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First non-opioid to treat withdrawal clears key hurdle

April 13, 2018

A new medication for treating opioid withdrawal is making its way toward the market. Last month, the Food and Drug Administration’s (FDA's) Psychopharmacologic Drugs Advisory Committee voted 11-1 to recommend approval of the medication, lofexidine. The decision was based on US WorldMeds' New Drug Application (NDA) for what would be sold as Lucemyra. The NDA includes data from two placebo-controlled trials and supporting studies.

In clinical trials, participants treated with lofexidine had less severe withdrawal symptoms than those given placebo, and were more likely to complete a seven-day detoxification period.

Typically, opioid medications such as morphine or buprenorphine are used to taper patients who are addicted to opioids. If approved, lofexidine would become the first non-opioid medication indicated for mitigation of opioid withdrawal.

The drug also could ease the “detox hurdle” for people with opioid use disorders who want the injectable naltrexone product Vivitrol, which cannot be administered unless the patient has been opioid-free for at least a week.

The most serious symptoms of withdrawal from opioids are gastrointestinal—vomiting and diarrhea can result in dehydration if not treated or prevented. But in general, opioid withdrawal is not life-threatening, compared to alcohol or benzodiazepine withdrawal. Yet in fact, it is the fear of withdrawal symptoms, and their onset, that keeps people using opioids, Mark Pirner, MD, PhD, US WorldMeds' senior medical director, tells Addiction Professional. A medication that can mitigate these symptoms, therefore, is an important part of fighting the opioid epidemic, says Pirner.

How lofexidine works

Lofexidine is a selective alpha 2-adrenergic receptor agonist that works by reducing the release of norepinephrine, says Pirner.

When opioids occupy the mu receptors, norepinephrine signaling is reduced. This system operates in the part of the brain that is responsible for arousal and awareness—the “fight or flight” center. Abrupt withdrawal of opioids results in a surge of overproduction of norepinephrine, but lofexidine reduces the amount of norepinephrine that is released, Pirner says.

“We did see reductions in diarrhea and in vomiting, but also reductions in aches and pains, yawning, and other symptoms across the board,” he says. “The heart rate comes down.”

But if patients are being tapered from opioids, withdrawal symptoms will be minimal. “Lofexidine works for symptoms of withdrawal, so if they’re on a taper, and they don’t have withdrawal symptoms, we haven’t studied it,” says Pirner. The company's trials only compared lofexidine to placebo, and did not compare lofexidine to a taper with opioids, which is the current standard of care.

Most of the studies' subjects had been using either heroin, which is short-acting, or a short-acting prescription opioid such as Percocet. Because the time course of treating withdrawal can vary depending on the duration of opioid use, and whether the patient had been using short- or long-acting opioids, the studies had to be focused so that researchers could measure time points over a course of withdrawal, Pirner says.

There is a market for non-opioid treatment of withdrawal, Pirner says. “If people are going to taper, methadone and buprenorphine would have been most effective,” he says. “But this is applicable for patients or health care providers who don’t want to use methadone or buprenorphine.”

Applicable to all opioids

Lofexidine isn’t only for withdrawal related to addiction. A patient could be dependent on opioids for pain, and no longer need them but not want to experience withdrawal symptoms. It doesn’t matter whether the patient was dependent on licit or illicit opioids, as lofexidine would work equally for either, says Pirner. “We’re agnostic to the patient type,” he says.

The proposed indication for Lucemyra is “mitigation of symptoms of opioid withdrawal,” says Pirner. A second indication is under discussion after the FDA advisory committee meeting, however. “We saw that symptoms were reduced, and also observed that a higher proportion of patients were able to complete withdrawal” compared to placebo, Pirner says. “So the second proposed indication would be completion of opioid withdrawal treatment.”

The benefits of lofexidine focus on its lack of abuse potential, he says. “It won’t require a waiver, or any restriction,” he says. It also could be valuable within the criminal justice system, which has tended to lean toward use of Vivitrol for offenders with opioid dependence.

Dropouts and follow-ups

What comes after lofexidine withdrawal? In most cases, some kind of treatment, says Pirner. The two clinical trials were only five and seven days long. “We tried to do a 30-day follow-up call with all of the subjects,” he says. “We were able to reach about 60% of them. Most were in some kind of treatment.”

The subjects who dropped out were “no longer accessible to our information gathering,” says Pirner. Did any overdose? “One, that we were aware of,” he says. “We know a lot of people in the placebo group did drop out because of lack of efficacy.”

US WorldMeds was not able to provide drug pricing information prior to approval.

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