Neuromodulation: More Than a Placebo Effect?

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


Pain. 2020;16(3):491-495. 

In This Article

Neuromodulation in Pain: Current Evidence

Analgesic effects of neuromodulation have been demonstrated in patients experiencing chronic pain caused by conditions such as osteoarthritis, back problems, or Parkinson disease.[11,18,20,42,47] Procedures of neuromodulation proposed for targeting pain involve both invasive procedures such as deep brain stimulation, spinal cord stimulation, peripheral nerve stimulation, nerve root stimulation, and epidural motor cortex stimulation, and noninvasive procedures such as transcutaneous electrical nerve stimulation, and repetitive transcranial magnetic stimulation.[14] Spinal cord stimulation is an example of neuromodulation for chronic pain, mainly for the treatment of peripheral vascular disease, complex regional pain syndrome, and postsurgical chronic back and leg pain.[15] In this article, the spinal cord stimulation literature will be used as an example to demonstrate some of the challenges in the field of neuromodulation regarding the inclusion of placebo controls.

Spinal cord stimulation is widely used for analgesia in research and clinical practice. Inspired by the gate control theory of pain,[39] the objective of spinal cord stimulation therapy is to inhibit nociceptive transmission in the dorsal horn of the spinal cord. Traditional spinal cord stimulation (<1000 Hz) entails implanting an electrode, which delivers electrical impulses, in the epidural space over the dorsal column structure of the spine.[16] Such stimulation often evokes paraesthesiae, an abnormal painless sensation in the target innervation.[24] Advancements in neuromodulation technology have allowed for the emergence of high-frequency spinal cord stimulation, which stimulates at 10,000 Hz, and at this frequency, pain relief is obtained without paraesthesiae.[17] It has been established that patients with chronic pain probably benefit from traditional low-frequency spinal cord stimulation as well as from high-frequency spinal cord stimulation.[3,6,31]

Previous research has drawn attention to the quality of evidence underlying neuromodulation, highlighting the need for further preclinical studies elucidating mechanisms, sufficient blinding and controls, and the consideration of placebo effects.[13,22] As a Cochrane review on the topic has been withdrawn due to being out of date,[37] there is currently a lack of recent reviews on the evidence of spinal cord stimulation for pain. Systematic reviews show that the majority of current evidence of spinal cord stimulation relies on small-scale studies, case studies, or prospective studies with a lack of randomized controlled trials.[43,55] Randomized controlled trials in the field often compare different modalities of spinal cord stimulation therapy, eg, various frequencies of stimulation. This is illustrated in a sample identified through PubMed for the purpose of this article (the latest 200 out of 2035 results searching for "spinal cord stimulation" AND "pain," with no restrictions regarding the year of publication, identified the sixth of May 2019). In this sample, 17 studies included control groups. Fourteen of these used another spinal cord stimulation therapy (eg, other frequencies of stimulation) as a control group, 2 studies compared results to a healthy control group,[27,28] and one to medical treatment.[49] These control groups may not be sufficient to evaluate treatment efficacy. Medical treatment, or standard care, reflects the course of symptoms without spinal cord stimulation, but cannot control for the placebo effects associated with an invasive technique. Healthy controls are also not an adequate control group, because they do not demonstrate these fluctuations in symptoms. Other types of spinal cord stimulation may act as a control; however, because the working mechanisms underlying this therapy are unclear, comparing 2 neuromodulation therapies may not be sufficient to demonstrate that they are truly effective and placebo-controlled trials will be needed.

In the existing spinal cord stimulation literature, there is a small number of neuromodulation studies that have included placebo procedures, but they have used various stimulation frequencies and produced mixed results regarding the efficacy of active stimulation over placebo.[2,33,44,52] In the following examples of placebo-controlled trials, placebo conditions entailed programming the same settings in the spinal cord stimulation device as the active stimulation, but with no amplitude in the placebo treatment, meaning that no electrical impulses were delivered. A small case series study, which included only 4 subjects, found beneficial effects of spinal cord stimulation in comparison with placebo.[52] In this study, subjects were assigned to placebo spinal cord stimulation and active high-density spinal cord stimulation (1200 Hz), which involves paraesthesiae-free stimulation through increased frequency and pulse width and reduced amplitude compared with traditional stimulation. While all subjects achieved pain relief as a result of active spinal cord stimulation, one subject also responded well to placebo stimulation. Larger studies have also produced mixed results regarding the efficacy of active stimulation and the most beneficial stimulation frequency. In a double-blind randomized two-period crossover study in 33 patients with chronic back pain, a similar proportion (N = 14/33) of patients responded to high-frequency stimulation (5000 Hz) and placebo condition without stimulation (N = 10/33).[44] In a study, placebo stimulation was compared to varying frequencies of stimulation (1200, 3030, and 5882 Hz).[2] Although stimulation at 5882 Hz produced statistically significant pain relief compared with both the lower frequencies and placebo stimulation, the lower frequencies of stimulation did not produce any effect beyond placebo.[2] By contrast, another trial showed no difference in pain reduction across 4 frequencies of stimulation (40, 500, 1200 Hz, and burst spinal cord stimulation), but found that all spinal cord stimulation frequencies outperformed placebo.[33] Thus, although stimulation at 1200 Hz produced analgesic effects beyond placebo in one trial, this effect was absent in another trial. Hence, the efficacy of stimulation frequencies over placebo has varied across studies, thereby questioning the efficacy of active stimulation over placebo. Differences between the trials might have been caused by bias because some patients may have been unblinded either in low-frequency spinal cord stimulation by paraesthesiae or in high-frequency stimulation by the higher number of recharge sessions during active stimulation.[2,33,52] Although all trials were set up to be double-blind, only one study tested whether blinding was obtained.[44] Thus, it seems that the placebo conditions may have been insufficiently robust in so far as blinding can be questioned, thereby potentially compromising the control for contextual factors and the findings of the studies.