An open-label study of “neuromodulation with percutaneous electrical nerve field stimulation” — a device put on the ear to treat opioid withdrawal symptoms in which patients were told that it would make withdrawal less painful — has shown promising results. But it’s an open-label study in which the placebo effect could have a huge effect on reducing subjective symptoms of withdrawal, such as anxiety, aches, yawning and restlessness — four of the 11 measures on the Clinical Opiate Withdrawal Scale (COWS), which was used to assess the patients’ symptoms in the study. The other measures are more objective: pulse rate, sweating, pupil size, runny nose or tearing, gastrointestinal symptoms, tremor and gooseflesh skin. All 11 measures are assessed based on severity.
The pilot study, “Neuromodulation with Percutaneous Electrical Nerve Field Stimulation Is Associated with Reduction in Signs and Symptoms of Opioid Withdrawal: A Multisite, Retrospective Assessment,” found that the device resulted in 64 of 73 treated patients being successfully transitioned to extended-release (ER) naltrexone. Treatment program staff — not the researcher — recorded COWS scores on patients on day 1 before the device was placed and at 20, 30 and 60 minutes after the device was placed, and a subset of patients (33 of the 64 who returned) had COWS scores analyzed when they returned to the clinic on day 5 when the device was removed and they were placed on ER naltrexone. The study is published in the current issue of the American Journal of Drug and Alcohol Abuse.
The research was a retrospective study, led by Adrian Miranda, M.D., who is with the Department of Pediatrics, Division of Gastroenterology and Hepatology, at the Medical College of Wisconsin in Milwaukee.
The mean COWS score before the device was placed was 20. Twenty minutes later, it was 7.5, reduced further to 4.0 at 30 minutes, and 3.1 at 60 minutes. There were no rescue medications.
The abstract for the article cites the name of the device (the Bridge) in full capital letters seven times, and says that the patients were transitioned to medication-assisted treatment (MAT) without indicating that it was to ER naltrexone only, not to buprenorphine or methadone. One of the two authors (Arturo Taca, M.D.) is a consultant to Alkermes, which makes the only patented form of ER naltrexone — Vivitrol. Taca is medical director of INSynergy Treatment Program in St. Louis, Missouri.
The Bridge is cleared by the Food and Drug Administration (FDA) but not approved. Made by Innovative Health Solutions, a company based in Versailles, Indiana, the Bridge is featured on the website of Taca’s treatment program, as is Vivitrol. It costs $500.
The reason the Bridge was used only with Vivitrol was because of Taca’s practice, said Miranda. “I know as a practicing physician we all have preferences in what we use and what we believe in, and in this case, that’s how Dr. Taca practices,” he told ADAW. “This was not a study that was planned.”
“Alkermes is not involved with the Bridge in any capacity,” said Matthew Henson, Alkermes spokesman, in response to our query. “Dr. Taca is a paid speaker for Alkermes, but any work on the Bridge has been conducted without any involvement from the company.” However, Alkermes recognizes “that there is strong interest from the medical community in studying additional methods to help transition patients onto antagonist therapies and help patients manage opioid withdrawal symptoms,” he added.
The theory is that the device can alleviate pain “through stimulating peripheral cranial neurovascular bundles in the external ear that could potentially gain access to brain areas involved in fear, pain and nociception,” according to the article. The amygdala, in particular, plays a role in fear conditioning and pain processing, as well as in “processing the negative emotional state of withdrawal.”
The original study used Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for opioid dependence, rather than Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for opioid use disorders, even though the subjects were enrolled in 2015 and 2016. DSM-5 was released in 2013. The decision was made by the clinics, apparently, said Miranda. “For the purpose of this study, it doesn’t make that much of a difference,” he said. However, dependence under DSM-5 is not necessarily pathological: a patient on a therapeutic dose of methadone or buprenorphine for the treatment of opioid use disorders would not have a diagnosis. “It’s a valid point,” Miranda conceded.
The subjects had a history of dependence on heroin or other opioids, including prescription opioids, methadone and buprenorphine/naloxone. The clinics were in St. Louis, Missouri (27 patients); Liberty, Indiana (13); Florence, Kentucky (12); Anchorage, Alaska (9); Rising Sun, Indiana (6); Richmond, Indiana (2); Dayton, Ohio (2); and Indianapolis, Indiana (2). Six of the clinics were private, and all were chosen because the Bridge had been used as the standard care in the initial treatment of opioid withdrawal.
COWS scores rated from 0 to 48, and were mild (5–12), moderate (13–24), moderately severe (25–36) or severe (more than 36). Immediately before Bridge placement, 53 of the 73 patients (72.6 percent) were in the moderate withdrawal range, 16 (21.9 percent) in the moderately severe range and four (5.4 percent) were in the mild range. None were in the severe range.
During the five-day period, no antipsychotic, opioid or benzodiazepine medications were given, but 28 patients (38 percent) received an oral antiemetic — typically Zofran. Nobody was drug-tested during the time they were home, so it is unknown whether they were using drugs at this time, Miranda said.
“The authors don’t deconstruct the COWS to see which symptoms respond to neuromodulation,” said H. Westley Clark, M.D., Dean’s Executive Professor of Public Health at Santa Clara University. For example, 38 percent of the subjects needed an antiemetic. “That subjects needed an antiemetic suggests that certain autonomic responses are not amenable to neuromodulation,” said Clark, who we asked to comment on the study. “By focusing on the scores alone we don’t know enough about the appropriate needs of the patient.”
When asked about the specific symptom responses rather than total COWS scores, Miranda said that data was unavailable. “We heard from the company [Innovative Health Solutions, which makes the Bridge] that there were all these reports from people saying how amazing this was,” he told ADAW. “But the scores were collected prospectively,” he said, adding that that part of the study was analyzed by Taca. “You’re not going to be able to get that data now,” he said. In the future, there will be a double-blind randomized controlled trial of the device, said Miranda, adding that he would not be involved in that.
The study noted that many of the COWS measures are objective and therefore cannot be feigned.
Most patients were sent home after Bridge placement and relief of withdrawal symptoms, after the first hour. Patients were told that the “Bridge is not a cure, but rather a tool to treat the pain associated with” opioid withdrawal, and instructed to follow up within one to five days depending on the clinic, and to leave the device on for the entire five-day period.
All patients (64 of 73) who returned to the clinic on day 5 and received their first dose of naltrexone were considered to be successfully transitioned.
The mean age of the subjects was 32.9, and 65 percent were male. Ninety percent of the subjects had been using opioids for at least two years, and the mean length of drug use was 70 months.
A subset of patients — 33 — also had withdrawal scores recorded five days after the device was placed and prior to transitioning to naltrexone.
The article noted that the uncontrolled, retrospective study design and small sample size were limitations. The study design also did not include long-term follow-up.
“Placebos are known to be effective in reducing symptoms, including pain,” said Miranda. “The only way to know for sure is to do a randomized controlled trial using a sham device.” There is another device that doesn’t provide continuous current, but turns off every two hours, said Miranda. That device anecdotally does not reduce withdrawal symptoms, he said.
But he stressed that it’s important to separate the placebo response from a real effect. We recalled the story of PROMETA, which had promised treatment for methamphetamine during that epidemic but after many years and finally a randomized controlled trial was found to be no more effective than placebo (see ADAW, Nov. 21, 2011; April 18, 2011; July 17, 2006; July 28, 2008). “In the addiction field, so much stuff has come out with everyone looking to make a quick buck, and there’s a big piece of the pie people want to get,” he said. “But I’m not promoting this company or this product, and I know the people doing it — they’re trying to do it the right way. They’re trying to show the science before they go to the FDA for approval.”
Patients transitioning to ER naltrexone seem “like a logical target population,” because the battery life of the device — five days — coincides with the time required for opioid abstinence before starting the medication, the article stated. (In fact, Vivitrol labeling calls for seven days of abstinence, but Miranda told us that most clinicians feel five days is adequate.) However, there is no reason that other patients undergoing withdrawal wouldn’t benefit from it, in any setting, the article concluded, noting that “it seems reasonable to consider that removing the fear of experiencing severe symptoms associated with opioid withdrawal may motivate and encourage more individuals to seek treatment in the future.”
None of the subjects was under criminal justice supervision, which is interesting, as many Vivitrol programs are aimed at this population.
A final note: Once it was written, instead of referring generically to MAT, the study should have always referenced only naltrexone for clarity. “I think it is a bit disingenuous to conflate MAT with XR-naltrexone alone, particularly since one of the authors is paid by Alkermes,” said Clark. “While withdrawal per se is not compelling with buprenorphine, it could be possible to facilitate the induction with buprenorphine or methadone using neuromodulation, even if the current study did not address this use,” he said. “This would have been an agnostic approach.”
Clark is not opposed to the concept of neuromodulation. “I like technology,” he told ADAW. “If neuromodulation holds promise, then great! But we need to consider the unintended consequences of what we recommend and to explore factors that extend out from our recommendations,” he said. “We need to acknowledge what we don’t know.”
A new device may — or may not — reduce opioid withdrawal symptoms.