Double blind seems to be one of those jazzy terms we get excited about when reading a paper because it boosts our faith in its credibility. This is when you perform an experiment where both the tester and the participant are unaware of who is receiving treatment and who is a control – ultimately it aims to reduce bias. Intuitively double blind studies seem completely necessary when testing placebos – but are they? Many don’t think so and are doing just the opposite – that is, an experiment where both the tester and the participant know who is receiving a placebo. This is called an open-label design and it really had me stumped. This summation explained my perplexion well …
1. Find people in pain.
2. Enrol them in a study.
3. Admit you can’t do much to help.
4. Give them a fake pill.
5. Tell them that’s exactly what you are doing.
Slightly oxymoronic
Perhaps, like me, you are new to this term ‘open-label’. Perhaps also, the idea of a open-label placebo study seems slightly oxymoronic. My understanding of placebo was that it involves some sort of trickery such that the patient thought they were receiving the experimental treatment, when in fact, they weren’t. I thought the aim of placebo testing was to assess the power of the perception of receiving a treatment, compared to actually receiving it. How then can you test this perceptual illusion if the patient is aware?
It turns out my understanding of placebo was somewhat misplaced (I console myself in the belief that I don’t think I’m alone here). It turns out deception is not necessary. To provide a placebo is to provide a treatment known to be inert or ineffective – like a sugar pill. The fact that most studies deceive, does not necessitate the need to do so.
Why run an open-label placebo trial?
These open-label trials often come after it has been shown that placebo is just as beneficial (if not more) than a certain treatment. Then comes into question, why does the placebo work? Some believe that it is due to the psychosocial effects of the therapeutic encounter – its interactions, rituals, and symbols. If this is the case, deception shouldn’t be required.
Open label studies also address the ethical conundrum that practitioners face when using treatments that are thought to work because of placebo effects. You see, concealing the knowledge that you are giving a placebo from a patient violates the ethical principles of respect for patient autonomy and informed consent. But if the placebo treatment works without having to lie about it – problem solved!
A few studies have shown positive results even when the placebo’s inert content was divulged to the participant – irritable bowel syndrome, major depressive disorder and ADHD. To add to this line-up, a randomised controlled trial published in Pain in October 2016 (open access) has investigated this phenomenon for those with chronic low back pain.
The test: Take 83 people with chronic low back pain who responded to a flier for “a novel mind–body clinical study”. Tell them that half will be given a placebo – an inactive substance like a flour pill, that contains no active medication. Explain that placebo can be powerful, that the body can automatically respond to it (like Pavlov’s dog), that a positive attitude is helpful but not necessary and that they must take the placebo pill faithfully for 21 days. Then randomly give half the pill (remember to write ‘placebo’ on the bottle) while the other half continue treatment as usual. Three weeks later check for changes to pain and perceived disability.
Are the results clinically relevant?
Turns out the placebo group recorded significantly lower pain scores (Numerical Rating Scale) and lower self-percieved disability (Roland-Morris Quesionnaire). Keep in mind that the pain score reduction was just over 1-point (0-10) and the disability quesionnaire dropped just under 3 points (0-24). While these may seem low for clinical relevance, they were both significantly better than the control group, and importantly had no side-effects or cost.
What, why, how …
There must be some mechanism at play that can explain why honest placebos work. Some offered by the present study include:
This all occurs in the presence of a postive practioner-patient relationship and rationale which may be convincing enough to allow participants to suspend their disbelief.
Participation implies a belief or hope that the treatment might work – and engendering hope when participants feel hopeless about their condition can be therapeutic.
Non-conscious processes actively contribute to placebo responses (i.e. twisting the bottle and swallowing) – but bear in mind, 90% of the participants in this trial were taking pain medication (primarily NSAIDs) before and during the trial.
Spontaneous fluctuations in pain might be interpreted as evidence that placebo is working, thereby strengthening expectations of relief.
So what do you take from all this? Obviously an open-label study introduces a lot of bias compounded by the fact that the outcome measures were subjective. But can placebos really work without the deception? Or have they still been deceptive by describing to the participant the powerful, beneficial effects of placebos prior to testing (after recruiting those interested in a ‘novel mind-body’ study)?
– Hayley Leake
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Interesting approach. It can only be a good thing to test the placebo enigma with a validation test of this nature. The whole placebo notion, seemingly, has engendered a growing tendency to overview subjective pain experiences more critically, where an assumption of delusion or fantasy of pain is not excluded at first encounter. That has obviously become a problem for those experiencing ‘real’ pain, where they must negotiate a degree of scepticism in order to convince, before treatment confidence can be attained.
For me, the problem is not so much whether placebo, either disguised or open-label, is a valid approach. Rather, it is more about having an ability to distinguish between ‘fantasised’ or ‘real’ pain, as presented. My concern would be this….where a placebo might seem to have a beneficial effect on ‘fantasised’ pain experiences, and the same expectations are then transposed onto a ‘real’ pain experience with little or no benefits. In short, outcomes from observations of lesser matters might influence an inappropriate approach to a more serious matter. If an operator is already thinking sceptically, due to an over-familiarity with placebo trials, it might lessen their sense of obligation to react as the circumstances require. I think the bottom line for assessing placebo power should be….that it must always be Plan B, unless the presented pain experience is proven to be delusional or fantasised.
Hey Gerry,
Thanks for the reply. I’m interested in your distinction between ‘real’ pain and a pain experience that is proven to be ‘delusional or fantasied’. Isn’t all pain a subjective experience that can only be described by the person experiencing it – therefore all pain must be real? When you make this distinction are you referring to pain that comes about from obvious tissue damage, compared to that which does not. Or acute pain vs. chronic pain? If this is what you mean, I feel it’s unhelpful and potentially harmful to refer to this kind of pain as ‘delusional or fantasised’.
Hayley
Hi Hayley,
If you might have missed it this is an interesting article in Nature:
“Placebos: Honest fakery”
Jo Marchant, Nature (14 July 2016) doi:10.1038/535S14a
“Kaptchuk, a researcher at Harvard Medical School in Boston, Massachusetts, was showing the audience a cartoon in which a doctor hands over a prescription note. “I want you to take this placebo,” says the white-coated medic to her bemused patient. “If your condition doesn’t improve, I’ll give you a stronger one.”
,….He made headlines in 2010 with a placebo study for irritable bowel syndrome (IBS) in which patients were told that they were receiving a sugar pill11. “Historically, the assumption has been that deception or concealment is necessary for placebos to work,” Kaptchuk says. “My logic was that maybe we could tell patients upfront that placebos may work and tell them to give it a try.” The results were startling: 59% of patients who knowingly took sugar pills reported adequate relief from their symptoms, compared with 35% in the no-treatment group — better than most IBS drugs, he adds. “I was very surprised by the results,” says Kaptchuk, “even though I hoped it would work.”
http://www.nature.com/nature/journal/v535/n7611_supp/full/535S14a.html
Hey Marcel,
Thanks for the article – definitely an interesting read. I quite enjoyed reading about the objective measurable effects found using placebo studies …
“Levine’s study was revolutionary because it suggested that patients don’t simply imagine or pretend that their pain is eased with placebos. Their analgesia reflects a measurable, physical change — mediated by the release in the brain of endogenous opioids called endorphins. This finding has since been confirmed by dozens of brain-imaging studies, which show increased binding of endorphins to opioid receptors in response to placebo painkillers, as well as reduced activity in areas of the brain involved in processing pain.”
Hi Hayley & Co,
For anyone with an interest who hasn’t seen Derren Brown’s two part series on ‘Fear & Faith Placebo’ (UK Chanel 4) it is absolutely mind boggling/blowing.
To Gerry above, I wonder if you can explain the difference between ‘real’ ‘fantasised’ and ‘delusional’ pain?
My understanding is all pain is real and utilising such language offers very little value, unless I have misinterpreted something in you post?
Lastly, can we build a neurophysiological picture of what a placebo/nocebo actually is so as we can better understand and even harness them to treat pain? It’s been a while since I have read specifically on the topics but from memory we are talking about a ‘psycho-neuroendocrine response’ (probably throw in immune into that!) which is predominantly mediated by the brain’s reward circuitry and probably the DNIS?
Max
Hi Max
Brief response. Delusional pain occurs when a person , experiencing a psychological abnormal condition, imagines that they are in pain, for various reasons other than physiological. Fantasised pain occurs when a person incorrectly assumes they must be in pain, mostly due to suggestion arising from an assumption of injury ( nail in the boot, but between the toes, being a typical example, much quoted). Real pain, whether a physiological source has been identified, or not, is the remaining option once the two former options have been discounted. Problem is there are many ‘crossover’ possibilities where the only safe assumption is to assume ‘real’ pain, and to treat as such….even at the expense of medicinally treating something that might be considered dubious. The operator’s judgement can be critically taxed in such circumstances, but the obligation is to offer relief if possible……and maybe, that’s an area where an operator needs to inhibit their notions about placebos, for the general good. Where real pain is concerned, and it is distressing enough, it’s best that tried and tested pain relief is offered, rather than an exploration of possible placebo effects to satisfy an operator’s enquiry.
Operator’s, of course, are entitled to make judgements about presented ailments, but where there is doubt, the obligation must be to treat as ‘real’, until proved otherwise. For me, placebo has little or no effect on real physiologically sourced pain…..except maybe to temporarily calm any catastrophising elements which might be affecting pain tolerance abilities.
Sorry…I did say ‘brief’ !
Gerry, could you name references for the scientific research that has been published let’s say on Pubmed that has identified the mere existence of “delusional or fantisized” pain?
Now you say: ” Real pain, whether a physiological source has been identified, or not, is the remaining option once the two former options have been discounted.”
That’s a contradictio in terminis.
Just wondering, do you see patients professionally (those with pain)?
Yes, what all humans seek is connection — genuine, authentic, interpersonal connection.
“This all occurs in the presence of a postive practioner-patient relationship and rationale which may be convincing enough to allow participants to suspend their disbelief.”
When Dr Herbert Benson was keen on conducting further research in to the mind body connection, through a serendipitous coincidence the Dalai Llama was visiting Harvard University,
Benson asked for his help in studying the breath of fire meditation with experienced monks. The Dalai Llama agreed to help on the condition Dr Benson also considered the difference in ‘Western’ and ‘Eastern’ Doctors approach to treating Patients.
The results are written up in Dr Benson’s follow up book to ‘The Relaxation Response’ – ‘Beyond The Relaxation Response’. His research showed the ‘Doctor – Patient’ relationship is a vital element in healing.