In the previous OE Original: Making Sense of “Placebos” in Healthcare Research, we provided an overview of using placebos in clinical trials, specifically in drug trials. However, the use of sham surgery as a placebo in a surgical clinical trial, which determines the efficacy of a surgical procedure, is a more complex issue.
For instance, in clinical trials of orally administered drugs, a placebo tablet, usually made of sugar or starch, poses minimal to no risk to the safety of the research participants; yet sham surgery differs from drug placebo controls because sham surgery poses substantial additional risks, which are unique to surgery. These include, but are not limited to, additional pain, bleeding, and infection for the research subjects (Vawter et al., 2003).
Generally speaking, using sham surgery in surgical trials is not as straightforward and has a greater ethical burden than using placebo tablets in drug trials. In this OE Original, we present 3 things you must know about using sham surgery in surgical trials.
1. What is sham surgery and why do we need it?
Sham surgery is a surgical procedure which mimics the actual intervention of interest in every way but leaves out the therapeutically necessary steps to ensure participants in the control group experience “the same incidental effects of the operation or procedure as do those participants on whom a true operation is performed” (Brim et al., 2013; Ciccozzi et al., 2016; Sutherland, 2007).
Similar to the role of placebo in drug trials, sham surgery is adopted in a surgical trial primarily for eliminating the placebo effect which was defined by Avins et al. (2012) as “the tendency for a patient’s condition to improve, not through a biologic mechanism specific to the disease pathophysiology, but because of ‘less-specific’ effects due to the patient’s belief that the therapy has specific biological effectiveness and the contextual effects of the intervention.” A systematic review, investigating the magnitude of the placebo effect associated with sham surgery procedures, revealed that sham surgery was associated with a large improvement in pain and other subjective patient-reported outcomes but with a relatively small effect on objective outcomes in 86 eligible randomized controlled trials (RCTs) comparing any type of surgery to a sham surgery group (Gu et al., 2017).
Sham surgery was first adopted as placebo in a trial done by Cobb et al. (1959), in which the results showed that there was no significant difference in outcome improvement between patients undergoing internal mammary artery ligature and those receiving a sham procedure for the treatment of angina pectoris. Similar negative results were also found in a sham-controlled trial conducted in 1960 (Dimond et al., 1960). With the aid of sham surgery to eliminate the placebo effect, these landmark sham-controlled trials were able to prove that internal mammary artery ligation was not effective and not beneficial to patients when at the time this procedure was praised as the “New Surgery for Ailing Hearts” by the media (Miller, 2012). This definitive evidence generated from sham-controlled trials potentially prevented thousands of patients from being harmed by a non-effective treatment.
2. Is it morally ethical to use sham controls?
Macklin R. (1999) found sham surgery was unethical in principle because “?… ?performing a surgical procedure that has no expected benefit other than the placebo effect violates the ethical and regulatory principle that the risk of harm to subjects must be minimized in the conduct of research.”
However, Emanuel et al., (2001) believed that absolute positions in which we either totally rejected sham surgery control due to its risk or unconditionally accepted it to pursue scientific validity were “neither tenable nor defensible.” Emanuel et al., (2001) proposed that there should be a middle ground where the benefits of using sham controls (e.g., increasing scientific validity) and the risk (e.g., causing harms to participants) can be balanced. Notably, determination of the balance between benefits and risks of using sham controls requires extremely careful contemplation from the perspective of scientific, clinical and social interests on a case-by-case basis (Horng et al., 2003; Wolf et al., 2006).
Horng et al. (2003) created a framework to guide the justification of the use of sham controls in clinical trials (Table 1). Albin (2005) further argued that there was no “blanket justification of sham surgery controls.” Sham surgery is permissible only under carefully selected circumstances (Albin, 2005).
Ethical framework for the use of sham procedures in clinical trials
(Horng et al., 2003)
There is a valuable, clinically relevant question to be answered by the research.
The placebo control is methodologically necessary to test the study hypothesis.
The risk of the placebo control itself has been minimized.
The risk of a placebo control does not exceed a threshold of acceptable research risk.
The risk of the placebo control is justified by valuable knowledge to be gained.
The misleading involved in the administration of a placebo control is adequately disclosed and authorized during the informed consent process.
3. What is the current state of sham surgery in orthopedics?
Evidence from sham-controlled RCTs is considered to be valuable in terms of helping clinicians identify ineffective surgeries, preventing patients from getting harms, and saving limited health care resources. Several RCTs in the field of orthopedics have been conducted. For instance, a landmark orthopedic RCT conducted by Moseley et al. (2002) was frequently cited in the field of placebo research (OE ACE Report). Moseley et al. (2002), adopting sham surgery as placebo, found that arthroscopic surgery (i.e., arthroscopic debridement, arthroscopic lavage) was not superior to and seemed to be equivalent to the sham procedure in the reduction of knee pain and improvement of function among patients with osteoarthritis of the knee, whereas a number of prior uncontrolled trials considered arthroscopic surgery to be effective for relieving pain for patients with knee osteoarthritis. This RCT is legendary because it not only fundamentally changed the role of arthroscopic surgery in patients with knee osteoarthritis, but also demonstrated the feasibility of conducting an orthopedic sham-controlled trial.
In 2011, another multicenter RCT (VERTOS IV) was carried out to mainly compare pain relief between patients with an acute osteoporotic vertebral compression fracture who received percutaneous vertebroplasty (PV) and patients who had a sham surgical procedure (NCT01200277, Firanescu et al., 2011). The 1-year follow-up found that PV did not result in significant pain relief compared to the sham procedure (Firanescu et al., 2018).
In 2013, the Finnish Degenerative Meniscal Lesion Study (FIDELITY) Group designed and conducted a multicentre, blinded, randomised, sham-controlled trial to investigate the efficacy of arthroscopic partial meniscectomy (APM) in patients with degenerative meniscus injury (NCT00549172, Sihvonen, Paavola, Malmivaara, & Järvinen, 2013). Since then, results from 1-year (Sihvonen, Paavola, Malmivaara, Itälä, et al., 2013; OE ACE Report) and 5-year (Sihvonen et al., 2020; OE ACE Report along with exclusive interview with the author) follow-up have been reported. Results were consistent between 1-year and 5-year follow-ups and showed that the outcomes (i.e., Western Ontario Meniscal Evaluation Tool, the Lysholm knee score, and knee pain scores after exercise) after APM were not superior to those after the sham procedure in patients with symptoms of a degenerative medial meniscus tear but without knee osteoarthritis (Sihvonen, Paavola, Malmivaara, Itälä, et al., 2013; Sihvonen et al., 2020).
In 2018, the CSAW (Can Shoulder Arthroscopy Work?) RCT, determining the efficacy of arthroscopic subacromial decompression (ASAD) in patients suffering from subacromial pain, was published (Beard et al., 2018). To our knowledge, this is the only orthopedic sham-controlled trials that also included a “no treatment” group in addition to the sham surgery (i.e., arthroscopy only) group. This RCT questioned the efficacy of ASAD due to the results showing that neither ASAD nor sham surgery (i.e., arthroscopy only) was superior to no treatment with a clinical significance, and there was also no significant difference in outcomes between ASAD and sham surgery (i.e., arthroscopy only) (Beard et al., 2018).
The above sham-controlled RCTs all showed no differences in outcomes between sham and respective active surgery, where the authors concluded that active surgery is as ineffective as sham surgery. However, a systematic review published in 2017 evaluating empirical evidence from 6 orthopedic sham-controlled RCTs to determine effectiveness of sham surgery in orthopedics, came to a surprising and controversial conclusion: that sham surgery in orthopedics trials was as effective as active surgery in pain reduction and disability improvement (Louw et al., 2017). The systematic review authors hypothesized that “the sham surgery likely altered the patient’s perception of the health of their tissues [or reconceptualized patients’ perception of pain]” (Louw et al., 2017), and listed some empirical evidence to support their statement. For example, patients who were shown and given their disc fragments after lumbar discectomy had superior postoperative outcomes, compared to traditional discectomy without presenting disc fragments (Tait et al., 2009). The conclusion from the systematic review done by Louw et al., (2017) was criticized and considered to be inappropriate. Enck (2019) argued that the statement sham surgery being as effective as active surgery still avoided answering the actual research question, which is whether the active surgical intervention is efficacious, and contradicted the true intention and the original hypothesis made by the authors of the sham-controlled trials. Moreover, Enck (2019) argued that there was a frequent misunderstanding about the power of placebo, in which we often attribute anything that occurred in the placebo control group to the effects of placebo. Yet such effects, in our case the treatment effects presented in the sham surgery group, are likely to be a result of several mechanisms which were very different from the power of placebo, such as response biases, regression to the mean, spontaneous variation of symptoms and their recovery (natural course of symptoms/disease) (Enck et al., 2013 and 2019).
As we discussed in the previous section, using sham surgery is morally permissible only when the scientific, clinical and/or social interests outweigh the risks of harm. However, a systematic review done by Ciccozzi et al. (2016), examining 52 studies, questioned the validity of sham-controlled clinical trials due to their study limitations, including methodological and statistical flaws. In terms of sham-controlled orthopedic trials, a recent systematic review published in October 2020 implies that sham-controlled trials in orthopedics might also be flawed in terms of significant methodological deficiencies, and therefore potentially unethical due to decreased scientific validity (Sochacki et al., 2020).
Sochacki et al. (2020) found that current sham-controlled trials in orthopedic surgery were often published in high-impact non-orthopedic-related general medical journals because sham-controlled trials were relatively uncommon but generally considered as gold standards. Sochacki et al. (2020) hypothesized that such preferential reporting in these high-impact journals might result in various biases which could affect the validity of the results from these sham-controlled trials. After carefully examining 7 sham-controlled trials, Sochacki et al., (2020) identified a number of methodological limitations that could potentially undermine the validity of these trials. One of the major limitations was that 6 out of 7 trials did not involve a “no surgery” group or “natural history” group (in which participants receive no treatment, and the patient's condition is allowed to run its natural course) in addition to the intervention and sham groups. Without a “natural history” our ability to account for the response we observed in the sham control was limited, specifically, we were not able to determine how much of the response was due to placebo effects and how much was due to the natural course of disease progression or fluctuations in symptoms (Enck et al., 2013; Sochacki et al., 2020). Other limitations of current orthopedic sham-controlled trials include but are not limited to failing to fully address the issue of poor compliance, lack of adequate statistical power, and lack of reporting of the funding source.
Sochacki et al. (2020) emphasized that identification of these limitations in current orthopedic sham-controlled trials did not mean such trials should be discontinued, but warrant the urgent need of necessary improvements in future trial design and conduct. Kalore (2020) proposed several mitigating measures to address the study limitations existing in current sham-controlled trials and further stressed that unless we carry out sham-controlled trials based on very high methodological standards, exposing participants to the risks of sham surgery is unethical. As the metaphor used by Kalore (2020) explains, sham-controlled trials may seem “innocuous like the sheep, but in fact hide a significant burden of metrological inconsistencies, risk influencing the patient, surgeons, payors and the society with wrong information and ignore basic tenets of human research and therefore cause significant harm like a Wolf.”
The scientific value of involving a sham surgery placebo in clinical trials has been proven in several fields such as orthopedics, in which these sham-controlled trials successfully prevented patients from receiving surgical interventions possessing no therapeutic benefits or even causing potential harms. However, as opposed to using placebos in drug trials, conducting trials with a sham surgery placebo group is a more complex and controversial issue from an ethical perspective due to the invasive nature of sham surgical procedures. Although we must acknowledge their importance and necessity, current sham-controlled trials for orthopedic surgeries still have quite a number of methodological deficiencies, which may pose potential threats to scientific validity and raise doubts about their ethical justification. Future sham-controlled trials need to learn from these lessons and make improvements in order to achieve a very high methodological quality that justifies their use.
Albin, R. L. (2005). Sham surgery controls are mitigated trolleys. Journal of Medical Ethics, 31(3), 149. doi:10.1136/jme.2003.006155
Avins, A. L., et al. (2012). Should we reconsider the routine use of placebo controls in clinical research? Trials, 13(1), 44. doi:10.1186/1745-6215-13-44
Beard, D. J., et al. (2018). Arthroscopic subacromial decompression for subacromial shoulder pain (CSAW): a multicentre, pragmatic, parallel group, placebo-controlled, three-group, randomised surgical trial. Lancet, 391(10118), 329-338. doi:10.1016/s0140-6736(17)32457-1
Brim, R. L., et al. (2013). The potential benefit of the placebo effect in sham-controlled trials: implications for risk-benefit assessments and informed consent. Journal of Medical Ethics, 39(11), 703. doi:10.1136/medethics-2012-101045
Ciccozzi, M., et al. (2016). Critical review of sham surgery clinical trials: Confounding factors analysis. Annals of medicine and surgery (2012), 12, 21-26. doi:10.1016/j.amsu.2016.10.007
Cobb LA., et al. (1959). An evaluation of internal mammary-artery ligation by a double-blind technique. N Engl J Med 260:1115-18
Dimond E.G., et al. (1960). Comparison of internal mammary artery ligation and sham operation for angina pectoris Am J Cardiol, 5 pp. 483-486
Emanuel, E. J., et al. (2001). The ethics of placebo-controlled trials--a middle ground. N Engl J Med, 345(12), 915-919. doi:10.1056/nejm200109203451211
Enck, P. (2019). A Matter of Perspective: Sham Surgery as Effective as Surgery, or Surgery as Uneffective as Sham? Pain Med, 20(1), 200-201. doi:10.1093/pm/pny127
Enck, P., et al. (2013). The placebo response in medicine: minimize, maximize or personalize? Nat Rev Drug Discov, 12(3), 191-204. doi:10.1038/nrd3923
Firanescu, C., et al. (2018). Vertebroplasty versus sham procedure for painful acute osteoporotic vertebral compression fractures (VERTOS IV): randomised sham controlled clinical trial. BMJ (Clinical research ed.), 361, k1551-k1551. doi:10.1136/bmj.k1551
Firanescu, C., et al. (2011). A randomised sham controlled trial of vertebroplasty for painful acute osteoporotic vertebral fractures (VERTOS IV). Trials, 12, 93-93. doi:10.1186/1745-6215-12-93
Gu, A. P., et al. (2017). Sham surgical procedures for pain intervention result in significant improvements in pain: systematic review and meta-analysis. J Clin Epidemiol, 83, 18-23. doi:10.1016/j.jclinepi.2016.12.010
Hall, K. T., et al. (2015). Genetics and the placebo effect: the placebome. Trends Mol Med, 21(5), 285-294. doi:10.1016/j.molmed.2015.02.009
Horng, S., et al. (2003). Ethical framework for the use of sham procedures in clinical trials. Crit Care Med, 31(3 Suppl), S126-130. doi:10.1097/01.ccm.0000054906.49187.67
Kalore, N. V. (2020). Editorial Commentary: Published Sham Trials in Orthopaedic Surgery Are Flawed and Potentially Unethical-A Wolf in Sheep's Clothing. Arthroscopy, 36(10), 2763-2764. doi:10.1016/j.arthro.2020.07.043
Louw, A., et al. (2017). Sham Surgery in Orthopedics: A Systematic Review of the Literature. Pain Med, 18(4), 736-750. doi:10.1093/pm/pnw164
Macklin R. (1999). The ethical problems with sham surgery in clinical research. N Engl J Med 341, 992-996
Miller, F. G. (2012). The Enduring Legacy of Sham-Controlled Trials of Internal Mammary Artery Ligation. Progress in Cardiovascular Diseases, 55(3), 246-250. doi:https://doi.org/10.1016/j.pcad.2012.09.002
Moseley, J. B., et al. (2002). A Controlled Trial of Arthroscopic Surgery for Osteoarthritis of the Knee. New England Journal of Medicine, 347(2), 81-88. doi:10.1056/NEJMoa013259
Sihvonen, R., et al. (2020). Arthroscopic partial meniscectomy for a degenerative meniscus tear: a 5 year follow-up of the placebo-surgery controlled FIDELITY (Finnish Degenerative Meniscus Lesion Study) trial. British journal of sports medicine, 54(22), 1332-1339. doi:10.1136/bjsports-2020-102813
Sihvonen, R., et al. (2013). Arthroscopic Partial Meniscectomy versus Sham Surgery for a Degenerative Meniscal Tear. New England Journal of Medicine, 369(26), 2515-2524. doi:10.1056/NEJMoa1305189
Sihvonen, R., et al. (2013). Finnish Degenerative Meniscal Lesion Study (FIDELITY): a protocol for a randomised, placebo surgery controlled trial on the efficacy of arthroscopic partial meniscectomy for patients with degenerative meniscus injury with a novel 'RCT within-a-cohort' study design. BMJ open, 3(3), e002510. doi:10.1136/bmjopen-2012-002510
Sochacki, K. R., et al. (2020). Sham Surgery Studies in Orthopaedic Surgery May Just Be a Sham: A Systematic Review of Randomized Placebo-Controlled Trials. Arthroscopy: The Journal of Arthroscopic & Related Surgery, 36(10), 2750-2762.e2752. doi:https://doi.org/10.1016/j.arthro.2020.05.001
Sutherland, E. R. (2007). Sham Procedure versus Usual Care as the Control in Clinical Trials of Devices. Proceedings of the American Thoracic Society, 4(7), 574-576. doi:10.1513/pats.200707-090JK
Tait, M. J., et al. (2009). Improved outcome after lumbar microdiscectomy in patients shown their excised disc fragments: a prospective, double blind, randomised, controlled trial. J Neurol Neurosurg Psychiatry, 80(9), 1044-1046. doi:10.1136/jnnp.2008.156356
Vawter, D. E., et al. (2003). Does placebo surgery-controlled research call for new provisions to protect human research participants? Am J Bioeth, 3(4), 50-53. doi:10.1162/152651603322614607
Wolf, B. R., et al. (2006). Randomized surgical trials and "sham" surgery: relevance to modern orthopaedics and minimally invasive surgery. The Iowa orthopaedic journal, 26, 107-111.