Cranial electrotherapy stimulation (CES), also known as cranial electrical stimulation, transcranial electrical stimulation, or electrical stimulation therapy, utilizes 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 cranial electrotherapy stimulation 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 with the 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 that assessed 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 (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<0.01). 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 or neurologic conditions who receive CES, the evidence includes a number of small sham-controlled randomized trials and systematic reviews.
Barclay et al. (2014) reported on a randomized, double-blind, sham-controlled trial evaluating the effectiveness of 1 hour of daily CES in individuals with anxiety (n=115) and comorbid depression (n=23). Analysis of covariance showed a significant advantage of active CES over sham for both anxiety (P=0.001) and depression (P=0.001) over 5 weeks of treatment. The mean decrease in the Hamilton Rating Scale for Anxiety score was 32.8% for active CES and 9.1% for sham. The mean decrease in the Hamilton Rating Scale for Depression score was 32.9% for active CES and 2.6% for sham. The trial was limited by small samples and short follow-up.
In a smaller, double-blind, sham-controlled randomized trial (N=30), Mischoulon et al. (2015) found no significant benefit of CES as an adjunctive therapy in individuals with treatment-resistant major depression. Both active and sham groups showed improvements in depression over the 3 weeks of the study, suggestive of a bias based on placebo effect.
A sham-controlled, double-blind randomized trial by Lyon et al. (2015) found no significant benefit of CES with the Alpha-Stim device for symptoms of depression, anxiety, pain, fatigue, and sleep disturbances in women receiving chemotherapy for breast cancer. This trial randomly assigned 167 women with early-stage breast cancer to 1 hour of daily CES or to sham stimulation beginning within 48 hours of the first chemotherapy session and continuing until 2 weeks after chemotherapy ended (range, 6–32 weeks). Stimulation intensity was below the level of sensation. Active and sham devices were factory preset, and neither evaluators nor participants were aware of the treatment assignment. Outcomes were measured using validated questionnaires that assessed pain, anxiety, and depression, fatigue, and sleep disturbance. There were no significant differences between the active and sham CES groups during treatment. However, the trial effectiveness might have been limited by the low symptoms levels at baseline, resulting in a floor effect, and the low level of stimulation.
Price et al. (2021) published a meta-analysis evaluating 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. Pooled data from nonrandomized studies showed a smaller effect of −0.43 standard deviations in favor of CES.
Kim et al. (2021) reported on a 3-week randomized, double-blind, sham-controlled trial evaluating the effectiveness of home-based CES (n=25) versus sham treatment (n=29) in nonclinical individuals with daily anxiety. Novel, headphone-like in-ear electrodes were used in this study. Results demonstrated a significant reduction in anxiety scores using the State Anxiety Inventory (SAI) with CES versus sham stimulation treatment. Depression inventory scores did not significantly differ between groups. Limitations of this study included the use of a small sample of nonclinical individuals, short follow-up, postrandomization withdrawals that did not contribute data to the analysis, and the unclear clinical significance of a decreased anxiety inventory score.
Other behavioral health and neurologic conditions investigated with CES, 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. A total of 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 that 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 3 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.
