Abstract and Introduction
Neuromodulation interventions use electrical stimulation to modulate neuronal activity and elicit a therapeutic response. These procedures are generally adjustable, reversible, and have demonstrated some efficacy in the treatment of several conditions, including chronic pain. Despite promising evidence in the field, the general quality of the evidence is weak or moderate. Improvements after neuromodulation therapy are typically attributed to the neuromodulation itself, but as the exact mechanisms responsible for improvement are unknown and as appropriate control conditions are lacking, more careful investigations of the mechanisms underlying these apparent effects are warranted. The advancement of neuromodulation techniques and the advent of new ways of controlling and evaluating neuromodulation trials will potentially help to advance our understanding of the mechanisms underlying neuromodulation.
Placebo controls are used to distinguish the effects of an intervention, i.e., effects specifically related to the active properties of the treatment from effects attributable to the treatment context, such as the ritual of the treatment, the invasiveness of the procedure, the doctor–patient relationship, and the patients' expectations towards the treatment. An adequate placebo control ensures that the active condition and the placebo condition are indistinguishable, the only difference being the presence of the supposed active component of the treatment, thereby simulating the treatment and its context without delivering the actual treatment. This approach allows for a double-blind administration of the intervention, so that neither the patients nor the health care providers know which treatment is given. Without an adequate placebo control and blinding, it is not possible to determine whether the apparent effect is due to the supposed active treatment component or contextual factors such as high expectations toward treatment.
Strong placebo analgesic effects have repeatedly been demonstrated for pharmacological treatments.[7,9,12,45] Factors through which placebo effects may influence treatment effects include enthusiasm about the new treatment, doctor–patient interactions, increased expectations of treatment effects, and decreased negative emotions such as anxiety, and these effects may increase with the invasiveness of the procedure. Recent meta-analyses of placebo-controlled trials of interventional procedures involving the introduction of medical devices inserted into the body demonstrated that the magnitude of change in the placebo arm is large and longlasting, and it accounts for about 80% of the improvement in the active arm, especially in studies with subjective outcomes such as pain.[23,25,58,59]
In the field of surgery and neuromodulation, placebo controls are sometimes referred to as sham interventions, but as both concepts involve interventions that simulate the treatment context without delivering actual treatment, they are conceptually similar. There is an ongoing debate on appropriate methods to control and evaluate treatment efficacy and when and how the placebo control should be implemented. First, it may be challenging to create appropriate placebo control conditions, which imitate all elements of treatment except for the active component so that blinding is possible. Moreover, an objection that is sometimes posited is that the inclusion of placebo controls in surgical trials poses ethical problems because it involves risks for the patient or may not offer the best possible treatment. However, not validating interventional procedures in placebo-controlled trials may also pose ethical concerns because patients might undergo invasive and risky treatments without proven efficacy.[21,56]
Like most medical procedures, neuromodulation involves risks, and it is, therefore, essential to demonstrate that its true efficacy outweighs potential harms. Furthermore, there are relatively high financial costs associated with the neuromodulation device and implantation surgery as well as battery replacement, and any complications or hardware malfunctions that may require additional surgery. For a new pharmacological treatment to be approved, it has to produce beneficial effects that outweigh placebo effects, biases, and fluctuations in symptoms; however, these rigorous requirements do not yet apply to treatments involving neuromodulation. Before widening the scope of neuromodulation therapy further, it is critical to evaluate treatment effects adequately.
In this article, we review the current evidence for neuromodulation therapy in chronic pain and reflect upon the challenges this field is facing when securing high-quality evidence.
Pain. 2020;16(3):491-495. © 2020 International Association for the Study of Pain