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Many observations support a major biological effect from the way in which people interpret the meaning of each component of their medical experience and the context in which this occurs. A recent systematic review of randomised controlled trials in osteoarthritis has demonstrated that the effect size of “placebo” is substantial and is usually greater than that obtained from the specific effect of an individual treatment. In the context of a randomised controlled trial, such a large placebo or “meaning” response is considered a nuisance, but in the context of clinical practice the optimisation of such meaning and contextual responses, through enhanced “care”, could greatly benefit people who suffer from osteoarthritis.
. This confirmed the appreciable effect size (ES) of “placebos” on pain relief and identified some of the factors that may determine the size of this effect in RCTs. These findings clearly are of relevance to the design of OA RCTs and to the interpretation of the true ES of treatments. More importantly, however, these results have important implications for clinical practice. Here we will: (1) briefly review the history, nomenclature and changing perspective of “placebo”; (2) summarise the findings of our meta-analysis; (3) present related key observations taken largely from the pain and mental health literature; and finally (4) explain how this knowledge might influence our behaviour as clinicians and the care that we offer patients with OA.
Historical changes in perspective concerning placebo
Prior to the mid 20th century it was commonplace for doctors to prescribe placebos with the assurance that they would lead to health and coping benefits
. Placebo means “I will please” and up until the 1950s the prevailing view was that products such as bread pills, coloured water, or water injections, would do no harm and by a psychological trick could comfort patients with incurable conditions, especially those low in intellect or “inadequate” and thus more susceptible to suggestion
In the second quarter of the 20th century, however, two parallel developments changed this perspective. Firstly, the advances in effective drug discovery, and secondly the developments in medical statistics and epidemiology that led to introduction of the RCT as the gold standard for clinical trials. In a landmark publication in 1955 entitled “The Powerful Placebo”
Henry Beecher described the occurrence in RCTs of real, not imagined, objective benefits from placebo in around 35% of patients. He reasoned that the total benefit from a treatment equals the “real” or specific effect of the treatment plus the non-specific placebo effect, and importantly concluded that response to placebo was irrespective of IQ. Subsequent research focused on how this effect may arise, and amongst mechanisms suggested were the Hawthorne effect (behaviour change through being observed); patient expectation of improvement; a “meaning response”; classic conditioning; relief of anxiety; contextual healing; response bias; and the patient–practitioner interaction
There has been much controversy over the meaning of the word ‘placebo’ and it is important to distinguish placebo responses (sometimes called ‘context effects’) from placebo interventions
; he distinguishes the characteristic effects of an intervention for the target condition, from all the non-characteristic (or incidental) effects related to the use of that intervention. Thus, for example, a sugar pill might be used as a placebo tablet in a trial of an antidepressant drug since sugar is not thought to have any specific (characteristic) effect on depression – but the same could not be said for diabetes. And if a sugar pill placebo was used in a trial of antidepressant therapy, then its effects will depend on a huge number of contextual factors surrounding its administration, as outlined below. Paterson and Dieppe have pointed out that in many complex interventions used for conditions such as OA these non-characteristic (context) effects may interact with the characteristic effects
. This not only makes it more difficult to interpret the results of trials, it can invalidate the use of the classical RCT as a way of assessing the value of such interventions (Fig. 1).
Fig. 1The effects of any treatment can be divided into ‘characteristic effects’ (the specific effects of the intervention on the target disorder), and incidental effects (also called non-characteristic effects, context effects, the meaning response or placebo effects), which are a complex combination of all the other factors affecting the outcome (box on left of diagram). For problems such as pain and depression the size of the incidental element is often larger than that of the characteristic element. In many complex interventions, such as physiotherapy, there is an interaction between characteristic elements (e.g., muscle strengthening) and incidental elements (e.g., motivation by the physiotherapist). This can lead to under-estimation of the effect of an intervention if a classical RCT is used to test it, as such trial designs only measure the difference between characteristic elements and non-characteristic elements.
At the turn of this century the existence of placebo response was challenged. In a systematic review of RCTs that randomised participants to either placebo or no treatment (observation only), Hrobjartsson and Gotzsche found no significant benefit from placebo for binary or objective outcomes, but possible small benefits for continuous subjective outcomes and for the treatment of pain
, this publication rekindled the debate about placebos. Alternative explanations for apparent placebo benefits in RCTs included unmeasured concomitant treatments and the patient's desire to please the doctor (the “patient's placebo”), but also impersonal statistical artefacts of measurement such as natural fluctuations in disease severity and regression to the mean
. A key reason for such controversy and confusion is that inclusion of a placebo in RCTs is the accepted gold standard for the assessment of intervention effects, and unless a no-treatment control is also included (an approach often considered unethical) it is impossible to ascertain what effect the placebo might have – in effect the RCT is a way of deliberately ignoring placebo responses
. It was because of such controversy and confusion that we decided to examine whether there was evidence for placebo response in OA RCTs, looking specifically for trials with no treatment control groups, and to identify possible determinants of the size of any such effects
We identified by systematic review 198 trials that met our inclusion criteria. These comprised 193 placebo groups (16,364 patients) and 14 untreated control groups (1167 patients) and examined a range of non-pharmacological, pharmacological and invasive treatments. There was clear evidence to support positive benefits from placebo. For pain relief the overall ES (the standard mean difference between baseline and endpoint) was 0.51 [95% confidence interval (CI) 0.46–0.55] for placebo, but almost 0 for untreated controls (ES 0.03, 95% CI −0.13 to 0.18). This ES was even higher (0.77, 95% CI 0.65–0.89) in the three trials that had head-to-head comparison between placebo and no treatment. The ES for pain relief was also higher (0.71, 95% CI 0.64–0.78) in the 15 trials that gave no rescue analgesia, perhaps reflecting a greater expectation of powerful effect if no rescue was offered. Placebo was also effective for other subjective outcomes, for example stiffness (ES 0.43, 95% CI 0.38–0.49), self-reported function (ES 0.49, 95% CI 0.44–0.54) and interestingly, physician's global assessment (ES 0.66, 95% CI 0.53–0.78).
With respect to determinants of magnitude, the following showed significant independent effects for the primary outcome of pain relief:
The ES of the treatment: the higher the treatment ES the higher the placebo effect, perhaps explained by higher expectation of benefit by participants.
The baseline level of pain: the higher this was, the greater the placebo ES.
The sample size: the larger the study numbers the higher the placebo effect. This might be explained by the power requirements to differentiate the relatively small additional benefit of treatments over placebo. Similarly, the funnel plot of ES for pain relief showed a skewed distribution, suggesting that trials with smaller placebo effects are more likely to be published, perhaps because it is easier to demonstrate superiority of a treatment when this occurs.
The route of delivery: RCTs involving repeated needling (acupuncture, intra-articular injection of hyaluronan) had the highest placebo effects (Fig. 2). Interestingly, the one steroid injection study that gave serial injections had a higher placebo ES than studies involving single injection. RCTs of topical NSAID also had higher than average placebo ES.
Fig. 2Treatments delivered by needling, such as acupuncture (shown above, with burning moxa) and intra-articular injection (shown below) seem to associate with greater expectancy, higher placebo effects, and more “magic”.
Such determinants provide reassurance of the validity of our main finding. Therefore, we found unequivocal evidence of a large placebo response in OA, particularly for pain relief. Notably the ES of placebo (0.5–0.7) is much larger than that achieved with most of our conventional therapies, such as analgesic and anti-inflammatory drugs (0.2–0.3)
and some Press to wrongly conclude that conventional therapy was of little or no value.
The determinants of “placebo responses”
Although hardly studied in OA, there is a large literature on placebo and the non-specific effects of care in other areas of medicine. Examples, especially from pain and mental health studies, are worth examining here since they are largely generic and therefore relevant to OA. Many observations point to a major biological effect from the way people interpret the meaning of each component of their medical experience and the context in which it occurs. The term “meaning response” encapsulates these explanatory mechanisms, and placebo is just one example of the responses that are integral to any clinical encounter or treatment
. Although most examples relate to drugs, the principles probably extend to any intervention.
Colour and number
In a classic experiment medical students were given either one or two blue or pink tablets and told that one was a stimulant and the other a sedative, though in fact both were inert. Overall, pink tablets caused stimulant effects and blue tablets sedation, and two tablets had more effect than one
. Clearly these effects are nothing to do with regression to the mean or disease fluctuation, but are explained by the meaning associated with the colour (pink for hot, blue for cool) and the expectancy that a double is more potent than a single dose. A systematic review in 1996 concluded that green and blue may have more sedative, and red and orange more stimulant effects, and that this difference is reflected in the colour of marketed drugs, perhaps boosting their efficacy
, perhaps because blue is the national soccer team colour and associates in men with feelings of excitement. Thus it is not the colour per se that influences the outcome, but the meaning attributed to it by an individual.
Branding and cost
Having the confidence that the treatment you are receiving is reputable and “high class” makes a difference to outcome. In a placebo-controlled trial of aspirin for relief of headache, patients were randomised to one of four treatments: aspirin labelled with a well-known brand; plain unbranded aspirin; placebo marked with the same brand; or plain placebo. Aspirin worked better than placebo, but branded tablets worked better than their unbranded counterparts
. A recent US placebo analgesic study also showed that patients who were told that their tablets were obtained at full cost ($2.50) obtained better pain relief than those who were told their tablets were discounted at just 10 cents
Surgery, of course, is one of the ultimate treatments in terms of magnitude. In OA, the report that invasive arthroscopic lavage, with or without debridement, is no better than sham procedure
since it implied that the benefit to the patient resulted from the expectancy and experience of the intervention rather than to whatever was done inside the joint. Understandably, for ethical reasons, there are very few placebo-controlled studies of surgery. However, in 1959
two small controlled studies examined the efficacy of bilateral internal mammary ligation (BIMAL) for treating angina. This procedure was widely practiced at the time; the rationale being that ligation of these arteries would redirect more blood through the coronary arteries. The combined results of the two studies showed that 73% of patients (24/33) undergoing BIMAL had significant improvement with reduced angina, better exercise tolerance, and reduced nitrate consumption. However, 83% of patients (10/12) who received sham surgery (anaesthesia, chest incision, artery exposed but not ligated) showed similar substantial improvement. Because of prevailing ethical considerations, whether many currently performed technical procedures give any benefit above the experience of surgery itself will remain open to question.
Response expectancy and concealment
The expectation of what a treatment will do is an important determinant of the outcome. In a study of aerobic exercise one group was told that their aerobic capacity should increase after 10 weeks of the programme, and the other group was told that their fitness would improve but also their wellbeing would be enhanced. Both groups equally improved aerobic capacity but only the second group reported feeling better
. In a study of the physiological effects of coffee, one group was given either regular or decaffeinated coffee in a double blind design, while a second group was told they would all receive regular coffee, but in fact was given decaffeinated. Increase in pulse rate, alertness and blood pressure changes were greater in the second group (who were all expecting such effects) than in those given decaffeinated coffee in the first group (who believed they had only a 50:50 chance of having active coffee)
. Such response expectancy can even reverse the pharmacological effect of a drug. For example, ipecachuana (a potent emetic) can improve nausea if patients are told that they are receiving an anti-emetic
Knowing that a treatment is being given is important. In a post-operative analgesia study, patients who could see morphine being administered into their line obtained rapid and effective pain relief, whereas patients who received morphine by concealed administration obtained much slower benefit, implying that the initial relief (from our strongest analgesic) is largely placebo effect. Equally, open discontinuation of morphine led to rapid return of pain whereas covert discontinuation did not
. Other studies of pain, anxiety and Parkinson's disease have similarly shown a decrease in treatment efficacy when the patient is unaware that they are receiving them
. This difference between open and covert administration is equivalent to the “placebo” component of the treatment, and investigating this difference has been suggested as an alternative strategy, at least for some treatments, to a classic placebo RCT design.
Behavioural conditioning
In a study of the immunosuppressive effects of cyclosporine A, the drug was given to healthy volunteers together with a novel green liquid drink. The expected degree of immunosuppression was observed. After “conditioning” the subjects in four sessions over three consecutive days, the experiment was repeated the following week with placebo tablets given with the same drink. The repeat exposure, with dummy tablets, resulted in immunosupression
. The authors of this work point out that although the mechanism of such responses remains to be elucidated, it might be possible to enhance the effects of immunomodulatory and other drugs by behavioural conditioning interventions – an approach that could have widespread implications in medicine.
How ‘new’ the intervention is?
In studies of interventions for various conditions, including depression and peptic ulcer healing, there are data to suggest that drugs or other interventions that are ‘new’ result in larger placebo responses than those which are established
, suggesting that meaning is enhanced if patients and practitioners believe that the intervention is ‘modern’.
Provider effects
Patients are influenced by the expectation and behaviour of the practitioner. In a double blind dental pain study patients were told that they would receive either fentanyl (which might reduce pain), the opioid antagonist naloxone (which might increase pain) or a placebo. However, early in the study the investigators, but not the patients, were told that due to administrative problems fentanyl was unavailable so patients would only be randomised to the naloxone or placebo arms (i.e., only two “negative” treatments). Later in the study investigators were informed that fentanyl was now available and included in the adjusted randomisation procedure. Patients receiving placebo in the second phase of the study experienced significant pain relief but patients on placebo in the first phase did not
. Thus the clinician's optimism or pessimism concerning treatment has a dynamic effect on the patient's outcome.
A recent audit has shown that intentional prescribing of “placebo treatments”, such as vitamins and over the counter products regarded as inert, is commonplace amongst US internists and rheumatologists, and that usually these are described to the patient as a potentially beneficial treatment not usually used for their condition
. Placebos are even commercially available in the US as “obecalp” (placebo spelt backwards), “cebocap” (placebo capsules) and “jujubes” (for parents to administer to their children). However, irrespective of the ethical issues of not being transparent with a patient, it would appear that placebo is less likely to give benefit when it is knowingly administered.
Biological effects, adherence and death
There is growing evidence that context effects and meaning responses can effect alterations in body systems (such as immune function, mentioned above
) in addition to changes in psyche and behaviour. For example, in some pain studies placebo effects are abolished by naloxone, implicating endogenous opioid release as one mechanism that can convert expectancy to “real” analgesia
. For example, positron-emission tomography with [11C] carfentanil has been used to provide graphic evidence that placebo analgesia causes endogenous opioid activity in the μ-opioid receptor rich regions that play a central role in pain and affect
The ultimate “reality” of placebo and meaning response is exemplified by studies of adherence and death. It is logical to expect that people who adhere to a treatment usually do better than non-adherers, but the same difference occurs with placebo. In a study of antibiotic prophylaxis following chemotherapy
non-adherers to placebo had twice the relapse rate of adherers (80% vs 40%). This differential outcome from adherence to placebo extends to mortality. In a large RCT examining the effect of the cholesterol-lowering agent clofibrate on 5-year survival following myocardial infarction, participants who took >80% of study medications did better than non-adherers, specifically: 15% vs 25% mortality for those on clofibrate; and 15% vs 28% for those on placebo
. In addition to heart disease, reduced mortality in adherers to placebo is reported in studies of diabetes, immunosuppression following transplantation, and anti-retroviral treatment for AIDS
. Therefore adherence to what you believe to be a beneficial treatment may prevent development of disease and even death.
Environment and context
The environment in which you receive treatment can modify your outcome. Matched patients who had undergone gall bladder surgery were allocated to one of two wards which were similar apart from their outlook – one had a pleasant green-field view and the other over-looked a high wall and parking lot. The patients with the natural view had fewer post-operative complications, required less analgesia, made fewer complaints and were discharged earlier than those with the bleak view
In an attempt to dissect out separate components of placebo Kaptchuk et al. recently undertook a study of sham acupuncture in patients with irritable bowel syndrome. Patients were randomised to one of three groups: waiting list (assessment and observation); sham acupuncture with only limited patient–practitioner interaction (the therapeutic “ritual”); or sham acupuncture with more usual patient–practitioner interaction augmented by warmth, attention and confidence. At 3 weeks the proportions in each group with adequate pain relief were 28% (observation), 44% (ritual) and 62% (augmented interaction). A similar trend was observed for quality of life (3.6, 4.1, 9.3) and all other measured outcomes
. Clearly all three components contributed to benefit but the most robust was patient–practitioner interaction.
The importance of the patient–practitioner interaction was also the focus of a study in general practice in which 200 patients with symptoms but no abnormal signs were randomly assigned to either: (1) a “positive” consultation, in which the patient was given a confident diagnosis and reassured that things would soon improve; or (2) a “negative” consultation, where the doctor admitted “I cannot be certain of what is the matter with you”. In both groups the doctor could also prescribe thiamine tablets as “placebo” medication. Two weeks later, 64% of patients who had the positive consult were better, compared to 39% of those who had the negative encounter. Receiving a prescription made no difference. The overriding factor appeared to be the patient response to the certainty of diagnosis and reassurance concerning prognosis
. Other contextual aspects that are suggested to encourage a beneficial meaning response include: when the patient regards the practitioner as experienced and competent
. Thus someone may have severe joint damage but no pain, or severe pain but only minor joint pathology. As outlined above, placebo responses can result in big effects on symptoms (the illness), but we have not found evidence that they affect X-rays and pathology (the disease). The fact that placebo responses are best documented in other painful conditions and in mental health disorders, suggests that the value of placebo interventions is mainly for patient symptoms and distress. These are the principal treatment targets in patients with OA. We believe 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.
From the above it is apparent that in the context of a clinical encounter many facets of the patient's experience determine their outcome from any intervention. In audits of care, including OA
that the doctor undertakes only a superficial examination, or no examination at all,
that the doctor didn't address key concerns,
that the doctor did not give a follow-up appointment.
Given these circumstances it is obvious that practitioners should capitalise on the impact of context effects to enhance the benefits to their patients, as a professional responsibility. Many of these aspects are nothing to do with the “ritual” of a drug or physical treatment. When a practitioner gives a patient their focused and unhurried attention in a comfortable environment, listens to them, undertakes a thorough examination, explains in understandable terms what is happening, addresses concerns and provides a way forward, the patient experiences a “good deal”. This is in itself a treatment (Fig. 4). The patient often leaves both looking and feeling better, long before they cash in any (adjunctive) prescription they have just received. The converse is also true. Recent studies of the “nocebo” effect (expectation of a negative effect leading to worse outcome) have shown, for example, that negative words that increase anxiety can result in increased pain
Fig. 4The difference between a positive encounter (above) and a negative encounter (below) with a practitioner can influence the outcome for the patient. It is our professional responsibility to address such aspects.
emphasises the importance of the meaning of a consultation and any suggested intervention to the patient. The meanings of interventions are culturally determined and depend in part on the health beliefs of the patient. Exorcism may work better than aspirin if a patient firmly believes that their pain is caused by their possession by evil spirits
. Furthermore, in many cases practitioners can help the patient towards a health belief that is more in tune with the interventions that are available to help them.
Practitioners of complementary and alternative medicine (CAM) often do this very well, and seem ahead of many of us more traditional physicians. We often pride ourselves on being over-worked and too busy to spend time on such “peripheral” matters, and feel more useful and important when we exercise our licence to prescribe potentially dangerous drugs. We often label practitioners of CAM as charlatans and explain their treatment success as “just placebo effect”, apparently oblivious of the surprisingly large ES of such “non-treatment” benefits. But if we did learn from the research literature, from practitioners of CAM, and from simple observation, and optimise these meaning responses
The ES of the treatment: the higher the treatment ES the higher the placebo effect, perhaps explained by higher expectation of benefit by participants.
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