Tackling an Epidemic

New and emerging treatments for opioid addiction hope to offer solutions to this crisis

Richard Ries

Richard Ries

Recently, the opioid epidemic is dominating news headlines and inspiring greater calls for political action in the United States. While opioid addiction isn’t a new issue, its devastating consequences are now being felt across the country. “What’s got everybody’s attention is that so many people are dying,” says Richard Ries (right), director of the University of Washington School of Medicine’s addictions divisions and medical director of the Outpatient Addictions Program at Harborview Medical Center. “Currently, the top reason for early death in people in under 50 is now overdose — more than cancer, AIDS, or accidents. The bulk of those overdoses involve opioids.”

Opioid addiction claims nearly 100 lives every day in the United States. According to the Centers for Disease Control and Prevention, there was a record 33,091 opioid overdose deaths in 2015, up 16 percent from the record set the previous year. In response to the crisis, researchers and policy makers are looking for effective treatments for opioid addiction. Some solutions, like medication-assisted treatment, have been in use for years but continue to be refined for better results. Others, like vaccines against addiction and brain stimulation, are still in the research stage, but hold great promise for helping people with opioid addiction.

Medication-Assisted Treatment

The body has a natural opiate system that is involved in pleasure, sleep, satiety, and more. When that system is dysregulated by heavy opioid use, it does not just bounce back on its own — the system stays dysregulated. People dependent on opioids experience withdrawal when they stop taking the drugs, enduring cramping, sweating, anxiety, sleeplessness, and cravings.

“If their systems are not stabilized with medications, 90 to 95 percent of people who detox off opiates relapse,” says Ries. “The problem with those relapses is that 5-10 percent are fatal or require emergency room or ICU admission. It’s lethal and costly.”

An effective way to help people maintain abstinence from opioids is the use of medications that reduce the negative effects of withdrawal and craving without producing the euphoric “high” of opioids.

“Medication-assisted treatment is a new term developed specifically around medications that help people who have addiction problems to stabilize their addictions and get better,” says Ries. “We don’t call it medication-assisted therapy when we use insulin for diabetes or anti-hypertensives for blood pressure problems; for other medical issues, we just call it treatment.”

Ries says that good opiate-stabilizing medications already exist, such as methadone, buprenorphine, and injectable naltrexone. “They work in a slightly different manner, but basically they stabilize the opioid system and prevent opioids from hijacking the brain,” says Ries.

These medications alter brain opioid signaling by binding to opioid receptors and activating them. The end result is the reduction of cravings and withdrawal symptoms without the euphoria associated with opioid abuse. Methadone and buprenorphine are both highly effective when they are administered at sufficient doses for a sufficient amount of time. However, these drugs are still not widely available, and many people, particularly in rural communities, face many barriers to accessing treatment.

Hilary Smith Connery

Hilary Smith Connery

“Research and development have focused on creating new forms of medication that will last a week, a month, or even six months, so the person needing the medication will have an easier time remaining on it,” says Hilary Smith Connery (right), clinical director of the alcohol and drug abuse treatment program at McLean Hospital and an assistant professor of psychiatry at Harvard Medical School.

One example is Probuphine, a buprenorphine implant approved last year by the U.S. Food and Drug Administration. The subdermal implant releases a constant low-level dose of buprenorphine into the bloodstream for six months. Another example is Vivitrol, an injectable, long-acting form of naltrexone that blocks the effects of opioids in the body for four weeks. In numerous studies, medication-assisted therapy has been shown to reduce relapses, keep people in treatment longer, and, ultimately, prevent overdoses.

“The most important research finding is that giving someone with opioid use disorder a medication will increase the probability of their success in abstaining from opioid use by at least two-fold,” says Connery.  “Yet medication-assisted therapy is not nearly accessible enough for a lethal illness.”

Only a fraction of people with opioid use disorder receive medication-assisted treatment, due to factors like limited access and treatment capacity, stigma around its use, and lack of provider training. “Methadone has been around for fifty years, buprenorphine has been around for fifteen years, and injectable naltrexone is now ten years old,” says Ries. “There are effective treatments, but there are a lot of barriers.”

Vaccinating Against Addiction

Kim Janda

Kim Janda

If addiction is a disease, can you vaccinate people against it? New research suggests vaccines that make the brain immune to the euphoric effects of certain opioids could help prevent relapses and overdoses. “Vaccines against addiction basically train the immune system to recognize heroin and its psychoactive metabolites as foreign, blocking the drug from getting to the brain,” says Kim Janda (right), a pharmaceutical chemist at the Scripps Research Institute.

Like other vaccines, an opioid vaccine would cause the body to create antibodies (proteins usually associated with fighting infections), but they would be specifically directed against opioid molecules. The idea is that if an inoculated person used the targeted drug, the drug and its metabolites would be rapidly bound up by antibodies, preventing them from reaching the brain and making the user feel high.

Janda’s laboratory is making progress on a vaccine for heroin, which has now been tested successfully in mice and monkeys. They are also working on a combination vaccine that offers protection from the effects of both heroin and the synthetic opioid fentanyl. So far, “the results have been spectacular,” says Janda.

In order to create an opioid vaccine, Janda’s team had to teach the immune system to recognize opioid drugs. The researchers designed small molecules called haptens that resemble opioid molecules, but with proteins attached that bind to antibodies. The idea is that the hapten-protein complex stimulates the body’s immune system to produce antibodies that recognize and bind to the hapten. Using haptens that closely resemble the targeted molecules trains the body to detect opioid drugs and mount a response to them.

The next step in this research will be to license the vaccine to a biotechnology company for partnering in clinical trials in humans. If those trials prove safe and effective, opioid vaccines could supplement current approaches to treating addiction. “I see vaccines being useful for cessation-type therapies for people who want to quit taking the drug,” says Janda.

Researchers like Janda say a vaccine — which would likely require multiple shots per year —would only work in people who are actively trying to recover from opioid addiction and want to stop taking drugs. The idea is that blocking the high of an opioid will decrease the motivation for many recovering addicts to relapse into drug use. However, vaccines are drug-specific and there are a lot of options of different opioids available. One major concern is that if a person who received a heroin vaccine really wanted to get high, he or she could turn to some other opioid drug. While vaccines for addiction may be a promising avenue of research, their use will still require supportive therapy for people working to quit opioids.

Neuromodulating the Addicted Brain

Other researchers are investigating ways to directly stimulate the brain to help ease withdrawal symptoms and help people addicted to opioids detox. A device called the Neuro-Stim System Bridge has been used by several thousand patients across 30 states. The device is attached directly onto the skin behind’s a patient’s ear, where it emits electrical pulses that stimulate certain cranial nerves and areas of the brain involved in processing pain information.

“Anatomical tracing studies have shown that these cranial nerve branches in the external ear project to brainstem nuclei that communicate with central brain structures involved in pain and withdrawal, such as the amygdala and spinal cord,” says Adrian Miranda of the Children’s Hospital of Wisconsin.

“By affecting neuronal firing in the amygdala (a structure known to be involved in the emotional response to pain) and the spinal cord (known to transmit pain impulses from the periphery), this type of neurostimulation is able to dampen symptoms of pain and acute withdrawal,” says Miranda.

The Bridge device is not a treatment for addiction. The idea is that it could help people make it through the withdrawal period so they can receive long-term medication-assisted therapy and counseling. However, there has been some criticism regarding the lack of randomized, controlled clinical trials to evaluate the device’s efficacy in treating opioid withdrawal.

Miranda, along with Arturo Taca, authored a retrospective paper last year looking at the Bridge’s effectiveness in treating opioid withdrawal. Although they found 89 percent of patients successfully transitioned to medication-assisted treatment, the small study was not randomized, controlled, or double-blind. “A randomized controlled trial would indeed be the ‘gold standard,’” says Miranda. “However, this could take one to two years to complete. We cannot forget that we are in the midst of a national crisis, which creates a sense of urgency. In my opinion, the FDA should be commended for making this technology available to patients and giving patient and families a choice.”

Although Miranda thinks the Bridge will play a major role in combating the opioid addiction epidemic, he agrees that more research is needed. For instance, it is not known how long the benefits of these devices can last. But at a time when opioid overdose deaths are skyrocketing, and only a fraction of people with opioid addiction receive medical treatment, new products like the Bridge inspire both hope and skepticism.

“I can definitely see why people are skeptical of new therapies with big claims, particularly in a field where the patient population is so vulnerable,” says Miranda. “Unless you witness the effects first-hand in a patient suffering from chronic pain or withdrawal, it is very easy to remain skeptical.”

The current opioid epidemic has inspired a flurry of research into new and better ways to help people fight addiction. Many of these show promise, but getting them into the hands of the people who need them remains a major challenge. Scientific innovations, such as longer-lasting medications, vaccines for addiction, and neuromodulation, could help people suffering from opioid use disorder. But matters of accessibility and stigma have to be addressed at the same time in order for these advances to have an impact.

Resources:

  • Bremer, P.T., Schlosburg, J. E., Banks, M. L., Steele, F. F., Zhou, B., Poklis, J. L., and Janda, K. D. (2017). Development of a Clinically Viable Heroin Vaccine. J Am Chem Soc 139(25): 8601-8611. Doi: 10.1021/jacs.7b03334
  • Connery, H.S. (2015). Medication-Assisted Treatment of Opioids Use Disorder: Review of the Evidence and Future Directions. Harv Rev Psychiatry 23(2): 63-75. Doi: 10.1097/HRP.0000000000000075.
  • Hwang, C. S. and Janda, K. D. (2017). A Vision for Vaccines: Combating the Opioid Epidemic. Biochemistry 56(42): 5625-5627. Doi: 10.1021/acs.biochem.7b00948.
  • Kelly, P. N. (2017). A vaccine for heroin addiction? Science 356(6345): 1347-1348. Doi: 10.1126/science.356.6345.1347-f.
  • Miranda, A. and Taca, A. (2017). Neuromodulation with percutaneous electrical nerve field stimulation is associated with reduction in signs and symptoms of opioid withdrawal: a multisite, retrospective assessment. Am J Drug Alcohol Abuse. Doi: 10.1080/00952990.2017.1295459.
  • Volkow, N. D., Frieden, T. R., Hyde, P. S., and Cha, S. S. (2014). Medication-Assisted Therapies – Tackling the Opioid-Overdose Epidemic. N Engl J Med 370: 2063-2066. Doi: 10.1056/NEJMp1402780.