Use of placebo controls in the evaluation of surgery: systematic reviewBMJ 2014; 348 doi: https://doi.org/10.1136/bmj.g3253 (Published 21 May 2014) Cite this as: BMJ 2014;348:g3253
All rapid responses
We are grateful to Dr Howick and Professor Heneghan for their interest in our article. As they rightly point out there is a pressing need for high quality evaluations of surgical techniques and the further development of evidence-based surgery. 1
The aim of our systematic review was to comprehensively identify all existing randomized trials in surgery that used a placebo as a control group. We have demonstrated that use of a surgical placebo is often feasible, and that there are ways to address many of the ethical concerns and to minimise the risks to patients in the placebo arm.
We systematically identified 53 randomized trials spanning over 50 years. Around half of these trials did not specify the primary outcome measure, with multiple outcome measures reported in individual studies (range 2-10). This was discussed on several occasions by the authors during preparation of this review. As a consequence of this, we chose to report only the outcomes for which the study had been powered, those reported in the abstract, or those used in other similar studies, and have highlighted this limitation within the paper. For clarity of the systematic review and due to space constraints we could not describe each trial in detail; rather we have presented the characteristics of the individual randomized trials, including the outcomes assessed, in Tables 1 and 2.
We agree that a meta-analysis of the effectiveness and serious adverse events of surgical trials with a placebo arm would have strengthened the findings of our systematic review. Sensitivity analyses are also sometimes performed as a way to measure the robustness of the review findings. However, in our systematic review it was not possible to combine the results of the individual trials due to the significant amount of heterogeneity of methods, conditions and outcome measures across the included trials. For this reason, we chose to present the results of the individual trials pictorially in forest plots and we did not calculate an overall summary effect measure for the effect size or odds ratio.2 The reporting of serious adverse events, across the 53 included trials, was generally very poor and is an important finding of our systematic review. For this reason, we did not attempt to quantify the harm and we only used descriptive methods to summarise them. We strongly recommend the reporting of future trials of surgical interventions and serious adverse events is improved and follows the guidelines set out by CONSORT3,4 so that the future trials can be used for a more formal quantitative analysis.
We agree that the use of either a surgical placebo or a placebo pill, may result in a “nocebo” effect whereby the expectation of a negative outcome may lead to a worsening of symptoms 5 or other reactions that are reported as related to placebo. 6 However, pharmacological placebos are widely used in randomized trials because the assumption is that they are inert and have no pharmacological effect; it is the verbal suggestion or therapeutic context that exerts the therapeutic effect.7 In comparison, a surgical placebo is never completely inert and is always associated with some potential risk, because, in order to imitate a surgical intervention, a surgical placebo requires a skin incision or use of an endoscopic method.
The conclusions of our review show that in the existing randomized trials of surgical interventions, the placebo arm was generally safe and that the risks associated with the placebo intervention could be made acceptably low. Without well designed placebo controlled trials of surgery ineffective treatment may continue unchallenged.
Competing interests: No competing interests
Failure to conduct placebo-controlled trials in surgery harms patients
Jeremy Howick and Carl Heneghan
For historical, cultural, and pragmatic reasons, surgeons have argued that randomized trials of surgical interventions are unfeasible. 1 However a recent study by Wartolowska et al 2 challenges this view and concludes that placebo controlled randomized trials are feasible and ethically acceptable. This is a significant message for the development of evidence-based surgery.
Using placebo controls in surgery has been deemed problematic because sham surgery involves potential risks that can violate the ethical principle of non-maleficence. For these apparent reasons, placebo controlled trials are not required for approval of surgical interventions. 3
We anticipate that the Wartolowska et al. review will make placebo-controlled trials of surgery more common, yet there are a number of methodological issues in the review that should be addressed.
1. A sensitivity analysis excluding trials in which inappropriate or biased methods for measuring harms should be conducted. (The authors cite a framework for reporting harms within systematic reviews 4 but do not seem to have used it.)
2. A comparison of the side effects in placebo surgery with side effects in placebo drugs (for the conditions covered in their review) would strengthen the conclusions. (The authors state: “Surgery of any form, including placebo surgery, is associated with some level of risk, whereas a placebo tablet or drug is not.” 2 If this were true then placebo controlled surgical trials seem ethically more dubious than placebo controlled drug trials. However drug placebos have nocebo effects. Trial participants who are warned about harmful side effects can experience these effects due to expectations even if they took the ‘inert’ placebo. 5 6 In addition, placebo ingredients (which are often underreported) have also been shown to produce adverse reactions. 7 8 The difference between drug placebo and surgical placebos is not that the latter are harmful while the former benign.)
3. A sensitivity analysis excluding trials where the primary outcome was unclear is required. (In cases where the primary outcome was unclear the authors chose the outcome based on its ability to fit into a forest plot with other studies, which is dubious.)
Addressing these concerns will make the Wartolowska et al. review more robust, and this increase the impact it will undoubtedly have on developing the evidence-base for surgery.
1. McCulloch P, Taylor I, Sasako M, Lovett B, Griffin D. Randomised trials in surgery: problems and possible solutions. BMJ 2002;324(7351):1448-51.
2. Wartolowska K, Judge A, Collins G, Dean B, Rombach I, Brindley D, et al. Use of placebo controls in the evaluation of surgery: systematic review. BMJ 2014(2014;348:g3253).
3. McCulloch P, Altman DG, Campbell WB, Flum DR, Glasziou P, Marshall JC, et al. No surgical innovation without evaluation: the IDEAL recommendations. Lancet 2009;374(9695):1105-12.
4. Loke YK, Price D, Herxheimer A, Cochrane Adverse Effects Methods G. Systematic reviews of adverse effects: framework for a structured approach. BMC Med Res Methodol 2007;7:32.
5. Howick J. Saying things the "right" way: avoiding "nocebo" effects and providing full informed consent. Am J Bioeth 2012;12(3):33-4.
6. Wells R, Kaptchuk TJ. To tell The Truth, The Whole Truth, May Do Patients Harm: The Problem of The Nocebo Effect for Informed Consent. American Journal of Bioethics 2012;2(3):22-9.
7. Golomb B. When Are Medication Side Effects Due to the Nocebo Phenomenon? JAMA 2002.
8. Golomb BA, Erickson LC, Koperski S, Sack D, Enkin M, Howick J. What's in placebos: who knows? Analysis of randomized, controlled trials. Annals of internal medicine 2010;153(8):532-5.
Competing interests: Dr. Howick's research on placebos is funded by the National Institute for Health Research (NIHR) School for Primary Care Research (SPCR).
Randomised placebo controlled clinical trials in surgery
Karolina Wartolowska’s landmark paper is of paramount importance, it brings back our attention to the necessity of placebo controls in surgical clinical trials. The examples below (also quoted by the Authors) should remind us all that there are procedures we do daily, convinced of their benefits, that will appear in a few decades just as ridiculous as some procedures done in the past seem risible today.
In the 1950s, ligature of internal mammary arteries (under local anaesthesia) was an accepted treatment for angina pectoris. Ligature of thoracic wall arteries was believed to create collateral vessels to the ischaemic myocardium, although such anastomoses were never detected (and are anatomical nonsense). Clinical improvement seen after mammary arteries had been prepared for ligature but not ligated prompted a placebo trial to be done. It showed that sham procedures were as effective as ligatures and that their effect lasted at least 6 months. (1) This trial is a milestone in the history of medicine (and of surgery).
History repeated itself. In 1999 The Lancet reported a trial of surgery for angina pectoris. (2) After thoracotomy under general anaesthesia, channels were pierced through ischaemic myocardium to the ventricular chamber by means of a laser beam. “Angiogenesis and growth of existing vessels ... due to inflammation ... in response to the microinjuries around the ... channels” was the putative mechanism of action (a mechanism compatible with clinical common sense?). Patients were assigned either surgery and medication or medication alone. Sham surgery was omitted. The investigators admitted that “improvements may (have been) due to a placebo effect”. To admit that bias exists does not waive the obligation to avoid it. How often is this procedure done nowadays (only 15 years later)? With what results?
The number of surgical procedures presently ceaselessly done—which obey the principle “the best surgery is no surgery” (e.g. arthroscopic meniscectomy (3), vertebroplasty (4), (5), anterior cruciate ligament reconstruction (6); the above are all papers printed in the New England Journal of Medicine and quoted by the Authors)―is bewildering.
By the way, anaesthesia too evokes a placebo response: sham spinal anaesthesia provides substantial and protracted relief of chronic pain. (7) (N.B. “Barbotage” of cerebro-spinal fluid refers to aspirating and re-injecting cerebro-spinal fluid during spinal tap).
Are sham procedures always unethical? But how ethical are methodologically flawed trials? Their results—inevitably biased—will guide other patients’ treatment.
All medical procedures, including surgery, should be rigorously subjected to the same strict methodological rules of the randomized placebo controlled double blind trial (as in other medical disciplines) before being accepted by the surgical community. Never mind the great hypocritical enthusiasm of “big pharma” which markets the myriad costly disposable surgical equipment used for the innumerable surgical techniques of unproven benefit all too often done: harming patients, emptying purses, fattening thesaurismotic capital-driven industry and corrupt colleagues.
1. Wall PD. The placebo and the placebo response. In: Wall PD, Melzack R, eds. Textbook of pain, 3rd ed. Edinburgh: Churchill-Livingstone, 1994: 1297–307.
2. Burkhoff D, Schmidt S, Schulman SP, et al. Trans-myocardial laser revascularisation compared with continued medical therapy for treatment of refractory angina pectoris: a prospective randomised trial. Lancet 1999; 354: 885–90.
3. Sihvonen, R, Paavola, M, Malmivaara A, et al. Arthroscopic Partial Meniscectomy versus Sham Surgery for a Degenerative Meniscal Tear. N Engl J Med 2013; 369:2515-2524.
4. Buchbinder R, Osborne RH, Ebeling PR, et al. A Randomized Trial of Vertebroplasty for Painful Osteoporotic Vertebral Fractures. N Engl J Med 2009;361:557-68.
5. Kallmes DF, Comstock BA, Heagerty PJ, et al.A Randomized Trial of Vertebroplasty for Osteoporotic Spinal Fractures. N Engl J Med 2009;361:569-79.
6. Frobell RB, Roos EM, Roos HP, Ranstam J, Lohmander LS. A Randomized Trial of Treatment for Acute Anterior Cruciate Ligament Tears. N Engl J Med 2010;363:331-42.
7. Lloyd JW, Hughes JT, Davies-Jones DAB. Relief of severe intractable pain by barbotage of cerebro-spinal fluid. Lancet 1972; i: 354–55.
Competing interests: No competing interests
Partial isolation of Russian medicine and medical research from the international community had consequences for the medical practice. Several examples are discussed here. In Moscow hospitals, the modified radical mastectomy (Patey) with resection of the pectoralis minor muscle has been the standard procedure during the last decades, but the Halsted operation with the removal of both major and minor pectoralis muscles was applied as well. The Halsted operation prevailed earlier; it was recommended by Russian textbooks of surgery and oncology for all types of breast cancer till the late 1990s [1,2]. The shift towards conservation in the treatment of breast cancer in the whole world remained largely unnoticed in the former Soviet Union (SU) for a long time.
The approach to the surgical treatment of gastric and duodenal ulcers in the former SU has deviated from international practice [3,4]. The use of partial gastrectomy for ulcer treatment remained relatively frequent in many institutions , owing to technical problems, conservatism of surgeons , and limited availability of the medical therapy [5,6]. During the 1960-70s, when the partial (2/3-3/4) gastrectomy was almost the single surgical treatment for gastroduodenal ulcers [7,8], about 60,000 of such operations were performed yearly in ulcer patients, while significant complications had become obvious . Nevertheless, instructive publications presenting gastrectomy as a main or single surgical method of ulcer treatment continued to appear [7,9,10]. In a textbook of surgery printed in 1995, the Billroth’s operations I and II were listed in the first place among the surgical treatment methods of gastroduodenal ulcers . Along with the partial gastrectomy, different types of vagotomy have been used mainly in specialized centers . It can be generalized about vagotomy that it was started in the former SU later than in other developed countries and is continued to be used [13-15], although abroad it tends to be abandoned in connection with the increasingly efficient medical therapy [16,17]. The so-called administrative factor has obviously played a role : the support of certain methods by the health care authorities, who sometimes favored less individualized approaches applicable to large categories of patients. This factor must have contributed also to the relatively high negative appendectomy rate in the former SU  and persistence of outdated practices in other fields of medicine, such as the routinely performed diathermocoagulation or cryotherapy of cervical pseudo-erosions (endocervical ectopia or ectropion) regardless of the presence of epithelial dysplasia. This practice is at variance with scientific evidence not supporting the hypothesis that coagulation of an ectopy protects against cervical cancer . Today, insufficient availability of the medical ulcer treatment brings about a revival of the surgical approach, especially of the partial gastrectomy also as a “primary-radical” treatment of perforated ulcers . Now as before, partial gastrectomy is used as the main surgical treatment for gastrointestinal ulcers at some institutions, in particular, for perforated ulcers [20-22]. Gastrectomy has been advocated referring to social indications [6,8]; while the term “non-compliance” has sometimes been used with the meaning of insufficient availability of medical treatment . In some publications advocating surgery for the ulcers it is stated that “the number of supporters of conservative ulcer treatment is decreasing” , that “modern medical treatment does not completely solve the problem” , “…does not lead to a complete recovery of patients with gastrointestinal ulcers”, whereas it is recommended to operate earlier, before the complications have appeared . It is at variance with the international literature, according to which medical therapy cures peptic ulcer in the vast majority of cases [16,25,26].
Furthermore, pancreatic excision biopsies 5x5 mm in size  were collected during the operations of “pancreatic blood shunting into the systemic blood flow in insulin-dependent diabetics.”  From 1986 to 1994, 409 of such operations in Type 1 diabetic patients were performed by this particular research group . From the same patients, 51 renal core biopsies were collected . Apart from several reports from Russia and Ukraine [29-36], no analogues of this surgical treatment method of Type 1 diabetes mellitus have been found in the literature. This method was applied also in Type 2 diabetic patients with severe hypertension . The anti-diabetic effect of the porto-systemic shunting was reported to be moderate both in humans [28,31] and in preceding experiments in dogs ; while thrombosis-related hazards [30,32], postoperative acidosis [33,35], peritoneal adhesions and other complications  were observed. Severe acidosis was pointed out as a characteristic postoperative phenomenon , which agrees with the known fact that surgical stress can cause hyperglycemia and ketosis in diabetics . It was reported that 27 % of the patients developed thrombosis of the splenorenal anastomosis, confirmed by angiography, during first 8 months after the operation . In the preceding experimental study, the majority of dogs did not survive the surgical or chemical diabetes induction and subsequent porto-systemic shunting , meaning that the condition of the surviving animals could have interfered with evaluation of the anti-diabetic effect of the shunting. The collection of biopsies from diabetic patients for research was planned in advance . It should be noted that renal and especially pancreatic biopsy is associated with risks, and is considered too hazardous a procedure to conduct only for research purposes , which is particularly true if the quality of morphological examination is suboptimal [42,43]. Finally, in the author’s opinion, indications to the operations of pancreatic blood shunting into the systemic blood flow in diabetics have not been sufficiently elaborated. This also pertains to angiographic procedures  involving the catheterization of renal and splenic veins as well as arteriography as described in .
Another surgical procedure without analogues in contemporary international practice is the lung denervation in bronchial asthma [44-49]. This procedure was utilized to treat severe asthma with the substantiation that it “interrupts pathological impulses from the nervous system” . Another reasoning was that morphologic changes of nervous structures e.g. sympathetic ganglia (cellular derangements, pigment accumulation, etc.) justified the denervation surgery for asthma . Corresponding articles contained morphological images of poor quality or no images at all. To achieve optimal denervation of the lung, its autotransplantation for the treatment of asthma was proposed and applied [51,52]. The surgical treatment of asthma was officially approved; Recommendations by the Ministry of Health were issued and recommended for further reprinting by local health care authorities . The method of lung denervation was presented in the main textbook of surgery for students . The open lung denervation via thoracotomy with “skeletonization” of the pulmonary root was designated as the most recognized surgical treatment method for severe asthma . It was recommended for infectious-allergic asthma with a “marked blocking” of beta-adrenergic receptors, for severe asthma with manifest glucocorticoid insufficiency, and after an inefficient carotid sinus denervation with glomectomy . Lung denervation and resection were advocated also for the cases when a medical treatment “had a temporarily good effect”, especially in the presence of inflammatory lung lesions . It was pointed out that the duration of medical treatment of asthma before the surgery should be reasonably limited . In 1990, it was reported on 457 of such operations performed in asthmatic patients by this particular group of researchers . Among those 457 patients, the following absolute complication rates were reported: postoperative complications in 58 patients, inflammatory complications in 27, broncho-pulmonary (including pneumonia, empyema and pneumothorax) – in 11, neurological complications (including dysphagia, vocal fold palsy, Horner syndrome, etc.) in 12, paraplegia or hemiparesis in 2, whereas 6 patients died during 32 days after the operation . In 2002 it was reported that the use of the surgical lung root denervation had been continued . Reported efficacy of the lung denervation against asthma was generally moderate, while approximately equal percentages (30-40 %) of the patients belonged to the groups with a good, satisfactory and absent effect . Immunity- and inflammation-related indices (serum immunoglobulins, T- and B-lymphocyte content, phagocytosis-related indices etc.) were reportedly influenced both by the medical and surgical treatment in the same direction, the surgery being consistently more efficient ; which is not immediately understandable from the viewpoint of physiology.
The denervation surgery was sometimes accompanied by a resection of pathologically altered segments of pulmonary tissue, or by lobectomy [45,48]. At the same time, the morphological images and descriptions of removed pulmonary tissue were unconvincing, having included emphysematous, inflammatory and sclerotic changes without specifying their extension. Moreover, lung resection was used as a principal method of asthma treatment, also in cases when medical treatment was effective, while the indications had initially included “pneumocirrhosis” and bronchiectasis but have been extended to include also “bronchitis deformans” . Pathologists sometimes received lobectomy specimens with moderately dilated bronchi. The resections were performed also in those cases when the pulmonary lesions could not be removed completely (extensive, bilateral lesions). It was reported by the same authors that “no more” than 10 % of their asthma patients had been treated by lung resections .
An outcome of a surgical treatment can be a cumulative effect of the critical surgical element, placebo effects, and non-specific effects [57,58]. It is reasonable to assume that surgery is associated with a placebo effect; and that invasive procedures have a stronger placebo effect than non-invasive ones [58, 59]. Reported moderate efficiency of the procedures described above could have been due to placebo effect and/or inexact evaluation. Placebo-controlled surgical trials would certainly not be indicated for the procedures so technically complicated as the porto-systemic shunting or lung denervation involving laparotomy and thoracotomy respectively. Other questionably substantiated or outdated methods used in the former SU were discussed previously . Among the mechanisms contributing to persistence of suboptimal and outdated methods both in research and in clinical practice has been the authoritative management style, ingrained also in science and medicine, whereas doctors tended to follow instructions of superiors or health care authorities without questioning them on the basis of the international literature. In surgery, particularly, a military influence has often been present, which, among others, can impede constructive discussions. Note that military and medical ethics are not the same. The relatively low life expectancy in Russia especially for men, who usually do not sit with grandchildren, is a strategic advantage: fewer pensions to be paid, etc. Many surgeons have been former military or originated from such families. Meshalkin and Babichev, who developed and applied lung autotransplantation  and root denervation  in asthmatics, had both been military surgeons. Disregard of the principle of informed consent coupled with the paternalistic attitude towards patients up to commanding (e.g. to undergo Halsted mastectomy) have facilitated the use of invasive methods with questionable clinical indications or for research: the patients were told that it is necessary for treatment or diagnostics, or simply not asked, e.g. in case of intra-operative biopsies. Today, the upturn in Russian economy enables acquisition of modern equipment; and medical research is on the increase. Under these circumstances, the purpose of this Rapid Response was to remind that, performing surgical or other invasive procedures, the risk-to-benefit ratio should be kept as low as possible.
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Competing interests: No competing interests