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FDA may approve implantable drug to ease opioid withdrawal

A drug that has shown success in helping opioid addicts control their dependence on heroin and painkillers soon could see increased use by patients and adoption by doctors if federal authorities approve a new delivery method for the medication.

The medication, called Probuphine, would be the first implantable version of the drug buprenorphine, which over the past 14 years has become a popular tool for eliminating opioid withdrawal symptoms in addicts.

During the period, opioid addiction has reached crisis proportions in the United States, where upwards of 80 people fatally overdose each day, and where the recent death of music superstar Prince is being investigated for a possible connection to painkillers.

Research has shown that recovering addicts who do not manage their dependence with medication are significantly more likely to relapse into illicit drug use than people who take buprenorphine, which is often sold under the brand name Suboxone, or other medications including methadone and naltrexone. About a quarter of the 2.8 million people estimated to have diagnosed opioid abuse disorder take buprenorphine.

Current versions of buprenorphine are "sublingual" — they require users to take a pill or a film every day and hold it under their tongue for about 15 minutes, without swallowing, until it dissolves.

In contrast, Probuphine has four small stick-like implants, which can be inserted by a doctor under the skin in the users' upper arm, during a session in the physician's office lasting less than 15 minutes.

The implant remains there for up to six months, delivering a steady dosage of buprenorphine to users' bloodstream. After that, it is extracted during a procedure lasting a half hour or less, and can be replaced with another implant.

The Food and Drug Administration is expected to rule on whether Probuphine can go on sale by the end of May. The product was developed by Titan Pharmaceuticals and is licensed to Braeburn Pharmaceuticals for sale in North America, which is the largest market by far for drugs to treat opioid dependence.

Braeburn Pharmaceuticals said there is already strong interest in Probuphine. About 4,000 doctors have already signed up to ask to be trained in how to implant and remove the drug. While 28,000 doctors are federally authorized to prescribe buphrenorphine, only about 6,000 write about 90 percent of the total prescriptions in the U.S.

The company says that the advantage of Probuphine would be not only in removing the need to hold a pill or film in one's mouth for a quarter hour every day, but also save the embarrassment and hassle of getting prescriptions refilled at a pharmacist. Probuphone also avoids either the chance for "diversion" — someone else other than the prescribed person taking the pill.

Behshad Sheldon, CEO of Braeburn Pharmaceuticals, said the relatively low percentage of authorized doctors writing prescriptions for buprenorphine reflects the fact that many physicians "don't like the idea of diversions" and their worry about getting scammed by patients who might sell the medication on the black market.

Probuphine, a buprenorphine implant for long-term maintenance treatment of opioid addiction.
Source: Braeburn Pharmaceuticals
Probuphine, a buprenorphine implant for long-term maintenance treatment of opioid addiction.

Sheldon noted that Probuphine could limit the risk of an addict stopping the buprenorphine dosage one day and relapsing to illegal drugs, perhaps fatally.

"Every time somebody uses there's a chance to die, especially if they've been clean," Sheldon said. "Their brain no longer knows what they're used to, and the same dosage that they used to get high could kill them."

And with Probuphine, Sheldon said, addicts "no longer have to be reminded to have to take your medicine" every day. "You can focus on different parts of your recovery," she said.

"What patients have is ... peace of mind and freedom. They don't get looks from the pharmacist [when they fill their prescription]. They don't have worry about their boyfriend stealing it or that kind of thing," Sheldon said.

Sheldon said doctors would be more inclined to prescribe implants because their concerns about diversion of buprenorphine would be mitigated.

"Just by coming on to the market, there's going to easily be 2,000 or 3,000 doctors that haven't taken patients and would be doing so," she said. "That in itself is going to expand the number of patients."

Sarah Wilson, a 40-year-old mom of four from Jacksonsville, Florida, said that buprenorphine "has been a lifesaver" for her. She also said the implant was both more convenient and safer for her and her family.

Wilson suffered serious spinal damage in 2008 when a suicidal man rammed his car at 65 mpg into Wilson's vehicle containing her and two of her children. After losing her secretarial job and her health insurance, Wilson was no longer able to afford the pricey specialty injections that had successfully managed her chronic pain.

But her doctor told her she could afford hydrocodone, a powerful painkiller pill.

Wilson began taking hydrocodone regularly in 2010, and "I realized I had a dependency in 2012."

"I was taking 300 milligrams a day," she said. "My recommended dosage was 90 milligrams a day."

Wilson fed her habit by buying hydrocodone from friends, and paid for the pills in part by stealing from her father, a retired police officer father, and her mother, a nurse. Although she knew what she was doing was illegal and wrong, her fear of withdrawal and of being in pain without medication kept her using hydrocodone.

She admitted her secret addiction after her parents voiced their suspicions — which were proven false — that Wilson's husband was the one stealing from them. But she told them "I can't go into detox. I said I can't face the pain of detox and the daily pain of my injuries."

But after her husband spotted an advertisement targeted at people suffering from opioid dependency, Wilson was in a doctor's office, where she was placed into a clinical research trial for buprenorphine.

She said she was "scared to death" before taking the drug, worried that the initial nausea she was already feeling from not taking her opioid painkiller would get worse as she withdrew further.

But within a half hour of taking buprenorphine, her withdrawal symptoms were "gone. And I was shocked," she said.

Wilson said she has never relapsed while on buprenorphine, which she notes not only has treated "my addiction, it also treats my pain." And after starting on 16 milligrams of the medication three years ago, she has since moved down to 8 milligrams daily.

Wilson last year participated in another trial involving buprenorphine, this one being a six-month double-blind, double-dummy trial of Probuphine.

She and more than 170 regular users of buprenorphine were given arm implants and an oral version of the drug, and not told which one actually contained the buprenorphine and which one contained a placebo. Participants had to already have been using buprenorphine for 90 days without evidence of illegal drug use.

She later found out that she was among half of the participants whose implant contained buprenorphine.

The trial found that more than 96 percent of the Probuphine users had been free of any opioid use for at least four months, compared with 87.6 percent of people who used the oral form of buphrenorphine.

And almost 86 percent of the people who used Probuphine in the trial managed to stay off illicit opioids for the entire six months, which was nearly 14 percentage points better than the group that used oral versions containing buprenorphine.

Sheldon said one of the relapses in an earlier trial of the implant was fatal. That was by a woman who was taking the oral version and stopped using the medication. Three days later, Sheldon said, the woman overdosed in front of her children, and died.

Sarah Wilson
Source: Sarah Wilson
Sarah Wilson

The latest trial results represented a big step forward for Titan Pharmaceuticals and Braeburn Pharmaceuticals. The companies had been asked to run the trial by the FDA because the agency was concerned that past trials, which has showed Probuphine performed better than a placebo for new users of the buprenophine, did not contain high enough dosages of buprenorphine for the results to be clinically meaningful.

In the latest trial, "the agreement with the FDA was that we would just meet 'non-inferiority,'" said Sheldon. Non-inferiority means that the new version of the drug would not lead to worse outcomes for patients — and Probuphine trial showed actual improvement.

"What this means is that in the population that we were treating, there's an advantage, probably, to having an implant," said Dr. Richard Rosenthal, medical director of addiction psychiatry in the Mount Sinai Behavioral Health System in New York City, and the investigator for the Probuphine trial.

Rosenthal said federal approval of the implant should be "a no-brainer" based on the results of the latest clinical trial.

He said addiction specialists such as himself are desperate for ways to help opioid-dependent people get off clean.

"We've got an epidemic," Rosenthal said. "I want to get people to get treatment. And the relapse rates for when people [aren't on dependency-controlling medication] are abysmal."

"Hopefully this medication gets approved, and we'll have another weapon against this epidemic."

The FDA declined to comment when CNBC asked about the status of its final review of Probuphine.

But there are signs that the agency is likely to approve Probuphine. An advisory committee voted 12 to 5 in January to recommend approval. Since then, in the past several months FDA officials have been in discussions with Braeburn about how Probuphine would be labeled, according to the company.

"We are cautiously optimistic," Sheldon said.

The label being discussed would call for Probuphine to be prescribed in cases in which a patient has spent three months without any evidence of illegal opioid use, and at least six months taking buprenorphine.

However, the label is only a recommendation for doctors. As with other drugs, physicians would be able to prescribe the implant to addicts even if they did not meet the minimum levels of time suggested by the label.

"Physicians can and make their own clinical decisions every day," Sheldon said.

Wilson said she would switch to using the implant if it becomes available. (It would also avoid situations where the pharmacy is out of buprenorphine.)

"Oh yeah. I'm a mom — it's safer."

After the test ended, Wilson has had to take oral versions of buprenorphine every day. And even though she keeps the pills locked in a safe in her home, "there's still a fear that ... my child could get a hold of it," or that someone could break into the house and steal the medication.