Cranial electrotherapy stimulation (CES), also known as cranial electrical stimulation, transcranial electrical stimulation, or electrical stimulation therapy, utilize devices such as Alpha-Stim (Electromedical Products International) to deliver weak pulses of electrical current to the earlobes, mastoid processes, or scalp. According to the manufacturer, CES can be performed in either setting: the outpatient office or at home as a durable medical device. The purpose of CES is to provide an alternative treatment option or to improve on the existing therapies, such as medical management and other conservative therapies for a variety of indications. CES has been evaluated for a variety of conditions including headache, pain (acute or chronic), sleep disturbances, depression, anxiety, Parkinson disease, and functional constipation.
HEADACHE
Headaches are common pain ailments that consist of painful sensations (e.g., pressure, tension) across areas of the head. The pain ranges from dull to sharp, and could be caused by underlying disease or by a number of other causes. Primary headache disorders include migraine, cluster, and tension headaches. Three trials have evaluated CES in the treatment of headache. Klawansky et al. (1995) published a meta-analysis of 14 randomized controlled trials (RCTs) comparing CES with sham for the treatment of various psychological and physiological conditions. The literature search, conducted through 1991, identified two trials evaluating CES for the treatment of headache. Pooled analysis of the two trials (total N=102 participants) favored CES over placebo (0.68; 95% confidence interval [CI], 0.09–1.28). Pooled analyses found marginal benefits for a headache with CES.
A Cochrane review by Bronfort et al. (2004) assessed noninvasive treatments for headaches; the reviewers conducted a literature search through November 2002. They identified one poor quality, placebo-controlled, randomized trial (N=100) of CES for a migraine or a tension-type headache. Results from the trial showed greater reductions in pain intensity in the CES group compared withthe placebo group (0.4; 95% CI, 0.0–0.8). The trial was under-powered and the evidence is limited to demonstrate efficacy. The evidence is insufficient to determine the effects of the technology on health outcomes.
PAIN
For individuals who have acute or chronic pain treated by CES, the evidence includes a number of small sham-controlled randomized trials and pooled analyses. Relevant outcomes are symptoms, morbid events, functional outcomes, and treatment-related morbidity.
O'Connell et al. (2014) reviewed five studies assessing chronic pain treated by CES. A meta-analysis of these five trials (n=270 participants) found no significant difference in pain scores between active and sham stimulation (−0.24; 95% CI,
−0.48–0.01) for the treatment for chronic pain. An updated Cochrane review by O'Connell et al. (2018) evaluated six low-quality studies on short-term outcomes for pain treated by CES. No individual study in this analysis demonstrated superiority of active stimulation over sham, and the results of the meta-analysis do not demonstrate a clear effect (standardized mean difference [SMD], −0.24; 95% CI, −0.48–0.01; P=0.06). The evidence is insufficient to determine the effects of the technology on health outcomes and does not support the use of CES in the treatment of pain.
Ahn et al. (2020) published a double-blind, randomized, sham-controlled pilot study of the feasibility and efficacy of remotely supervised CES via secure videoconferencing in 30 older adults with chronic pain due to knee osteoarthritis. Mean age was 59.43 years. CES was delivered via the Alpha-Stim M Stimulator, which was preset at 01 mA at a frequency of 0.5 Hz, and applied for 1 hour daily on weekdays for 2 weeks. The sham electrodes were identical in appearance and placement, but the stimulator did not deliver electrical current. The study was conducted in a single center in Houston. All 30 participants completed the study and were included in the outcome analyses. For the primary outcome of clinical pain at 2 weeks as assessed by a Numeric Rating Scale, a significantly greater reduction occurred in the active CES group (−17.00 vs. +5.73; P<.01). No individuals reported any adverse effects. Important relevancy limitations include lack of assessment of important health outcomes or long-term efficacy. An important conduct and design limitation is that it is unclear how convincing the sham procedure was as it did not involve any feature designed to simulate a tingling sensation and give the individual the feeling of being treated (i.e., subtherapeutic amplitude, initial current slowly turned to zero). Thus, findings may be subject to the placebo effect. This trial was also limited by the small number of participants. These limitations preclude drawing conclusions based on these findings.
BEHAVIORAL HEALTH, NEUROLOGIC INDICATIONS
For individuals who have behavioral health conditions receiving CES, the evidence includes systematic reviews and meta-analyses, and a sham-controlled randomized trial.
Several
systematic reviews and meta-analyses were conducted investigating the efficacy
of a cranial electrotherapy stimulation (CES) device known as Alpha-Stim
compared to a control therapy on various depression and anxiety disorders (Price et al, 2021;
Ching et al., 2022). Price et al. evaluated CES for the treatment of depression and/or anxiety and depression. Five RCTs and 12 open-label, nonrandomized studies that utilized Alpha-Stim were included. When considering pooled data from RCTs, results demonstrated that the mean depression level at posttest for the CES group was −0.69 standard deviations lower than the mean depression level for the sham stimulation group, which corresponds to a medium effect size (95%
Confidence Interval [CI] -0.96 to -0.43, P <
0.001). Pooled data from nonrandomized studies on interventions (NRSI) showed a smaller effect of −0.43 standard deviations in favor of CES (CI -0.49 to -0.36, P < 0.001). The
evidence is limited by varying depression scales among both RCT and NSRI analyses (e.g.,
Beck Depression Inventory, Clinical Global Impression, Hamilton Depression
Inventory, etc.) and lack of medication dictation during CES treatment. Ching
and colleagues' made a similar analysis primarily studying mean change in anxiety symptoms and
secondarily depression symptoms. All were measured via validated scales
including but not limited to the Hamilton Anxiety/Depression Rating Scale
[HAM-A/HAM-D] and/or the Zung Self-Rating Anxiety/Depression Scale [SAS/SDS]).
Eleven randomized controlled trials showed improved anxiety (standard mean
difference [SMD] -0.625, 95% CI -0.952 to -0.298, P
< 0.001). Further, among eight studies, the authors demonstrated favorable
depression scores (SMD -0.660, CI -1.082 to -0.238, P = 0.002); however, both results had significant heterogeneity
(Anxiety: I2 = 78.608, P <
0.001; Depression: I2 = 80.315, P < 0.001) due to the disparate differences
among implementation (500 μA to 500 mA), duration (10 to 60 minutes), total sessions (14 to 70 sessions), and control groups (e.g., sham, aerobic exercise, biofeedback, and paroxetine). A subgroup analysis was
performed to compare efficacy of cranial electrotherapy stimulation for
individuals with primary or secondary anxiety. The treatment had a favorable
impact on primary anxiety (RCT = 3) over secondary anxiety (RCT = 8) (SMD
-1.218 versus -0.334; between group analysis P <
0.001). The analysis is limited by significant variability among session
duration, number of sessions, and control groups, as well as varying outcome
scales and small sample sizes in each trial. Further, it is unclear when follow-up was completed post-treatment, limiting an understanding of long-term durability. Despite
the efficacious results of CES on pooled anxiety and depression scores among
both meta-analyses, the cumulative limitations preclude the ability to determine the treatment's relevant impact compared to conventional alternatives. Future trials with standardized treatments,
controls, and anxiety/depression rating scales with larger cohorts and documented follow-up are needed.
Morriss et al. (2023) performed a multi-center, double-blind randomized controlled trial evaluating the clinical effectiveness of a CES device (i.e., Alpha-Stim AID) compared to a sham control in improving depression and anxiety symptoms. Eligible individuals were 16 and older with a current diagnosis of primary major depression who have taken antidepressants for at least six weeks within three months prior to starting the trial, though discontinuation of medication was required to participate. The primary outcome of interest was score change from baseline to 16-weeks post-randomization on the 17-item Hamilton Depression Rating Scale (HDRS-17, GRID version), an internationally utilized depression scale administered by clinicians. Individuals were advised to use the device 60 minutes a day for eight weeks preset to a subsensory therapeutic dose of 100 μA. An intention to treat (ITT) analysis demonstrated no significant mean HDRS-17 score differences between groups (Active: -5.9 [95% CI -7.1 to -4.8]; Sham: -6.5 [-7.7 to -5.4]). Both groups sustained a clinically significant decrease in score change up to 16 weeks, suggestive of a bias based on placebo effect. Although the trial demonstrated safety, addressed clinically relevant outcomes, and was adequately powered, blinded, and randomized, efficacy of the treatment could not be established over the sham control. Future studies may yield greater contrast between cohorts with modifications to the primary endpoint.
Other behavioral health and neurologic conditions investigated include studies for Parkinson disease, smoking cessation, and tic disorders. The results of these trials do not support the use of CES for these conditions. Shill et al. (2011) found no benefit of CES with the Nexalin device for motor or psychological symptoms in a crossover study of 23 participants with early Parkinson disease. Pickworth et al. (1997) reported that 5 days of CES was ineffective for reducing withdrawal symptoms or facilitating smoking cessation in a double-blind RCT of 101 cigarette smokers who wanted to stop smoking. The evidence is insufficient to determine the effects of the technology on health outcomes. Wu et al. (2020) published a double-blind, randomized, sham-controlled trial of the efficacy and safety of CES as an add-on treatment for tic disorders in 62 children and adolescents who lacked a clinical response to prior treatment of 4 weeks of pharmacotherapy. CES was delivered via the CES Ultra stimulator (American Neuro Fitness LLC) at 500 μA–2 mA and applied for 30 minutes daily on weekdays for 40 days. The sham CES was delivered at lower than 100 μA. The study was conducted at a single academic medical center in China. Nine participants (14.5%) discontinued the intervention early and were excluded from the analyses. There was no significant difference between the active CES and sham groups in the change in Yale Global Tic Severity Scale (YGTSS) score (−31.66% vs 23.96%; P=0.13).
FUNCTIONAL CONSTIPATION
For individuals who have functional constipation who receive CES, the evidence includes an RCT. Relevant outcomes are symptoms, morbid events, functional outcomes, and treatment related morbidity. The single RCT by Gong et al. (2016) reported on a single-center unblinded RCT, which compared 74 participants with functional constipation. The authors report positive results for the treatment of constipation with CES. Individuals were randomly assigned to biofeedback with CES (n=38) or biofeedback alone (n=36) and followed at four time points (baseline and three follow-up visits); however, the duration of time between each follow-up visit was not specified. In a repeated-measures analysis of variance model for change from baseline, at the second and third follow-up visits, there were significant differences between groups in: self-rating anxiety scale score (41.8 for CES group vs 46.8 for controls; P<0.001); self-rating depression scale score (43.08 for CES group vs 48.8 for controls; P<0.001) and the Wexner Constipation Score (10.0 for CES arm vs 12.6 for controls; P<0.001). Serious methodology limitations were observed in the trials and the outcomes were self-reported. The evidence does not permit firm conclusions to be drawn on the effects of this technology on health outcomes for constipation.
