Some history: double-blind trials are a hundred years old (give or take a year)

Sorry, no bad science trashing this week – a bit of scientific historical rambling instead, reflecting another of my part-time interests. Probably too serious, too. I blame the clocks going back – pesky SAD.

The recent plethora of (often rather good) TV and radio programmes commemorating the 90th anniversary of the end of World War One set me to thinking this week.

What is the link between the WW1 trenches, a best-selling modern novel and a pretty good film, and the history of double-blind trials?

The answer is a man – William Halse Rivers FRS (1864-1922), Gold Medallist and Croonian Lecturer of the Royal Society, scientist, ethnographer, founding father of British anthropology, psychology and psychotherapy, Cambridge don, physician, wartime Royal Army Medical Corps doctor and author of a key early account [1] of treating ”war neurosis” – shell shock as they might have said then, post-traumatic stress disorder (PTSD) as we would say now.

Rivers died comparatively young (58), from an acutely ischaemic bowel. He fell ill while alone, and by the time he was discovered it was too late to operate. He was much mourned by his scientific colleagues – for instance, the then President of the Royal Society, the Nobel Laureate Charles Sherrington, referred to Rivers’ death as “cutting short in the fullness of his activity and powers a psychologist and ethnologist of exceptional significance”. Rivers was also mourned by the many young officers with “war neurosis” who he had helped at the Craiglockhart War Hospital near Edinburgh, notable among them the writer and poet Siegfried Sassoon. It is this episode in Rivers’ and Sassoon’s lives that has made Rivers famous again. Their relationship as doctor and patient features centrally in Pat Barker’s novel Regeneration.(1991) and the 1997 film of the same name, aired again recently on the BBC digital channels, in which Jonathan Pryce portrays Rivers.

[The book and film also portray Sassoon’s friendship with another Craiglockhart patient, the war poet Wilfred_Owen. There is a good interview with Pat Barker which discusses her work here]

wartime-riversPryce as Rivers

Caffeine, alcohol, and double-blind trials

As already noted above, Rivers’ career took in an amazing range of disciplines. His role in the instigation of double-blind trials comes from one of the less well-known bits, his researches into the effects of caffeine and alcohol on muscle fatigue. This work was carried out around 1906-7 in Cambridge, and is described in a 1907 paper in the Journal of Physiology [2] and in Rivers’ 1908 Croonian Lectures to the Royal Society [3]. Rivers had been appointed to a Cambridge University lectureship in ‘physiological and experimental psychology’ in 1897, and worked in Cambridge for the rest of his career, barring anthropological expeditions and his wartime work. As the job title suggests, Rivers’ interest was in the interplay of the physiological and the psychological. This can be seen in his interest in the effects of alcohol, where the measured “physiological” changes in a subject’s exercise performance were clearly heavily influenced by his psychological state and reactions. In addition, there was a possible psychological effect on the experimenter, who might bias the results by, for instance, being more encouraging and enthusiastic if he knew the experiment was using the drug rather than the control.

The placebo and blinding techniques Rivers and Webber used were an attempt to minimize these psychological influences. In the 1907 paper they describe the method for the caffeine experiments:

“Each experiment was prolonged over a number of days, on some of which a dose of caffeine was taken, and on others a dose of the control. Both the caffeine and control mixtures were in most cases prepared for us by Dr W. E. Dixon for whose kind help in this respect we are very greatly indebted.

We took the caffeine in the form of the citrate, and the control consisted of a mixture of gentian and citric acid … it was not till the end of the whole experiment that we acquainted ourselves with the nature of the dose on any given day.’

Walter.E. Dixon FRS (1871-1931) was a famous early British pharmacologist who you can read about here. Dixon shared River’s interest in disentangling the psychological and physiological aspects of the effects of things like alcohol. Gentian was presumably used because it has a strong bitter taste, mimicking the bitterness of caffeine; Gentian is one of the main flavours in Angostura Bitters, a fairly loathsome herbal concoction used to this day in making cocktails. For enthusiasts of British Imperial Tradition, Angostura is one of the ingredients in the British Naval officer’s traditional Pink Gin.

Rivers and Webber’s experiments with alcohol used a similar double-blind placebo design, with the alcohol, or (placebo) control, again prepared by a third person and with the experimenter and subject (Rivers and Webber alternated in these roles) not knowing which was which. Disguising the taste of alcohol required a more complex concoction containing capsicum, (hot chilli pepper extract), cardamoms, chloroform and peppermint. What this would have tasted like I cannot imagine, but it must have been quite something.

“Ancient wisdom”, belief, and medicine

Rivers was clearly regarded in his time as a significant scientific figure. Though many of his ideas have inevitably been superseded or disproved, his place as a key founder of British psychology and anthropology, is secure. Indeed, in the age of vanishing habitats, languages, tribal customs and indeed entire ways of life, many of his remarks about primitive peoples, and their endangerment by the actions of Western society, seem prophetic. Rivers studied the social structures of the tribal people of Melanesia – he is said to have felt that his History of Melanesian Society, published in 1914, was his finest work – as well as their traditional healing practises [4]:

I hope that the facts brought forward in these lectures are sufficient to show that in the department of his activity by which he endeavours to cope with disease, ”savage” man is no illogical or prelogical creature, but that his actions are guided by reasoning as definite as that which we can claim for our own medical practices.”

- Rivers, second Fitzpatrick lecture, 1915

So does this mean Rivers would have been a fan of modern alternative medicine, with its enthusiasm for “Ancient Healing Wisdom”? Personally I think not. Rivers was clear that in all his many activities he tried to apply the best of the scientific method as it stood at the time. In the passage above he is saying that “ancient healing wisdom” is based on a clear and structured set of beliefs. He is not saying that these beliefs are true, or that the practises work. Indeed, I suspect Rivers would have believed that any effectiveness of these methods depended on suggestibility, and particularly the patient’s and healer’s shared belief. This shared belief is culturally specific; a traditional healing practise would have a psychological effect dependent on its setting and culture, not due to any “intrinsic power” of the actual healing method.  So what Rivers is saying here is nothing like the “it is traditional and therefore it is just as good as the modern scientific stuff” view popular with modern Alternative Reality types.

Rivers’ treatments of the shell-shocked officers were psychotherapeutic in nature – “talking therapy” – and Rivers was clearly aware of, and fascinated by, the interplay between the physiological and psychological side of medicine and treatment. In this his thinking somewhat puts me in mind of modern medical social scientists who emphasise ”Health_Beliefs” as part of understanding the process of treatment, and the perception of how well it is working.

“As medicine has progressed and has been differentiated from magic and religion, [the] play of psychological factors has not ceased.

Few can now be found who will deny that the success which attended [many remedies and treatment regimes] of the last generation was due mainly, if not entirely, to the play of faith and suggestion. The salient feature of the medicine of today is that these psychical factors are no longer allowed to play their part unwittingly, but are themselves becoming the subject of study, so that the present age is seeing the growth of a rational system of psychotherapeutics.”

- Rivers, final Fitzpatrick lecture, 1917.

Rivers would doubtless have found modern psychological therapies, like Cognitive behavioral therapy (CBT), fascinating. A bit fancifully, I would guess that a Rivers re-born in the modern age would also be fascinated by contemporary research into the placebo effect, in all its different manifestations. I like to think that, faced by modern Alternative Therapy, Rivers would want to insist on a clear-headed scientific discussion of the role played by beliefs and suggestion. He would certainly have insisted on the need to design experiments and trials rigorously to take account of, and where necessary exclude, such effects. After all, before one can study where physiology and psychology interact, one needs to make the effort to be able, as far as possible, to tell them apart. This is as true now as it was when Rivers was doing his caffeine and alcohol experiments a century ago.

Memorials

Rivers is not much remembered these days for his pioneering use of the double-blind experimental design, though he does get an honourable mention for it over at the James Lind Library site. And while Rivers’ role as a founder of modern British psychology and ethnology is well-known in academic circles, it probably does not go far beyond that.

Perhaps fittingly, given the affection in which Rivers was held by so many of those he came into contact with, the aspect of his life that has given him his most lasting memorial was the wise and concerned doctor and therapist, helping his Craiglockhart patients cope with their war nightmares and flashbacks. Apart from Pat Barker’s fictionalized account, Sassoon and his friend Robert Graves both wrote about Rivers in their respective memoirs [5], and Sassoon made clear that he felt Rivers had saved his life –as the poem below, written many years after the war, attests. It is not a terribly good poem, but the last couple of lines of each stanza give a sense of the debt Sassoon felt he owed Rivers. Finally, in a discussion a few years back in the British Medical Journal about “portrayals of doctors in fiction that would be good role models”, the Rivers character portrayed in Regeneration was mentioned several times. Which strikes me as a pretty good way to be remembered.

Revisitation 1934 – Dr W H R Rivers – Siegfried Sassoon

What voice revisits me this night? What face

To my heart’s room returns?

From that perpetual silence where the grace

Of human sainthood burns

Hastes he once more to harmonise and heal?

I know not. Only I feel

His influence undiminished.

And his life’s work, in me and many unfinished.

————————————-

O fathering friend and scientist of good

Who in solitude, one bygone summer’s day,

And in throes of bodily anguish, passed away

From dream and conflict and research-lit lands

Of ethnological learning, – even as you stood

Selfless and ardent, resolute and gay,

So in this hour, in strange survival stands

Your ghost, whom I am powerless to repay.

1. Rivers WHR “The Repression of War Experience” Lancet, XCVI., pp. 513-33, 1918. The article can be found on the net here.

2. Rivers WHR and Webber HN. The action of caffeine on the capacity for muscular work” Journal of Physiology 36: 33-47: 1907 (August).

3. Rivers WHR. “The influence of alcohol and other drugs on fatigue”: Croonian lectures 1906” London: Arnold, 1908 Some pages from the lectures can be read.here.

4. Rivers WHR. “Medicine, Magic and Religion” Fitzpatrick Lectures 1915, 1917.. Lancet 1916; i: 59-65, 117-123; 1917;2: 919-23, 959-64.

5 Sassoon writes about Craiglockhart and Rivers in Sherstons Progress, the third and final part of his memoirs of WW1; Graves mentions Rivers in his famous memoir Goodbye To All That

[BPSDB]

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17 Responses to “Some history: double-blind trials are a hundred years old (give or take a year)”

  1. Neuroskeptic Says:

    Wow – I’d never heard of him. What an interesting guy. Thanks!

  2. draust Says:

    Thanks, Neuro. Rivers certainly is a fascinating character, both in the books and in the historical record.

    The other thing Rivers is best remembered for in experimental neuroscience, which I didn’t mention, was a famous experiment he was involved in with his rather more (neuroscientifically) well-known friend, the pioneering neurologist Henry Head. In 1903 Rivers and Head got a surgeon to cut and then rejoin one of the sensory nerves in Head’s forearm; they then plotted the return of sensation over the next several years (1903-7). Thanks to the wonders of Wikisource, you can now read the whole text of this one online.

    Henry Head actually also appears briefly as a character in the Regeneration trilogy, in the third book The Ghost Road if memory serves. Head was also involved in treated the war wounded in WW1, in his case the more seriously neurologically injured.

  3. Kayleigh Fitzgerald Says:

    Thank you so much for writing this! Having written both Rivers’s and Head’s Wikipedia articles (and hoping to get a biography of the former published), I have many times been dismayed at the lack of interest shown to these great men. I believe draust is not entirely correct in stating that the whole text of Rivers’s and Head’s experiment on nerve regeneration is on Wikisource (mainly because I have been putting it up there and haven’t had time to finish yet) but it is well worth commenting upon. You might also be interested to read Arnold Bennett’s chapter on Rivers in ‘Things that Have Interested Me’- it is both amusing and touching.

    Once again, thank you for this!

  4. dvnutrix Says:

    Remarkably interesting – not least because there are some pre-holiday season experiments being conducted in-house that involve rectified spirit and various flavourings (not gentian but yes, cardamom is having an outing).

    It is always fascinating to read about researchers and scientists with such a diverse range of interests and who are influential in several fields.

  5. Mojo Says:

    “…a hundred years old (give or take a year)”?

    Also from the James Lind Library, an account of the Nuremberg salt test of 1835:

    http://www.jameslindlibrary.org/trial_records/19th_Century/lohner/lohner-commentary.html

    Homoeopathy: failing double-blind trials for 173 years!

  6. draust Says:

    Hi Kayleigh

    Glad you liked the post. I’ve obviously read your very useful Wikipedia entries – in fact when I wrote an earlier brief (non-online) article about Rivers I cited the Wikipedia entry as a good “route” to other material about him.

    Do you mean the Slobodin biography of Rivers? I have read a couple of reviews of it, and a short academic article Slobodin wrote about WHR, but I’ve not read the bio itself. Do I gather you weren’t impressed? I would guess it was a consciously “scholarly academic” book so possibly not written for maximum readability!

    There is apparently a new biography of Henry Head out (which I haven’t read). Pricey, but the sort of thing a University library might have a copy of. There is an extended review of it / account of Head’s life and work here, if you can get past the paywall (Athens/academic login needed, to be technical).

  7. Ephistopeles Says:

    I affirm! The soul is received and registered! ;)

    Thank you for profitable dealing, Doc! :P

  8. draust Says:

    Apparently there is one of Svetlana’s multiple aliases still operating.

    Svetlana – you are on a “trial period” here. Please behave yourself – relevant comments with something to say only -or I will ban this one as well.

  9. draust Says:

    Mojo, that is a great find in the Lind library. The place appears to be a real treasure trove of stuff

    There is another really interesting one about an 1830-ish Russian trial of homeopathy. This one, which had a placebo group, was on Russian soldiers and carried out for the Russian army, though by rather Germanic-sounding physicians. Apparently it led to the banning of homeopathy in Russia for some years afterwards.

    The irony of there having been evidence, by around 1835, that Hahnemann’s ideas about “dilution power” did not cut it in clinical tests is… well, jaw-dropping. This was, after all, only 25 years after the first edition of Hahnemann’s Organon appeared, and within Hahnemann’s own lifetime.

    Of course, other contemporary medical men and scientists could see that the “dilution makes it powerful” idea was a crock, even before it became possible (in 1865, as David Colquhoun has discussed elsewhere) to calculate definitively that many of Hahnemann’s remedies had no molecules in them.

    One is tempted to write something like:

    “By 1865, medical men and scientists had shown that homeopathy didn’t work; it was a placebo, with no effect beyond suggestion, and with remedies containing nothing but water.

    A hundred and forty years on, some people STILL don’t seem to have caught up.

    - Homeopathy: fooling the gullible for 190 years. …And counting. “

  10. David Colquhoun Says:

    Very nice, but the odd thing is that the author of this article, Michael Emmans Dean, still seems to take homeopathy quite seriously,

    His recent Cochrane review of homeopathy for ADHD concluded

    “There is currently little evidence for the efficacy of homeopathy for the treatment of ADHD”

    but then went on

    “Development of optimal treatment protocols is recommended prior to further randomised controlled trials being undertaken”

    Some people never give up flogging of dead horses.

  11. Kayleigh Fitzgerald Says:

    Hi draust,

    I have, for my sins, read the Slobodin book. It is generally awful and I wouldn’t advise anyone to read it. The best source of biographical information on Rivers at the moment is Ian Langham’s book ‘The Building of British Social Anthropology’ but, as Langham points out many times in the course of the book, it is not truly an account of Rivers’s life but more an account of his influence. I have been researching him for the past three years and intend to have a biography published within a few years because one is sorely needed!

    As for Head’s biography, the new one, ‘Medicine and Modernism’, is much more like it! It actually cares about its subject’s life (which is more than can be said about Slobodin’s). As you said, it is expensive, but I find that the Bodleian comes in handy at such times.

    All the best,

    Kayleigh

  12. draust Says:

    David

    - You’re right, Michael Emmans Dean does seem to be pretty pro-homeopathy. There is an enlightening commentary he wrote in that repository of Alt.Reality activist nonsense the Journal for Alternative and Complementary Medicine back when he was a Ph.D. student that gives a sense of his views.

    Dean’s main gripe, from the JACM piece and other things he published (e.g. e-Letters in the BMJ) seems to be that scientists and other “mainstream” types insist there would need to be strong evidence in large-scale clinical trials in order to accept that homeopathy is more than a placebo. Like a lot of social scientists who have worked within the EBM (Evidence-based medicine) and clinical evaluation fields, Dean seems to think it is unfair that scientists view the “prior probability” of things (the underlying theory and proposed mechanism, and how it relates to known and experimentally verified physical reality) as being important.

    Thus scientists and skeptics are unimpressed by weak clinical trial evidence of apparent positive results for homeopathy, because to accept homeopathy requires you to ditch everything we know about physics and chemistry. To a scientist, the likelihood that the apparent positive is a result of poor trial construction, non-excluded biases, or simple random statistics, is greater than the likelihood that homeopathy is more than a placebo and all the underlying chemistry and physics is wrong.

    The best online discussion of this problem is in Kimball Attwood’s masterly article over at Science Based Medicine. In fact, Attwood, Orac and the other SBM folks prefer the term “SBM” specifically because they think the EBM paradigms overrate poor / small clinical trials vis-a-vis good lab experimental evidence when it comes to assessing “scientifically implausible therapies” …select example of your choice. The arguments are laid out in Attwood’s post.

    I don’t know what Michael Emmans Dean is doing these days. He doesn’t seem to be on the University of York’s staff lists, and was never actually on the academic staff – he was a Ph.D. student and then a research fellow. Dean published a book about the history of trials of homeopathy – probably derived from his Ph.D. Thesis – and also apparently wrote a second book on “homeopathic prescribing”, though this one has never been printed as far as I know.

  13. draust Says:

    Kayleigh – there is no doubt having one of the world’s great copyright libraries on your doorstep is very handy for a budding historian or biographer!

    Having met a fair few academic historians of science, I am not altogether surprised some of the biographies they turn out are unreadably turgid. It is a view frequently expressed by scientists that the academic HoS people are writing squarely for people exactly like themselves, not for the general public or even for the “interested reader with some knowledge” (like scientists). Of course, as the HoS folk are academics in a system where they are judged by their peers (RAE and all that) this isn’t a major surprise.

    The main theme of academic bios is often setting the subject in the context of a socio-cultural movement or movements (like “modernism” in the case of Rivers, say), and it is quite often these movements that the writer is most interested in – far more than in the person as a person, and their deeds and character.

    Now it must be admitted that this is a gross generalisation – the person who wrote the Henry Head biography, for instance, is an academic science historian, and the late Roy Porter was especially notable for being a star both in the academic field of science history and in the wider world via his popular books.

    One trend you sometimes see is for a bio written by an academic to become both a strictly academic book (e.g. published in an edition of under a thousand by OUP, or similar, and sold only to University libraries) and a more “popular” book aimed at a wider market. Although even then the readability would be very dependent on exactly how popular the writer wanted to get, or was interested in getting. I sometimes think that the bios that start as academic works, but ultimately make it into the best-seller lists in popular form, tend to be the ones written by people who have done Ph.D.s but then specifically decided not to become academics…!

    Of course, it is often said that bios of scientists are scarce because the public doesn’t see scientists as people they are interested in reading about. Georgina Ferry (who has written several good biographies of 20th century scientists, e.g. of Dorothy Hodgkin and Max Perutz) was saying this not so long ago in the pages of Nature (here, but paywalled). There was also a bit of subsequent discussion on this over at Nature Network.

  14. John H (Lingua Pedantis) Says:

    I loved the Lind library so many thanks ot whoever pointed me in the right direction.

    There are extracts from a book by a doctor called Forbes which rather criticises homeopathy.

    http://www.jameslindlibrary.org/trial_records/19th_Century/forbes/forbes_kp_1.html

    It was a “gratuitous . . .. . outrage to human reason” then and perhaps even more so nowadays.

    Ironic then that the best way to cure someone back in 1846 seemed to be to do nothing, although that could almost be a definition of homeopathy I suppose.

  15. draust Says:

    Perhaps the most famous early 19th century denunciation of homeopathy is that of the distinguished American doctor and writer Oliver Wendell Holmes Sr. (Father of the Supreme Court justice Oliver Wendell Holmes Jr).

    Holmes Sr. gave two public lectures in 1842, published as a pamphlet, called “Homeopathy and its kindred delusions” Some choice Holmes Sr. quotes on homeopathy are in this comment from an earlier post, but I will reproduce one favourite one again:

    “Some of you will probably be more or less troubled by that parody of medieval theology which finds its dogma in the doctrine of homeopathy, its miracle of transubstantiation in the mystery of its dilutions, its church in the people who have mistaken their century, and its priests in those who have mistaken their calling.”

    Holmes, “Medical Essays”

    I first came across this Holmes quote in a wonderful editorial by noted US sceptic and scientist Gerald Weissmann. In his editorial Weissmann also takes the Quacktitioner Royal to task for HRH’s enthusiasm for magical nonsense.

  16. jdc325 Says:

    Nice one DrAust. I like blog posts that delve into the past. Something about science pre-WWII really grabs me. (I find that the period during WWII is an interesting time too, though).

  17. warneurosis Says:

    Great article about dear old Rivers : )

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