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On August 23, 1965, scientists first reported an effective treatment for heroin addiction. Taken regularly, this medication – methadone – could control cravings and withdrawal that often lead to relapse in people with opioid addiction who try to quit. The discovery marked a sea change in addiction treatment by defining opioid addiction as a chronic condition requiring long-term treatment, similar to diabetes or heart disease.

About 20 years ago, in 2002, another effective treatment, buprenorphine, became available to promote recovery from opioid use disorder. Combined with naloxone to discourage people from injecting it, buprenorphine is available by prescription as a dissolvable film placed either under the tongue or in the cheek. Many people can get up to a month’s supply.

Yet today, more than 50 years after the discovery of methadone, it and other effective medications for opioid use disorder remain vastly underused either because they are inconvenient to take or because of entrenched stigma: both for prescribing these medications and for taking them. The Helping to End Addiction Long-term® Initiative, or NIH HEAL Initiative®, is committed to finding every possible way to get safe and effective treatments to those who need and want them.

Lowering Barriers

Unlike opioids such as heroin, oxycodone, and fentanyl that are often injected or snorted, oral medications used to treat opioid use disorder (like methadone and buprenorphine) are slow to travel to the brain, and thus do not produce a high. If taken long-term, these medications prevent withdrawal symptoms and also block any pleasurable effects of other opioids that people might take at the same time.

Although they are lifesaving, these medications can be hard to get.

While people with diabetes can use a glucose monitor and implanted pump to automatically deliver insulin they need, individuals with opioid use disorder who choose to take methadone long-term (called maintenance therapy) must visit a highly regulated and visible clinic every day. That is challenging if you don’t have reliable transportation, childcare, or a work schedule that allows it – creating barriers many are unable or unwilling to overcome.

Given these and other limitations, only 1 in 5 people take medication for addiction – putting them at risk for drug-related complications like infections from contaminated needles or overdose.

A New Approach

Toward developing friendlier and more flexible versions of medications for opioid use disorder, NIH HEAL Initiative-funded researchers have created a long-acting form of levomethadone, the main active component in methadone that has been used to treat opioid use disorder in Europe for decades. Especially for people new to treatment or early in recovery, methadone is often more effective than buprenorphine, so it is an important option.

Normally, the stomach quickly passes ingested food (or medications) into the intestine for digestion. Put simply, any long-acting form of a medication works by slowing down this process. By using levomethadone, an enriched, “strong,” form of methadone, the scientists can deliver more active drug over time. Led by Stephen Zale, Ph.D., and his colleagues at Lyndra Therapeutics in Watertown, Massachusetts, the research team is also developing an extended-release version of buprenorphine that would outlast current versions of this treatment.

When this new type of medication is swallowed, its outer shell dissolves in the stomach and its methadone-containing elements “unfold” into an expanded structure that can freely move around the stomach but is too big to pass into the intestine.

The structure stays in the stomach and gradually releases the medication so that it can be taken up and distributed throughout the body. When the dosing period ends, the elements that hold the structure together are designed to soften and break apart, forming smaller pieces that can enter the intestine and safely leave the body. The pills would remain in the stomach for a week or longer and during that time steadily release their contents while people go about their lives.

Helping People Live Life

This research is in its early stages, and many other projects are looking for ways to improve delivery and access to medications we already know are safe and effective. Although clinical trials will begin soon for levomethadone and buprenorphine long-acting pills, it will take a few years at least for the approaches to be available to patients.

The goal of this and other NIH HEAL Initiative research is to make it easier and more discreet for people to stay in treatment through a medication that only needs to be taken once a week or even less often. Encouragingly, federal policy changes have recently expanded treatment access to methadone, such as through mobile vans across the country.

Medications for opioid use disorder remain a key tool to help people feel well and overcome cravings that can lead to relapse and addiction. Easy-to-take forms of medications are one of many different solutions needed to offer these safe and effective treatments to people who need them.



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