“Of course, the Holy Grail of pain treatment would be to treat the affected site directly,” said Max M. Klein, PhD, Instructor of Neurology, Massachusetts General Hospital, Boston, at the 2016 American Academy of Pain Medicine meeting.
What we now have, however, is the delivery of analgesic agents through the diffusion of oral or intravenous medications throughout the body, which is the polar opposite to that ideal. The frequent undesired adverse effects at sites distant to the target are well known.
Deep brain stimulation, which has demonstrated efficacy in the treatment of chronic pain, Parkinson’s disease, essential tremor, dystonia, and psychiatric disorders, directly targets the brain and entails invasive surgery. Epidural motor cortex stimulation applied to the precentral gyrus also affects the deeper brain structures, and although it is less risky than deep brain stimulation, it is also invasive.
Noninvasive brain stimulation, which overcomes the disadvantages of these strategies, is based on the brain’s plasticity—its ability to adapt to external stimuli in a manner that brings therapeutic change, said Dr Klein.
Applications of Noninvasive Brain Stimulation
Among the several noninvasive brain stimulation methods, “the ones with the most traction and the most promise are transcranial direct current stimulation [tDCS] and transcranial magnetic stimulation [TMS].”
tDCS is neuromodulatory; it influences neuronal firing, changing the threshold for firing within the neural membrane—either raising or lowering membrane potentials with battery-powered direct current (1-2 mA) given through saline-soaked electrodes (sponges or EEG-type) held to the scalp by straps or caps. Anodal stimulation facilitates neuronal firing and cathodal stimulation inhibits neuronal firing.
With TMS, a rapidly changing electric current in a coil induces a pulsed electromagnetic field in the brain, hyperpolarizing or depolarizing axons to alter neuronal firing. Induction of >5 Hz increases brain excitability, and induction of <5 Hz decreases it. TMS stimulation intensity is tailored to the individual’s resting motor threshold, determined by electromyographic monitoring at the first dorsal interosseous as the motor response to stimulation (motor-evoked potential).
Resting motor threshold can be influenced by medications, mental state, relaxation, age, sex, and handedness. Magnetic resonance imaging guidance of coil positioning can improve the precision and accuracy of TMS.
Dr Klein noted that although TMS application is more complex than tDCS, it provides a greater variety of treatment conditions than tDCS.
The risks for the 2 modalities are dissimilar, noted Anne Louise Oaklander, MD, PhD, Associate Professor of Neurology, Harvard Medical School, Boston. The direct application of electrical current with tDCS can irritate the scalp, whereas TMS can heat metal in the head and disable implanted devices. Repetitive TMS (rTMS) has triggered single seizures, but these occurrences were rare (1/10,000 among all rTMS studies). In addition, hearing damage from “clicks” with rTMS treatment is a potential concern, Dr Oaklander said.
Unresolved questions remain regarding noninvasive brain stimulation testing. What are the best outcome measures? How will sham treatments be devised? How will safety be ensured? How will approval be gained for combined noninvasive techniques with pharmaceuticals?
To circumvent the unresolved FDA regulatory issues, some device developers are promoting “nontherapeutic use.” Thync, for example, is a transcutaneous electrical nerve stimulation device that is marketed as “a pure, digital way to focus and energize.”
Dr Oaklander concluded that although noninvasive brain stimulation is here, a Wild West environment remains, because of unresolved ethical and regulatory issues. Pain societies need to take the lead in developing standards, she said.
Evidence Supports Brain Stimulation for Pain
The only FDA-approved treatment with a single-pulse TMS device (SpringTMS; eNeura) is for migraine; 2 rTMS devices (NeuroStar; Neuronetics; and Deep TMS [H-coil]; Brainsway) are approved for the treatment of patients with major depression.
Although no pain treatments are FDA approved, evidence supports the efficacy of rTMS across a range of pain indications, including migraine, central neuropathic, peripheral neuropathic, phantom limb, chronic widespread, fibromyalgia, chronic pancreatitis, complex regional pain syndrome, and visceral pain. A 2009 meta-analysis of rTMS showed the highest efficacy for trigeminal pain, with a mean reduction in pain scores of 29%. And a 2008 study showed more than a 40% reduction in acute postoperative pain with rTMS.
Ophthalmic postherpetic neuralgia is among the most promising research indications, because a sufficient number of patients are available, postherpetic neuralgia has a precise anatomic location, and the motor cortex of the eye is favorably located for TMS.
Dr Klein emphasized that it remains “unclear whether to stimulate the cortical representation of the painful area or the area itself.” In the majority of studies, he said, rTMS is used to stimulate the primary motor cortex. Maintenance rTMS every 3 to 4 weeks may be needed to maintain benefit.
“TMS offers potential medical benefits for various conditions,” he concluded.
Home Use of Transcranial Direct Current Stimulation
Turning to the prospect of at-home use of tDCS, Dr Klein noted that although there are no FDA-approved tDCS indications, the most common sensations reported during tDCS use (tingling, burning, headache, and itching) were reported at relatively similar rates as with sham treatment. Studies of tDCS administered for multiple days have demonstrated effectiveness in treating chronic pain, fibromyalgia pain, neuropathic pain, and chronic abdominal pain. Cochrane reviews of tDCS, however, showed only near significance for pooled data on short-term pain (11 studies), and nonsignificance on medium-term relief (5 studies).
Dr Klein noted that affordable tDCS home units make taking many variables into account, such as interpatient variability in response, session differences, mental states, and concomitant medications, very difficult. No clinical trials of tDCS home use have been conducted.
In Dr Klein’s pilot tDCS studies, 5 patients with postherpetic neuralgia were loaned sophisticated portable tDCS units and received treatment with tDCS for 10 days, followed by a 3-week washout period. Analysis showed a trend toward decreasing pain scores (2-3 points) during and immediately after treatment with tDCS, and scores reverted to baseline values during the washout period.
“That offers proof of concept that at-home tDCS can provide short-term relief of V1 (ophthalmic) PHN [postherpetic neuralgia] pain,” Dr Klein concluded.