Considerations and methods for placebo controls in surgical trials (ASPIRE guidelines)

Abstract

Placebo comparisons are increasingly being considered for randomised trials assessing the efficacy of surgical interventions. The aim of this paper is to provide a summary of current knowledge on placebo controls in surgical trials. A placebo control is a complex type of comparison group and, although powerful, presents many challenges in a surgical setting. This review outlines what a placebosurgical control entails and our understanding of the placebo phenomenon in the context of surgery. It considers when placebo-surgical controls are acceptable (and when they are desirable) in terms of ethical arguments and regulatory requirements, how a placebo-surgical control should be designed, how to identify and mitigate risk for participants in placebo surgical trials, how such trials should be conducted and interpreted. Use of placebo control is justified in randomised controlled trials of surgical interventions provided there is a strong scientific and ethical rationale. Surgical placebos may be most appropriate where there is poor evidence on the efficacy of the procedure and a justified concern that results of a trial would be associated with high risk of bias, particularly due to the placebo effect. Feasibility work is recommended to optimise RCT design and conduct. This review forms an outline for best practice and provides guidance, in the form of the ASPIRE (Applying Surgical Placebo in Randomised Evaluations) checklist, for those considering the use of a placebo-control in a surgical randomised controlled trial.

Re: Surgical removal of superficial peritoneal endometriosis for managing women with chronic pelvic pain: time for a rethink?

“…3 Further, placebo-controlled testing is required to ascertain that the therapeutic element or elements of surgery are responsible for the effect, particularly so when the effect is measured in patient-reported outcomes such as pain. 2,3 Second, while Horne et al 1 outline the problem of post-surgical pain in women with SPE, we believe more attention should be given to the women who develop neuropathic pain following surgery. Chronic post-surgical neuropathic pain (CPNP) is a serious complication that may amplify the patient's suffering, incur greater societal costs, and is difficult to treat.…”

“…We have read the commentary by Horne et al 1 and agree with the authors: placebocontrolled surgical trials for superficial peritoneal endometriosis (SPE) are needed. Such designs are the gold standard of testing treatment efficacy for chronic pain 2 and without placebo-control, it is ultimately unknown whether women with SPE are subjected to repeated surgeries that are not only unnecessary but also potentially harmful. Based on other surgeries for chronic pain, there is reason to believe that the effect of surgery for SPE may not be due to the surgery itself but that non-specific factors (e.g.…”

“…First, when there is genuine doubt about the effect of a standard treatment (such as surgery for SPE, as described by Horne et al 1 ), placebo-controlled designs are needed to ascertain whether the treatment is effective. 2 For women with SPE, the placebo arm can be operationalised as a diagnostic laparoscopy without histology. In this way, the placebo arm remains valuable to the patient and can assist in ensuring a sample of women with SPE, while omitting the removal of endometrial tissue.…”

“…In this way, the placebo arm remains valuable to the patient and can assist in ensuring a sample of women with SPE, while omitting the removal of endometrial tissue. These trials should also consider a no-surgery control group as a third arm to control for the natural history of pain, 2 which enables an estimate to be made of how large the effect of expectations is. Opponents of placebo-controlling surgical interventions argue that these designs are unlikely to succeed in practice, subjecting patients in the placebo arm to unnecessary risks and denying patients in the placebo arm effective treatment.…”

“…Opponents of placebo-controlling surgical interventions argue that these designs are unlikely to succeed in practice, subjecting patients in the placebo arm to unnecessary risks and denying patients in the placebo arm effective treatment. 2 However, metaanalyses indicate that not only are placebocontrolled surgical trials feasible, 2 the placebo arms are generally safe. 3 Further, placebo-controlled testing is required to ascertain that the therapeutic element or elements of surgery are responsible for the effect, particularly so when the effect is measured in patient-reported outcomes such as pain.…”