Neuromodulation: More Than a Placebo Effect?

Sophie W. Kjær; Andrew S.C. Rice; Karolina Wartolowska; Lene Vase

Disclosures

Pain. 2020;16(3):491-495. 

In This Article

Future Evidence: Possible Placebo Controls in Neuromodulation

For many years, the inclusion of placebo controls in low-frequency spinal cord stimulation trials has been regarded as impossible,[53] due to paraesthesiae potentially unblinding patients to intervention allocation. This is not a limitation of high-frequency spinal cord stimulation because it does not evoke paraesthesiae. Recently, a new high-frequency spinal cord stimulation device has been endorsed by the National Institute for Health and Care Excellence.[41] This spinal cord stimulation device avoids paraesthesiae and thereby potentially allows for adequate blinding. Although the title "Senza spinal cord stimulation system for delivering HF10 therapy to treat chronic neuropathic pain" of this Medical Technologies Guidance implies generic effectiveness in neuropathic pain, the randomized controlled trial–derived evidence considered was restricted to studies of patients with what was described as chronic back or leg pain or failed back surgery syndrome.[1,3–6,10,29,48,50,54] The studies were retrospective analyses of patients with spinal cord stimulation implants,[10,50] prospective studies of implants,[3,4,48,54] or randomized studies comparing high-frequency spinal cord stimulation with traditional spinal cord stimulation.[5,6,29] No studies included control groups other than the active spinal cord stimulation therapy as controls. This approval is one of many examples in the neuromodulation literature of the seemingly underlying assumption that it is not possible or necessary to compare these procedures to placebo controls. However, with the advancement of neuromodulation techniques that enable inclusion of adequate placebo controls, this assumption is increasingly challenged. One ongoing study includes a placebo control group in the evaluation of the high-frequency Senza spinal cord stimulation device[51] and this study might be followed by additional placebo-controlled studies.

Placebo effects are typically investigated through comparison of active vs placebo treatment and as illustrated in the surgical literature placebo control of invasive procedures are feasible.[58,59] In addition, so-called placebo-like effects[8] can be investigated using open vs hidden administration of active treatment. In open–hidden designs, patients only receive active treatment, and therefore no inactive placebo treatment is given. Yet, the active treatment is either administered openly so that the effect of the treatment plus the contextual effect of knowing that an effective treatment is administered is tested, or the active treatment is administered hidden to the patients so that only the effect of the active treatment is measured. This design has been used in a neuromodulation trial of Parkinson disease, in which deep brain stimulation treatment was turned on and off while information about treatment and thus expectations toward the treatment were altered.[40] Information about treatment (open condition) enhanced the clinical effect compared with no information about treatment (hidden condition), showing that placebo effects represented 34.8% of the magnitude of the effect of active treatment.[40] In another study in patients with Parkinson disease, instead of switching off the stimulation, deep brain stimulation intensity was lowered from 80% to 20%, but this fact was not revealed to the patients. When patients were informed that stimulation was not changed, they showed a significantly better movement velocity of the hand compared with patients who were correctly informed that stimulation was reduced.[46] This result has been replicated in related studies.[30,35] Similar designs might offer an opportunity to include placebo controls in patients treated with neuromodulation devices. Correspondingly, an open–hidden design could be applied in high-frequency paraesthesiae-free spinal cord stimulation. In both the open condition and the hidden condition, patients would receive active spinal cord stimulation. However, in the open condition, patients would receive positive verbal suggestions about the treatment effect, whereas patients in the hidden condition would receive suggestions that treatment was not given. Including and controlling for a no-treatment group further allows for a more precise estimation of the specific effects of actual treatment and the additional nonspecific effects of the patients' knowledge of treatment.

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