Abstract and Introduction
The aims of this review were to systematically identify the current evidence base of placebo (or "sham") randomised controlled trials (RCTs) of spinal cord stimulation (SCS) for neuropathic pain and to undertake a meta-analysis to investigate the effectiveness of SCS when compared with a placebo comparator arm. Electronic databases were searched from inception until January 2019 for RCTs of SCS using a placebo/sham control. Searches identified 8 eligible placebo-controlled randomised trials of SCS for neuropathic pain. Meta-analysis shows a statistically significant reduction in pain intensity during the active stimulation treatment periods compared with the control treatment periods, pooled mean difference −1.15 (95% confidence interval −1.75 to −0.55, P = 0.001) on a 10-point scale. Exploratory study–level subgroup analysis suggests a larger treatment effect in RCTs using a placebo control (defined as studies where the device was inactive and at least one of the study procedures was different between the arms) than a sham control (defined as all study procedures being equal between arms including SCS device behaviour). Our findings demonstrate limited evidence that SCS is effective in reducing pain intensity when compared with a placebo intervention. Our analyses suggest that the magnitude of treatment effect varies across trials and, in part, depends on the quality of patient blinding and minimisation of carryover effects. Improved reporting and further methodological research is needed into placebo and blinding approaches in SCS trials. Furthermore, we introduce a differentiation between placebo and sham concepts that may be generalisable to trials evaluating surgical or medical procedures.
Spinal cord stimulation (SCS) is a recognised option for the management of chronic neuropathic pain with randomised controlled trials (RCTs) performed to investigate its effectiveness for conditions such as failed back surgery syndrome (FBSS), complex regional pain syndrome, and painful diabetic neuropathy. Conventional medical management has however been the comparator most commonly used in RCTs to date evaluating SCS for neuropathic pain.
Reports have suggested that at least some part of pain relief observed at early stages of SCS therapy may be the result of a placebo effect with long-term follow-up revealing loss of efficacy for a proportion of participants when compared with the earlier primary endpoint.[8,19,21,25,33] It is widely accepted that use of placebo or sham controls in a clinical trial can reduce bias as the result of unblinding (knowing the treatment received) of patients and clinicians, and researchers can result in nonspecific treatment effects reported by patients. The literature suggests that factors relating to patient expectation of treatment success are central in the development of the placebo response; these are highly relevant in SCS use.
In the past decade, several RCTs have evaluated SCS for neuropathic pain conditions when compared with a placebo arm. These RCTs have been possible due to the emergence of new sensation-free SCS modalities such as burst, high frequency, or high density. Despite difficulties with blinding, conventional or paraesthesia producing SCS has been compared with placebo in a number of small studies with varied results, including the effects of placebo stimulation being similar to those of active treatments.[1,36]
In our context, "placebo trials" are trials that specifically set out to select a comparator to "find out" what might be the placebo effect of the active intervention, eg, RCT of low-dose SCS vs traditional SCS (both groups get implant, etc). However, as we know, in this design, there is high likelihood that patients will be aware of their allocation, and therefore, the design is effectively "open label." Within this framework, we could therefore define "sham trials" as a specific subgroup of placebo trials where there is the possibility to "fully blind" patients, clinicians, and researchers. In the neuromodulation setting, this would need to be an active intervention vs comparator that is completely paraesthesia-free, eg, RCT of HF10 vs no stimulation. Given the complexities in enabling a sham for a treatment such as SCS and for the purposes of this review, sham was defined as a control where all study procedures were equal between arms including implantable pulse generator (IPG) behaviour (ie, need for recharging). Placebo was defined as a control where the IPG was inactive and at least one of the study procedures was different between the arms (ie, no IPG spontaneous discharge, ie, built-in current leak), admitting overtly the possibility of unblinding.
We have recently conducted a systematic review that focused on the methodological facets of randomised placebo-controlled trials of SCS. The aim of this systematic review was to investigate the effectiveness of SCS for patients with neuropathic pain when compared with a placebo comparator arm.
Pain. 2020;161(1):24-35. © 2020 International Association for the Study of Pain