Electrical Stimulation May Prevent Opioid-Overdose Death

Electrical stimulation delivered by either an implantable device similar to a pacemaker or externally, via an automated external defibrillator (AED)–type device, may restart respiration and get patients who have overdosed on opioids breathing again, new research shows.

Dr Howard Levin

The proof-of-concept study, conducted in pigs, showed that drug-induced respiratory arrest could be detected and that rescue could be achieved using electrical stimulation. The study also showed that with such an approach, physiologic respiration could be maintained for up to 2 hours.

Fentanyl has become the culprit in an increasing percentage of the overdoses we are seeing, and while Narcan (naloxone) is effective in heroin overdoses, it is, to a large degree, insufficient to maintain adequate respiration in fentanyl overdoses,” Howard Levin, MD, managing partner of Coridea LLC, New York City, told Medscape Medical News.

In addition, naloxone is ineffective in cases of multiple drug–induced overdoses involving a combination of an opioid and alcohol or an opioid and a benzodiazepine. Moreover, with naloxone, the duration of effect is fixed, whereas a device that delivers electrical stimulation could provide enough stimulation to support an individual through an entire overdose episode without requiring pharmacologic therapy, said Levin, an engineering cardiologist who helped develop the devices.

The findings were presented here at the American Academy of Addiction Psychiatry (AAAP) 29th Annual Meeting.

Just Like a Pacemaker

Levin was instrumental in developing a similar device for central sleep apnea (CSA), as reported by Medscape Medical News. CSA is a condition in which the brain fails to send signals to breathe through the phrenic nerve,

The device, called the remedē System (Respicardia, Inc), is an implantable phrenic nerve stimulator that was approved in November 2017 by the US Food and Drug Administration for the treatment of moderate to severe CSA.

Dr Nasir Naqvi

Senior study investigator Nasir Naqvi, MD, PhD, Department of Psychiatry, Columbia University, New York City, believed a similar device could be used to save the lives of people who stopped breathing because of overdose.

“I thought it might be important in certain patient populations, where you would have something that would automatically detect critical respiratory depression and then electrically support physiological respiration until lifesaving treatment could be provided or until the drug-induced hypoventilation wore off,” Naqvi told Medscape Medical News.

Both the implantable device, which is similar to a pacemaker or implantable cardioverter-defibrillator, and the external device, which is an automatic external respiration system (AERS), similar to an AED, were tested in a swine model of respiratory arrest.

In the study, six animals were given fentanyl plus isoflurane to induce respiratory depression. When the animals stopped breathing, the devices were turned on, and respiration was rescued.

“The pigs started breathing again with the aid of these devices. We were able to maintain physiological respiration for up to 120 minutes using both transvenous or implantable and transcutaneous or external approaches, as assessed by the maintenance of normal ventilation rates (mean, 12 breaths per minute) and tidal volumes (mean, 0.84L) and general homeostasis, including heart rate, blood pressure, and blood gases,” Naqvi said.

“We see this being used just like a pacemaker,” Naqvi said. “It can be implanted in a one-time procedure, 16 minutes under conscious sedation. It is continuously sensing the person’s respiration and will automatically be triggered if breathing stops. The patient does not have to do anything.”

The investigators believe that the ideal candidate for such a device is a patient who has suffered multiple overdoses or who takes multiple substances.

“The data, at least in the pig model, are highly suggestive that this will sustain life. I think the most immediate clinical application, and the first clinical test we are going to do, is in people who have had multiple overdoses. We would approach them in the intensive care unit and tell them they are at very high risk for future overdoses and give them the option to be implanted with the device,” Naqvi said.

Both investigators said that the National Institute on Drug Abuse has shown interest in their research, and they hope to move into human trials “fairly soon.”

Novel Idea, More Research Needed

“I think electrical stimulation to treat respiratory depression due to drug overdoses is a novel idea which will need clinical research to support its use for that indication,” said Jonathan C. Lee, MD, medical director at the Farley Center in Williamsburg, Virginia.

“I commend Dr Levin for thinking of alternatives to naloxone for rescuing patients from opioid overdoses, especially in the context of the fentanyl epidemic,” Lee, who was not part of the study, commented to Medscape Medical News.

Dr Carla Marienfeld

Also commenting on the findings for Medscape Medical News, Carla Marienfeld, MD, University of California, San Diego, noted that traditional medications, such as naloxone, revive patients by reversing the effect of opioids, but they are not as effective with stronger opioids, such as fentanyl.

Marienfeld said that targeting respiration is a unique approach.

“Keeping the person breathing until they can get the help they need medically is a new and different approach to saving lives. We always need more tools in our toolbox. Learning from and sharing with other medical fields — in this case, treatment for sleep apnea, when a person stops breathing in their sleep — is a great way to help people without reinventing the wheel,” she said.

Electrical Stimulation Works as Add-On in Bipolar Depression

Transcranial direct current stimulation (tDCS) is a safe and effective add-on therapy for type I or II bipolar depression, researchers found.

In an intention-to-treat analysis of 52 patients in the randomized, double-blind, Bipolar Depression Electrical Treatment Trial (BETTER), active tDCS had significantly greater antidepressive effects than a sham procedure (differential effect size of −1.68 with a number needed to treat of 5.8, P=0.01), André Russowsky Brunoni, MD, PhD, of the University of São Paulo in Brazil, and colleagues reported online in JAMA Psychiatry.

“We were excited to show evidence that tDCS can be clinically effective for this population,” Brunoni told MedPage Today, adding that in their study, the rate of treatment-emergent affective switches (TEAS) was similar between groups. “Nonetheless,” he said, “I would recommend extra caution when applying tDCS for bipolar depressed patients who frequently present manic switches.”

The study of tDCS was devised as an add-on trial in patients with bipolar depression receiving a stable pharmacologic regimen in the sham-controlled BETTER trial, which was conducted from July 1, 2014, to March 30, 2016. A parallel design was used to randomly assign 59 patients to either sham or active tDCS.

All patients had type I or II bipolar disorder with a major depressive episode and were receiving a stable pharmacologic regimen with Hamilton Depression Rating Scale-17 (HDRS-17) scores scores higher than 17. There was also a high prevalence of comorbid anxiety disorders in the study population. A third of patients had experienced an acute depressive episode that was unresponsive to at least two treatment regimens.

Of the 59 patients, a total of 52 (26 active and 26 sham) received all 12 tDCS treatment sessions. This included 10 daily 30-minute sessions of active or sham tDCS on weekdays and then one session every 2 weeks until week 6.

Participants lay in comfortable reclining chairs while scalp electrodes delivered weak, direct currents into the dorsolateral prefrontal cortex (DLPFC) region of the brain — an area responsible for cognitive control and emotion regulation, which is hypoactive in depression. Patients were allowed to read or use their smartphones but not sleep. Talking with staff was minimal.

As for secondary outcomes, the researchers found 19 patients in the active group and eight patients in the sham group achieved sustained response, with significantly greater effects for the tDCS group (HR 2.86, 95% CI 1.25 to 6.61, P=0.01) and a number needed to treat of 2.69.

Similarly, 10 active-group patients and five sham-treated patients achieved sustained remission, though benefit wasn’t significantly greater for tDCS in further analyses.

Adverse events, including TEAS leading to manic or hypomanic episodes, were similar between active and sham tDCS. Patients receiving active treatment had more localized skin redness than those receiving sham (54% versus 19%, P=0.01) but these effects were short-lived, and didn’t result in any study discontinuations, or affect blinding.

Brunoni and colleagues concluded that their results suggest tDCS is an “effective and tolerable add-on treatment in this subsample of patients with type I or II bipolar disorder who were in a major depressive episode … Although preliminary, our results are promising and encourage further trials to examine the efficacy of tDCS in a large bipolar disorder sample.”

They noted that since tDCS effects are subtle, as they induce “small changes in the membrane potential, greater effects may be achieved when simultaneously combining tDCS with other treatments such as pharmacotherapy, other brain stimulation therapy, or psychotherapy. Therefore, different tDCS protocols, particularly combination therapies, could be explored in further studies.”

Recently, the research group published a large non-inferiority trial investigating tDCS efficacy in unipolar depression, and just completed a trial testing tDCS efficacy for schizophrenia. A trial looking at the efficacy of using tDCS in obsessive-compulsive disorder is underway, Brunoni said.

“Our next steps will be to better understand the mechanisms of action of tDCS,” he said, “using it in combination with neuroimaging techniques such as spectroscopy and resting state MRI.”

Researchers Use Electrical Stimulation and Intense Physical Therapy to Help Paralyzed Man Move His Legs

Mayo Clinic and UCLA research supports growing evidence of benefits of electrical stimulation; similar research under way at Shepherd Center.

 Mayo Clinic researchers in Rochester, Minn., used electrical stimulation on the spinal cord and intense physical therapy to help a man intentionally move his paralyzed legs, stand and make steplike motions for the first time in three years.

The case, the result of collaboration with UCLA researchers, was published this week in Mayo Clinic Proceedings. Researchers say these results offer further evidence that a combination of this technology and rehabilitation may help people with spinal cord injuriesregain control over previously paralyzed movements, such as steplike actions, balance control and standing.

“We’re really excited because our results went beyond our expectations,” said neurosurgeon Kendall Lee, M.D., Ph.D., principal investigator and director of Mayo Clinic’s Neural Engineering Laboratory. “These are initial findings, but the patient is continuing to make progress.”

The 26-year-old patient sustained a T-6 complete spinal cord injury three years ago. The injury left him unable to move or feel anything below the middle of his torso.

The Mayo study started with the patient going through 22 weeks of physical therapy. He had three training sessions a week to prepare his muscles for attempting tasks during spinal cord stimulation. He was tested for changes regularly. Some results led researchers to characterize his injury further as discomplete, suggesting dormant connections across his injury may remain.

Following physical therapy, he underwent surgery to implant an electrode in the epidural space near the spinal cord below the injured area. The electrode is connected to a computer-controlled device under the skin in the patient’s abdomen. This device, for which Mayo Clinic received permission from the U.S. Food and Drug Administration for off-label use, sends electrical current to the spinal cord, enabling the patient to create movement.

After a three-week recovery period from surgery, the patient resumed physical therapy with stimulation settings adjusted to enable movements. In the first two weeks, he intentionally was able to:

  • Control his muscles while lying on his side, resulting in leg movements
  • Make steplike motions while lying on his side and standing with partial support
  • Stand independently using his arms on support bars for balance

Intentional, or volitional, movement means the patient’s brain is sending a signal to motor neurons in his spinal cord to move his legs purposefully.

“This study supports the growing evidence that when a small amount of electrical stimulation is added to the spinal cord, it can increase the ability of the spinal cord to carry information from the brain to the muscles,” said Edelle Field-Fote, PT, Ph.D., FAPTA, director of spinal cord injury research at Shepherd Center in Atlanta.

The earliest published record of this type of research dates back to the 1980s. Shepherd Center research scientist William (Barry) McKay made significant contributions to this work during its early development. Now, Shepherd Center researcher Stephen Estes, Ph.D., is performing similar studies using more clinically available types of electrical stimulation that do not require surgical implantation.

“The goal of the study is to determine whether this more accessible, non-invasive type of stimulation, combined with physical therapy, can improve the ability to voluntarily move the legs and reduce spasticity in people with spinal cord injury,” Dr. Field-Fote explained.

Source: Mayo Clinic