Placebo is an inert substance – or at least, a substance that is objectively without specific activity for the condition being treated. Dan Moerman has written about the so-called ‘placebo response’ and suggests that it should be called the ‘meaning response’ because humans attribute meaning to the interaction between a health care provider and a patient, and he argues that it is this meaning that influences the response in the patient. This definition is helpful for moving the source of ‘action’ in a placebo away from the inert substance and on to the interaction between the treatment provider and the person in whom the response occurs.
There are loads of reasons for researchers to be bothered by the meaning response – all of these randomised controlled trials in which one arm of the research uses placebo are confounded by the numbers of people who respond positively despite receiving the placebo dose (oh and yes, they can also respond negatively – the ‘nocebo’ effect that might include ‘side effects’ like nausea or headache). The gold standard in research is to compare the results of giving nothing with the results from giving an active ‘something’ – so to have the ‘nothing’ produce an effect is pretty awkward.
This paper by Doherty and Dieppe reviews the evidence for placebo response in randomised controlled trials in treatments for osteoarthritis. The authors specifically looked for trials with no treatment control groups, and to identify possible determinants of the size of any such effects. They reviewed 198 trials that met the inclusion criteria – 16,364 patients who had received placebo and 1,167 patients who had received active treatments of many types including pharmacological, nonpharmacological and invasive treatments.
The good news? Well, receiving placebo had a positive response for pain reduction (effect size of 0.51 (95%CI 0.46 to 0.55). Oh darn, that wasn’t what was being tested? If the patients received nothing (ie the research didn’t include a placebo group, but instead had a non-treatment comparison group), the effect size was almost zero (ES 0.03, 95% CI -0.13 to 0.18). So giving nothing at all meant nothing changed. The effect size was even higher in head-to-head comparisons between placebo and no treatment (ES 0.77, 95% CI 0.65 to 0.89). So giving something that doesn’t have an active ingredient works better than giving nothing at all. Curious.
The authors go on to identify significant independent effects for the outcome of pain relief – these include that the higher the treatment effect size, the higher the placebo effect; the higher the pain was initially, the greater the effect size in the placebo group; the larger the study, the higher the placebo effect; and finally, how the treatment was delivered made a difference as well – repeated needling had the highest placebo effect.
The scary thing for me is knowing that there is a systematic bias, demonstrated by a skewed distribution of the effect size, suggesting that ‘trials with smaller placebo effects are more likely to be published, perhaps because it is easeir to demonstrate the superiority of a treatment when this occurs’. But this effect size is influenced by the size of the study – so be aware!
Back to what this means in practice. We need to review what may be going on when a person receives a placebo (and, for that matter, an active treatment). There is a good deal of research on the factors that are known to influence the ‘meaning response’ in people. Dan Moerman’s book ‘Meaning, Medicine and the ‘Placebo Effect’ reads well, and describes some of the known factors – such as mode of delivery (injections are more likely to produce a greater effect than a pill); colour of pill (pink pills are responded to as stimulating, while blue pills are responded to as sedating); number of pills (more pills = greater effect); and the bits I’m most interested in, response expectancy, conditioning and the relationship between the person and the treatment provider.
Response expectancy is the expectation a person holds about what the treatment will do. Being told what a treatment is meant to achieve influences outcome – so we know that if we infuse our instructions about going for a walk with the idea that not only does it help with mobility and fitness, but it makes you feel good – then participants are more likely to report feeling good after a walk than those who didn’t get that instruction. Simply knowing that a treatment is being given has an effect – whether that treatment is placebo or not.
In conditioning, the response is associated with an aspect of the treatment – for example, in this paper, the authors describe people being given a green liquid to drink along with an immunosuppressant. After four doses given this way over a week, the participants were then given four doses of a placebo and the green liquid over a week – and lo and behold, the same immunosuppression response occurred.
Where the treatment occurs is also highly significant. Pleasant surroundings seems to improve recovery, a quiet tranquil setting aids relaxation, a messy office does not inspire confidence (hence I don’t see people in my office!).
And the final ingredient is the relationship between the person receiving the treatment and the person giving the treatment. From the words used, the attention given, the ‘therapeutic ritual’, even the amount of time spent with the person – these all influence the response in the patient.
What does it mean?
Doherty and Dieppe suggest that because placebo affects ‘the illness’ rather than ‘the disease’ (ie pain rather than x-rays), the value of it is primarily for patient symptoms and distress. I’m not surprised – these are the targets of many interventions for painful conditions such as low back pain, headache and so on. They, somewhat surprisingly, suggest that ‘we should be more aware of the power of the placebo response to relieve pain and suffering in people with OA, and that we should learn how to use it better’. My surprise is that it’s not the placebo that we want to use – after all, placebo is inert – it’s the meaning response we want to influence in patients, so they can maximise the positive benefits from the interactions they have with us as treatment providers.
The recommendations Doherty and Dieppe suggest don’t sound over the top – being calm, unhurried, focusing on the patient, having a comfortable environment, explaining what is going on in terms the patient understands – isn’t this basic human compassion? This is, as Doherty and Dieppe acknowledge, a treatment. (Isn’t this so true of so-called complementary health consultations? Maybe that’s why they have such a profound effect on some people). Perhaps if we valued time and caring (and made sure these were never compromised irrespective of the demands to ‘increase throughput’), our patients might benefit as much as we would?
Doherty, M., & Dieppe, P. (2009). The “placebo” response in osteoarthritis and its implications for clinical practice Osteoarthritis and Cartilage DOI: 10.1016/j.joca.2009.03.023