Introduction

Although the use of placebo interventions outside clinical trials without full informed consent is generally considered unethical [1–3], surveys in various countries show that many physicians prescribe “placebos” in routine clinical practice [4–7]. A major problem when investigating the prevalence of placebo use is that it is far from clear what kind of intervention qualifies as a placebo in routine clinical practice [8,9]. There is little disagreement about what is called “pure placebo”, such as sugar pills or saline injections. However, placebo definitions in most surveys also include many potentially active interventions, which are thought to have no specific activity on the condition being treated beyond a placebo effect [4–6]. These interventions sometimes are called “impure placebos” [4,6] or “non-specific therapies” [7]. To emphasize the clinically important difference to “pure placebos” we prefer the term “non-specific therapies” in this report. Typical examples are antibiotics in viral infections or vitamins in patients without deficiency, but some surveys also included treatments not backed up by solid evidence, positive suggestions or non-essential physical or technical examinations.

In recent years, the use of placebos has been investigated more often among general practitioners (GPs) than among any other medical disciplines [4–7,10]. It seems plausible to assume that GPs use placebos more frequently because they see many patients with unclear, non-specific complaints or minor ailments as well as chronically ill patients coming back from specialists without a fully satisfying therapy. In this report, we present a systematic review and meta-analysis of all available cross-sectional quantitative surveys on the use of placebo interventions among general practitioners. Our objective was to summarize current knowledge on 1) the frequency of use of any placebo interventions, pure placebos and non-specific therapies; 2) what kind of placebo interventions actually are used; and 3) whether placebo use among GPs differs from that in other medical specialties.

Methods

The methods of the review were pre-defined in a protocol (see S1 File); we have considered registering our protocol in PROSPERO, but this register is limited to reviews with “a health related outcome” (https://www.crd.york.ac.uk/prospero/aboutreg.php?reg=inclusioncriteria).

Results

Literature search and selection process

Our literature search identified 674 unique hits (see Fig 1 for a flow chart). Twenty-five potentially relevant articles were formally checked against inclusion criteria. Nine articles were excluded: five [16–20] reported additional findings or protocols of included studies not providing information relevant to our review, two did not have GPs as an identifiable subgroup [21,22], one was a qualitative study [23], and one did not address actual placebo use but a hypothetic case [24].

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Fig 1. Flow diagram of the study selection process.

https://doi.org/10.1371/journal.pone.0202211.g001

Characteristics of included studies

We included 16 studies (reported in 16 publications) for which data on placebo use by GPs were available [5–7,10,11,25–35]. The 16 studies were published between 2003 and 2017 and had been performed in 13 different countries (Table 1). Eight studies used high-quality sampling strategies [5–7,10,28–30,33], the remaining eight used less adequate or unclear sampling methods. Response rates ranged from 16% to 79% in studies with high-quality sampling and from 8% to 100% in studies with suboptimal sampling methods. Only one study was rated high quality both regarding for sampling and response rate [29] (see S1 Table for the full rating of all studies). The number of participating GPs was much higher in studies with high quality sampling (2,471 in total, range 165 to 783; compared to 520 in total, range 27 to 157). Eight studies also surveyed physicians from other medical specialties. Definitions of placebo interventions (see S2 Table), topics covered, wording of questions, and answer options varied greatly among included studies creating considerable difficulties for consistent data extraction. Definitions either included non-specific therapies or separated pure placebos and non-specific therapies, but no study exclusively focused on pure placebos. Eleven studies presented data on reasons for prescribing placebo interventions (S3 Table). In the four studies offering this answer option, 48% to 79% of GPs ticked that they hoped to elicit placebo or psychological effects. A larger number of studies included a variety of answer options related to patient expectations and demands, e.g. to calm the patient (agreement between 21% and 58%; 8 studies), to avoid conflict (29% to 70%; 2 studies), or to handle an unjustified demand of a patient (9% to 47%; 8 studies). A third group of answer options covered “medical” reasons, e.g. treating non-specific complaints (22% to 61%; 10 studies), use as a supplement to other therapies (16% to 54%; 7 studies) or using placebo treatment as a diagnostic tool (13% to 60%; 10 studies).

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Table 1. Characteristics of included studies (2,911 participating GPs).

https://doi.org/10.1371/journal.pone.0202211.t001

Four (out of a total of seven) studies including also other medical specialties did not report GP findings separately in the publication, but on request authors either provided subgroup analyses [28,31] or relevant raw data for re-analysis [25,26]. Full raw data for re-analysis was available for further three studies [6,7,33].

Frequency of placebo use

Four studies reported data on only one of our 12 outcomes addressing frequency of placebo use and further nine studies on two to four outcomes. For three studies with a total of 1,310 GPs with available raw data, all 12 outcomes could be calculated. The reported use of any form of placebo or non-specific therapies varied much more than it could have been expected by chance alone. The percentage of GPs having used any form of placebo at least once in their career ranged from 29% to 97% (13 studies), of those having used it at least once in the last year from 46% to 95% (8 studies), at least monthly from 15% to 89% (10 studies), and at least weekly from 1% to 75% (8 studies; see upper parts of Fig 2 and S4 Table). Pooled random estimates were 79% (95%CI 68% to 87%), 76% (61% to 86%), 57% (37% to 74%), and 30% (12% to 57%), respectively. However, due to the pronounced heterogeneity (I² between 96% and 99%), pooled estimates need to be interpreted with great caution. Four studies provided data on the use of pure placebos and three on the use of non-specific therapies separately, with three studies investigating both (Fig 2 and S4 Table, lower parts). The use of non-specific therapies by far outnumbered the use of pure placebo, but again estimates of usage varied strongly between studies. For example, the proportion of GPs with use at least monthly varied between 2% and 15% for pure placebos and between 53% and 89% for non-specific therapies, with use at least weekly between 1% and 3% for pure placebos and between 16% and 75% for non-specific therapies.

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Fig 2. Percentages (95% confidence intervals) of GPs having used a placebo intervention (upper part), a pure placebo or a non-specific therapy (lower part) at least once in their career (light grey), last year (grey), using it at least monthly (dark grey) or at least weekly (black).

RE = random effects.

https://doi.org/10.1371/journal.pone.0202211.g002

Interventions used as placebos

Eleven studies reported which interventions GPs used as pure placebos or non-specific therapies at least once in their career (see Fig 3). Again, the use of non-specific interventions by far outperformed the use of pure placebos, but the percentage of users varied greatly across studies. Saline injections had been used by 2% to 24% of GPs and placebo pills by 3% to 7%. Instead, use of vitamins was reported by 23% to 75% of GPs, of homeopathic remedies by 33% to 58%, of antibiotics by 17% to 69%, and of supplements by 35% to 59%. With the exception of the use of placebo pills (I² = 0%) study findings varied much more than expected by chance alone (all I² > 80%; see S5 Table providing findings of individual studies and details of meta-analyses).

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Fig 3. Percentage of GPs having use a defined intervention at least once as a placebo.

Graphically presented values are pooled estimates (95% confidence intervals) n = number of studies in which the intervention was investigated.

https://doi.org/10.1371/journal.pone.0202211.g003

Comparison with other medical specialties

Seven studies provided data for our comparative analysis of use of any placebo interventions between disciplines (Table 2). Three studies compared GPs with specialists in private practice. The two larger studies with high quality sampling found a statistically significantly higher prevalence of placebo use among GPs while the third smaller study with low quality sampling did not. Three studies compared GPs and hospital physicians. Results differed strongly with one larger study with high quality sampling finding higher placebo use among GPs and the two smaller studies finding no differences. Three small studies compared placebo use among GPs with that of pediatricians and two with internists providing primary care. Differences were not statistically significant.

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Table 2. Placebo use (ever of of any form of placebo) among GP compared to other disciplines.

https://doi.org/10.1371/journal.pone.0202211.t002

Discussion

Despite highly variable methods and prevalence estimates, the available surveys from a total of twelve countries provide clear evidence that many GPs use interventions which are considered placebos in the studies included. Only few (but comparably large) studies provide frequency estimates on pure placebos and non-specific therapies separately, but together with the data on which defined interventions have been used as placebos it is obvious that non-specific therapies are used far more often than pure placebos. The data suggest that frequency and patterns of usage vary considerably between countries. Only few studies compare placebo prescription across medical specialties. The available findings are inconsistent and inconclusive.

This is the first systematic review and meta-analysis of the use of placebo interventions among GPs. Based on the experiences from a broader qualitative review of empirical studies of placebo use in clinical practice published in the year 2010 [4] and thanks to the great cooperation of many of the survey authors who provided original questionnaires (and, if necessary, help with translation), additional analyses or raw data, we were able to compile reasonably comparable data from a quite diverse set of studies. When the literature search for the 2010 review was completed, only three [10,11,28] of the 16 studies now included had been available. A systematic analysis of the frequency of placebo use had not been performed.

In the past, the publication of placebo surveys among physicians has repeatedly triggered sensational reports in mass media. For example, based on a survey among US internists published in the British Medical Journal [12] on October 23, 2008, the New York Times published an article titled “Half of Doctors Routinely Prescribe Placebos” [36]. Articles with a similar message were published in the mass media after surveys among GPs. Do the data compiled in our review really justify the interpretation of such broad placebo use?

According to a survey in eleven countries [37,38], primary care physicians on average see between 96 (USA as country with the lowest estimate) and 242 (Germany as country with the highest estimate) patients per week, with GPs in the UK seeing 130 patients per week. Based on these figures, we roughly estimate that GPs have about 500 patient contacts per month in the UK and 1,000 in Germany. A combination of these figures with the findings of our review would mean that 2% of UK GPs use a pure placebo in at least 1 of 500 patient contacts [6], and that 9% to 15% of German GPs do so in at least 1 of 1,000 patient contacts [7,33]. This can hardly be considered frequent use. What seems to be used “routinely” by many GPs are non-specific therapies. Using the same approximation as for pure placebo, we estimate that 89% of GPs in the UK use a non-specific therapy in at least 1 of 500 patient contacts, and that between 57% and 69% of German GPs do so in at least 1 of 1,000 patient contacts.

However, is it really adequate to interpret the widespread use of non-specific therapies as use of placebos? The main argument for doing so is nicely summarized by Miller and Colloca: “… what makes substances or interventions count as placebos is the lack of specific efficacy in treating a specific patient’s condition based on the inherent properties of the treatment” [39]. However, there are several problems with this view. First, when hearing the word ‘placebo’ both physicians [16,23] and patients [29] usually intuitively think of pure placebos or words attributed to pure placebos (such as “inert”). As a consequence, many lay persons and physicians are surprised when they hear about the high prevalence of “placebo use”. Second, even from the perspective of research, it is not always clear whether a treatment has “specific efficacy” or not. For patients and practicing physicians, own beliefs and experiences strongly influence what is considered specifically active or not. For example, among German physicians the belief whether treatments such as acupuncture, homeopathy, herbs or osteopathy have effects over placebo varies strongly [40]. It seems very likely that subjective views and the wording of questions and answer options strongly influence survey findings on the use of non-specific therapies [4,8,9]. This is related to the third challenge. In our view, placebo researchers often misinterpret why physicians prescribe placebos in general and non-specific treatments in particular. Most researchers administering surveys assume implicitly or even explicitly that physicians use “placebos” mainly for eliciting placebo effects. For example, in the BMJ 2008 survey, the authors state that “placebo treatments include … physiologically active agents, such as vitamins or antibiotics, that the physicians prescribe solely or primarily to promote positive psychological effects” [12]. Only few respondents in the quantitative surveys actively argue against such definitions (but some do; see, for example [16]). However, there are reasons to assume that promoting placebo effects is more often an a posteriori justification than an a priori reason. For example, when checking qualitative studies on reasons for antibiotic prescribing in viral infections–a typical example for an impure placebo in surveys—included in a systematic review [41], we could not find a single study mentioning the word placebo or a related motive. Reported important reasons for antibiotic prescribing are perceived pressure by patients, lack of time, preserving an unstable patient-physician relationship, or diagnostic uncertainty. Qualitative studies on “irrational” [42], “nonscientific” [43] or otherwise difficult prescribing [44,45] suggest that the use of non-specific therapies is a strategy to deal with a variety of challenges in busy routine practice. Most of the reasons for placebo use reported in the studies included in our review strengthen this interpretation. Due to its conceptual problems Louhiala et al. consider the concept of impure placebos (which we call non-specific therapies in this paper) as useless, scientifically unsound and potentially harmful [9].

Hrobjartsson has argued that in the majority of cases physicians use (mostly impure) placebos for “convenience”, either to get a patient stop complaining or to avoid conflict [1]. Instead, Louhiala et al. believe that at least some of what in surveys is called impure placebo (for example, positive suggestions) actually can be considered “good doctoring” [9]. We are aware that the term non-specific therapies which we use in this review suffers from similar conceptual problems as the term impure placebo. But at least, it greatly reduces the risk of a simplistic interpretation of a complex phenomenon.

Currently, there is considerable interest in the prescription of (pure) placebos without deception (sometimes referred to as “open-label placebo” [46]). The idea is that patients are informed about the placebo effect and, after giving informed consent, openly receive an inert intervention. This is a fascinating approach respecting the autonomy of the patient and the professional integrity of the physician. The (few) available randomized trials suggest it can be feasible and effective [47]. It is clearly desirable to test and possibly implement this strategy on a larger scale in general practice. However, there might be a long way to go as placebo without deception might not be a solution to many of the problems in which GPs currently use non-specific therapies (e.g., when a patient with a cold demands an antibiotic).

Due to diversity of the studies included in our review regarding main focus, definitions, questionnaires, sampling methods, response rates, sample sizes and other quality issues the frequency estimates found in our review should only be considered crude indicators. The statistical heterogeneity of almost all of our pooled estimates is very high, but given the limited number of studies contributing to meta-analyses, problems in reliably operationalizing potential confounders, and the unclear interactions between the confounders we refrained from performing meta-regression analyses. Based on the data it seems likely that the use of placebos varies between countries regarding what is actually done (e.g., more German GPs seem to use pure placebos than GPs from the UK), but it also seems plausible that there are cultural differences regarding what is considered a non-specific therapy (e.g., GPs from the UK may follow more what is evidence-based, while German GPs may have a stronger belief in their own experience). Furthermore, it is likely that definitions and methods of asking make a difference. For example, one of the included studies [25] showed that using the term “non-specific therapies” instead of “placebo” was associated with higher placebo use estimates although the definition of the terms was exactly the same. Also, we assume that asking to rate a long list of examples of non-specific therapies (as in the large UK survey [6]) is associated with higher estimates than a global question. Finally, it is also possible that selection bias differs between countries.

In conclusion, high prevalence estimates of placebo use among GPs are primarily driven by the frequent use of non-specific therapies; pure placebos are used rarely. It seems likely that in the majority of cases non-specific therapies are not primarily used to elicit placebo effects but to cope with difficult situations in busy routine practice. In the view of the authors it can be misleading to subsume the use of non-specific therapies simply as ‘placebo use’. The issue of placebo and non-specific interventions should be addressed in GP training programs. Future research is needed to better understand why many GPs are using such interventions. Also, investigations should be conducted about how GPs, who do not use such strategies (or claim to do so), cope with the challenges in busy daily practice. We believe that such research primarily should be qualitative. International, large-scale surveys are needed to be able to directly compare the differences in placebo prescription behavior of GPs (and across medical disciplines) between countries. However, such surveys should carefully consider the major problems of the concept of impure placebos/non-specific therapies in the planning phase, avoid suggestive wording in questionnaires, and carefully discuss the limitations of the findings for avoiding simplistic interpretations in the mass media.

Supporting information

Acknowledgments

We thank Jeremy Howick for providing the full data set of his study and details on the questionnaire; Przemyslaw Babel for providing raw data on relevant variables, questionnaires incl. help with translation problems; Margrit Fässler for re-analysis of subgroup data and providing questionnaires; Eszter Ferentzi for providing the questionnaire and help with translation problems; Natasha Campbell and Cory Harris for re-analysis of subgroup data; Shaun Holt and Seemab Khan for their attempts to answer our questions.