort of psychological construct, shaped by psychological processes, whereas the potency conveys something determined in the herb or whatever, some organized totality of effect, various functions of which can be elicited in a dis218
The British HomceopathicJournal
coordinate fashion by the molecular action of various fractions of the raw material. Personally I feel we have to postulate some subtle "receptor" activity in the organism to assimilate, or ignore and reject, the message of the potency and project it into the physiological activity, but that is quite a side-issue at present. The question is: having this relation and distinction between placebo and homoeopathic effects in mind, how are we to substantiate, demonstrate or test, the distinction. One thinks immediately of the apparent specificity of the hom~eopathic effect. The placebo effect depends on the situation and not on the material given, which is meant to be inert, and it does not matter what that material is, provided it fulfils this condition and that of indistinguishability from the active material under trial. The concept of homaeopathy implies that only one, or very few, out of a vast range of potency remedies will elicit the effect. It does matter what remedy is given. Or do we merely believe that it matters? Is the possibility of error and failure in homoeopathic prescribing capable of being developed into an objective distinction between homoeopathic effect and placebo effect? We certainly all observe cases where a first--and perhaps a second or further--trial remedy has no action but a second or later choice is followed by quite amazing results: can we in such cases say that the initial failures have shown that the patient is not a placebo-reactor and therefore support belief that the ultimate effect was not a placebo effect? Do we know enough about placebo effects and their incidence to place any reliance on such an argument? Then there is the specificity not only of remedy to patient, but also, and complementarily, the specific range of effects elicited by any remedy in provings. Does Dr Davey's hypothesis imply--as I think it would--that the development of symptoms in provings is the end result of changes in neuropeptide secretion initiated by the potency? The most direct experimental development of Dr Davey's hypothesis would be to look for changes in circulating peptide levels at appropriate times after administration of placebo or potency, to compare the appearance of any such changes with the manner of response. I do not know if it would be technically feasible, or technically prohibitive, to do this in a large number of cases, studying the levels of many peptides. From the use of a battery of estimations there might emerge characteristic patterns or spectrums of change, differentiating placebo effects and the effects of diverse homaeopathic remedies. In simpler clinical observation a distinction between placebo effects and homaeopathic effects might emerge from a study of time relations. Many homoeopathic responses show a striking delay from the time of administration of a short (e.g. three dose) course of treatment, though others are rapid. Can the placebo responses be similarly delayed? There might at least be some difference between the distribution of dose-response time intervals recorded for a group of placebo responses, and that recorded for a group of ostensible homoeopathic responses, sufficient to indicate that they were probably sample groups of different populations. As Dr Davey indicates, the placebo effect appears to be in some way related to diverse other phenomena which most people would be willing to gather, in a vague Volume 69, Number 4, October 1980
219
and uncritical way, under the heading of suggestion effects. In fact in these instances of changes in physiological state or capacity arising from heightened mental activity, and of altered endurance of injury and pain during intensely emotional activity, the "higher mechanisms" and directing factors must be very diverse. What they have in common is that some kind of non-physical, or certainly non-pharmacological, activity is projected into physiological effects, and one certainly goes with Dr Davey in finding it logical to hypothesize that they all have the same point, or level, of initial impact on physiological process as that postulated for the homoeopathic and placebo effects. REFERENCE Kosterlitz R W. The distinctive characteristic of homceopathic activity. Br Horn J 1944; 34: 95.
Obituary DR F R A N K B O D M A N 1900-1980
It was very much hoped that Dr Margery Blackie would have been able to give the memorial address for her lifelong friend, Dr Frank Bodman . . . and I know she was very anxious to do so. Most unfortunately she is not well enough. I am very conscious of the honour of being asked to pay tribute to such a distinguished friend and colleague. Francis Hervey Bodman M.D. died at his home on 17 January, in his 80th year. He was born in Bristol on 27 November 1900 and educated at Bristol Grammar School. Frank Bodman came from a family with a most remarkable tradition of service to the community in the field of medicine: his father and grandfather were both practising homoeopaths, and two cousins, a brother and a nephew all practised medicine in his life-time. He graduated from Bristol Royal Infirmary in 1925, and he was an unusually gifted student, winning three gold medals. It was perhaps indicative of his diverse interests that he was also a keen member of the hospital rugger team. His house job was in obstetrics, in the days when home deliveries were the rule, and he saw an enormous amount of domiciliary midwifery. After studying homoeopathy in the Royal London Homceopathic Hospital for a year, where he was a contemporary of Dr Margery Blackie, he returned to Bristol to work in general practice. Address given at the Memorial Service held at the Lord Mayor's Chapel in Bristol on 26 March 1980.
220
TheBritish Homoeopathic Journal
In this comment I am really only dotting a few i's in Dr Davey's paper, but I feel it worthwhile to try and focus from a slightly different viewpoint some of the questions he raises for us. Placebo response is for most of us a concept arising from observation in clinical trials, and implies that changes in a patient's condition have followed the administration of a "treatment" and are ostensibly consequences of the "treatment" although they cannot be direct biochemical or pharmacological consequences, because the material administered in the "treatment" is known to have been inert. Clinical trials are meant to guard us against all the possible sources of error which may distort impressions of the effectiveness of a treatment: fallacy of judgment, self-deception, and sheer coincidence. But it seems that there is also a quite objective process which may be initiated by the pure appearance of a treatment being given under certain conditions. From the point of view of someone organizing a trial to evaluate a drug or treatment, there is no need to distinguish these various kinds of irrelevant effect from each other; the sole purpose is to set their total against the total performance of the active treatment. So if we find that in a certain trial there was a placebo response rate of, say, 30%, we do not know just how much of this was what I would call "objective placebo response" in the sense above defined, and how much represented the operation of more superficial causes of misjudgment. The existence of this objective placebo effect was probably less present in the minds of those who originally designed clinical trials than other sources of error, such as coincidence and wishful thinking. But the emergence of placebo response as something distinct from, and subtler than, these superficial causes of false impression has not really been any great surprise. It merely has borne out what has been widely recognized in a general w a y - - t h a t a patient's attitude and expectations do play a part in determining the outcome of a treatment. But it has shown that this influence can in certain cases be very powerful, can operate in the absence of any specific treatment (provided the motions of giving treatment are gone through) and can have objectively demonstrable effects as well as merely subjective effects. While the results of few, if indeed any, trials have ever been analysed with the aim of distinguishing between "objective placebo effects" and the other types of event or influence that might contribute to a total score of results recorded in a group of patients on placebo, it seems pretty certain that these objective placebo effects can be exceedingly diverse. It would be rash to try and name any clinical 216
The British HomoeopathicJournal
situation in which they could not occur. Moreover there certainly can be such things as placebo reactions (if we distinguish as forms of placebo effect the "response" as a symptomatic improvement from the "reaction" as a symptomatic aggravation or a development of additional symptoms). Thus apparent sideeffects of a drug under trial may be recorded in patients who are in fact getting placebo, as may aggravations in trials of a treatment which could bring them about when the actual substance is given. I have had this very vividly presented to me in the results of a vaccine trial in patients with chronic vasomotor rhinitis, where it was recognized that the vaccine dose selected for use would be excessive for some individuals though suitable for others. It was expected that patients receiving vaccine would varyingly give reports of symptom remission or symptom aggravation, the purpose of the trial being simply to check the impression that a single dose of the vaccine would elicit some kind of symptomatic effect. It was a surprise to find as many instances of aggravation as of improvement among those who reported positive results on placebo. There were in fact even some instances of report of a biphasic effect, aggravation followed by improvement, a pattern which I had assumed would surely be limited to those who had actually had vaccine. The change of physiological behaviour elicited by a placebo in a suitably reactive subject is then capable of great variety and complexity and it is in some way orientated on the clinical situation and the nature of the treatment which has been imitated in administration of the placebo. It is far from being a simple wishful thinking effect, or a mere Coutistic self-suggestion o f " I ' m getting better". The problem of its mechanism breaks down into steps. The end-effect is physiological, observable in changed physiological parameters, or in clinical observation (e.g. of the nasal mucosa in the experiment I have referred to). But what initiates this effect is not a primarily physiological or pharmacological event. It appears to be a mental content of some sort. One thinks of it as an expectation or a pictured possible consequence in the patient's mind---except that there is not as a rule any such conscious content: some of my placebo reactors expressed surprise and it seemed quite genuine surprise; if they had had expectations, the event had been different from what they had been consciously expecting. In any case the basic determinant of what happens appears to be something psychological, rather than physiological, and how this acts is the "psycho-somatic" step in the mechanism. The prior step, which does not concern us at the moment, is how this "subconscious" picture or p r o g r a m m e is formed in a trial situation where treatment is given with a minimum of suggestive communication. Dr Davey's hypothesis deals with this psycho-somatic step. There must be a first step in the sequence of physiological changes that make up the whole effect. He proposes that we consider this to consist in the liberation of neuropeptides from various cells of origin in the central nervous system and the pituitary. In the case of placebo response in a trial of an analgesic the response might be mediated by activation of encephalins, solely or largely, whereas in other cases quite different peptide activations and liberations might be expected to occur, e.g. in initiating changes which end in improved functioning or aggravated dysfunctioning of the nasal mucosa. So we get the notion that a "programme", a psychic Volume 69, Number 4, October 1980
217
pattern developed by some obscure interaction of communication, imagination and speculation, is as it were projected in some way into a specific pattern of neuropeptide liberation. This presumably means a pattern of neuronal excitation. I am reminded of a declaration by Eccles (in a symposium in Studies on the philosophy of Biology, ed: Ayala and Dobzhansky 1974) "When thought leads to action, I am constrained, as a neurophysiologist, to postulate that, in some way completely beyond my understanding, my thinking changes the operant pattern of neuronal activities in my brain". Eccles was talking about the potential changes recorded from the cerebral cortex while a subject decided on and performed a simple voluntary movement. Perhaps we should think of the sort of process Eccles is envisaging transposed to neurosecretory areas or to the brain-stem. Anyhow the point is that we have in the placebo effect a clear-cut specimen case of changes in organic functioning initiated from a non-pharmacological origin. The response to homoeopathic potencies--the "hom~eopathic effect"mis likewise initiated by a stimulus which is "non-pharmacological", in the sense that the material administered introduces no molecule of active drug: the term pharmacology, I take it, is linked to the interaction of molecules with cells or with molecular systems in cell and body fluids. Dr Davey's original and far-reaching hypothesis i s - - i f I may phrase the matter a bit differently--that the physiological impact of potency action occurs at the same point as the physiological impact of placebo action, the action of what I have called the "programme" in the mind of the placebo-reactor, i.e. that as in the placebo effect we picture a mental "programme" projecting physiologically into a particular pattern of neurosecretory activation, so we could try to think of a "potency" similarly projecting into a specific pattern of neurosecretory activation in the hom0eopathic effect. This hypothetical identification of the point of impact and subsequent manner of sequential physiological action in the placebo effect and in the hom~eopathic effect stands on its own as a most important and far-reaching hypothesis even if the detailed development of it, locating this point of impact at the neurosecretory level, should not fully stand the test of time. This identification enables us to consider the distinction between placebo effect and hom~eopathic effect, and it is very important that we should do so. It must be kept very clear that we are not identifying homoeopathic effect and placebo effect entirely. It would be all too easy for superficial people to take away the notion that we are saying that hom0eopathic results are secured through placebo action. The distinction is clear enough in principle. We are postulating that a final common path of action is initiated either by a mental pattern or by a potency. So much of course is evident if the results are the same, but in this hypothesis we are specifically saying that the common path begins at the very first physiological effect, in that the mental programme projects or imprints a pattern on neurosecretory activity and so does the potency. But they will be different patterns and they arise from different kinds of active source. In particular the "programme" is some sort of psychological construct, shaped by psychological processes, whereas the potency conveys something determined in the herb or whatever, some organized totality of effect, various functions of which can be elicited in a dis218
The British HomceopathicJournal
coordinate fashion by the molecular action of various fractions of the raw material. Personally I feel we have to postulate some subtle "receptor" activity in the organism to assimilate, or ignore and reject, the message of the potency and project it into the physiological activity, but that is quite a side-issue at present. The question is: having this relation and distinction between placebo and homoeopathic effects in mind, how are we to substantiate, demonstrate or test, the distinction. One thinks immediately of the apparent specificity of the hom~eopathic effect. The placebo effect depends on the situation and not on the material given, which is meant to be inert, and it does not matter what that material is, provided it fulfils this condition and that of indistinguishability from the active material under trial. The concept of homaeopathy implies that only one, or very few, out of a vast range of potency remedies will elicit the effect. It does matter what remedy is given. Or do we merely believe that it matters? Is the possibility of error and failure in homoeopathic prescribing capable of being developed into an objective distinction between homoeopathic effect and placebo effect? We certainly all observe cases where a first--and perhaps a second or further--trial remedy has no action but a second or later choice is followed by quite amazing results: can we in such cases say that the initial failures have shown that the patient is not a placebo-reactor and therefore support belief that the ultimate effect was not a placebo effect? Do we know enough about placebo effects and their incidence to place any reliance on such an argument? Then there is the specificity not only of remedy to patient, but also, and complementarily, the specific range of effects elicited by any remedy in provings. Does Dr Davey's hypothesis imply--as I think it would--that the development of symptoms in provings is the end result of changes in neuropeptide secretion initiated by the potency? The most direct experimental development of Dr Davey's hypothesis would be to look for changes in circulating peptide levels at appropriate times after administration of placebo or potency, to compare the appearance of any such changes with the manner of response. I do not know if it would be technically feasible, or technically prohibitive, to do this in a large number of cases, studying the levels of many peptides. From the use of a battery of estimations there might emerge characteristic patterns or spectrums of change, differentiating placebo effects and the effects of diverse homaeopathic remedies. In simpler clinical observation a distinction between placebo effects and homaeopathic effects might emerge from a study of time relations. Many homoeopathic responses show a striking delay from the time of administration of a short (e.g. three dose) course of treatment, though others are rapid. Can the placebo responses be similarly delayed? There might at least be some difference between the distribution of dose-response time intervals recorded for a group of placebo responses, and that recorded for a group of ostensible homoeopathic responses, sufficient to indicate that they were probably sample groups of different populations. As Dr Davey indicates, the placebo effect appears to be in some way related to diverse other phenomena which most people would be willing to gather, in a vague Volume 69, Number 4, October 1980
219
and uncritical way, under the heading of suggestion effects. In fact in these instances of changes in physiological state or capacity arising from heightened mental activity, and of altered endurance of injury and pain during intensely emotional activity, the "higher mechanisms" and directing factors must be very diverse. What they have in common is that some kind of non-physical, or certainly non-pharmacological, activity is projected into physiological effects, and one certainly goes with Dr Davey in finding it logical to hypothesize that they all have the same point, or level, of initial impact on physiological process as that postulated for the homoeopathic and placebo effects. REFERENCE Kosterlitz R W. The distinctive characteristic of homceopathic activity. Br Horn J 1944; 34: 95.
Obituary DR F R A N K B O D M A N 1900-1980
It was very much hoped that Dr Margery Blackie would have been able to give the memorial address for her lifelong friend, Dr Frank Bodman . . . and I know she was very anxious to do so. Most unfortunately she is not well enough. I am very conscious of the honour of being asked to pay tribute to such a distinguished friend and colleague. Francis Hervey Bodman M.D. died at his home on 17 January, in his 80th year. He was born in Bristol on 27 November 1900 and educated at Bristol Grammar School. Frank Bodman came from a family with a most remarkable tradition of service to the community in the field of medicine: his father and grandfather were both practising homoeopaths, and two cousins, a brother and a nephew all practised medicine in his life-time. He graduated from Bristol Royal Infirmary in 1925, and he was an unusually gifted student, winning three gold medals. It was perhaps indicative of his diverse interests that he was also a keen member of the hospital rugger team. His house job was in obstetrics, in the days when home deliveries were the rule, and he saw an enormous amount of domiciliary midwifery. After studying homoeopathy in the Royal London Homceopathic Hospital for a year, where he was a contemporary of Dr Margery Blackie, he returned to Bristol to work in general practice. Address given at the Memorial Service held at the Lord Mayor's Chapel in Bristol on 26 March 1980.
220
TheBritish Homoeopathic Journal