Emma Hitt, PhD

April 29, 2012

April 29, 2012 (Atlanta, Georgia) — Buprenorphine implants (Probuphine, Titan Pharmaceuticals, Inc) demonstrated increased efficacy compared with placebo and noninferiority compared with sublingual buprenorphine/naloxone in the treatment of opioid dependence, according to new phase 3 study data.

Katherine L. Beebe, PhD, executive vice-president and chief development officer of Titan Pharmaceuticals, Inc, in San Francisco, presented the findings here at a he American Society of Addiction Medicine (ASAM) 43rd Annual Medical-Scientific Conference.

"The advantage of this form of buprenorphine is that you have ensured compliance, which is a huge issue in the addiction population," Dr. Beebe told Medscape Medical News.

"The patient doesn't have to make a choice about whether they are going to take their medication or not," she said. "You also don't have the issue of misuse or diversion as you do with the oral forms of the medication," she added.

According to Dr. Beebe and colleagues, subcutaneous buprenorphine implants deliver "constant, low levels of buprenorphine for up to 6 months with minimal fluctuations in steady-state plasma concentration."

The current phase 3 study sought to confirm the efficacy and safety of the product.

Well-Tolerated

The study included 287 opioid-dependent patients enrolled at 20 US centers.

Patients were briefly induced with sublingual buprenorphine/naloxone tablets (12 to 16 mg/day) and then were randomly assigned to receive either buprenorphine implants, placebo implants, or open-label sublingual buprenorphine tablets. All patients also received regular counseling.

During the first 24 weeks, more patients receiving buprenorphine (either implant or sublingual) achieved opioid-negative results on urine testing (P < .0001) compared with those receiving placebo.

Nearly two thirds of participants receiving buprenorphine implants stayed in the study compared with only one fourth of placebo-treated patients (P < .0002).

In addition, the implants were found to be noninferior to sublingual buprenorphine in their ability to reduce illicit opioid use.

Treatment groups were similar with respect to adverse events. Headache was the most common adverse event, present in 13.2% (implant), 16.0% (sublingual), and 9.3% (placebo). There were no serious study-related events.

The procedure to deliver and remove implants was well tolerated, the investigators report. Minor implant site reactions were comparable in the buprenorphine implant group (27.2%) and the placebo groups (25.9%).

Quick, Simple Procedure

At the end of 24-week study period, patients completing the study were given the option of receiving 6 months of buprenorphine implant on an open-label basis.

These patients "reported high levels of satisfaction with the implants in comparison to sublingual buprenorphine," the authors report.

The implant, Dr. Beebe said, is inserted during a 10-minute, in-office procedure under local anesthetic and can be left in for 6 months.

Although it is "theoretically possible," there was no evidence that any of the participants in the study removed the implants during the study, she said.

A new drug application is in process and is expected to be submitted to the US Food and Drug Administration (FDA) in September 2012.

"There's a possibility that the buprenorphine implant will receive FDA priority review, and if that happens, and if the drug is approved, then it could potentially be on the market by mid-2013," Dr. Beebe said.

She added that there is no other implantable form of buprenorphine currently on the market or, as far as she knows, in development.

Potential Concerns

Commenting on the findings for Medscape Medical News, Erik Gunderson, MD, assistant professor in the Department of Psychiatry and Neurobehavioral Sciences at the University of Virginia, in Charlottesville, noted that the main advantage involves medication adherence.

"Patients don't need to remember or think about taking a medication or not," he said in an interview.

He noted that disadvantages are potentially cost and the requirement for a minor surgical implantation procedure, which was associated with minor site reactions in one quarter of patients.

"Another factor will be to consider the difficulty for implant removal by untrained personnel, which could be necessary if a patient requires opioid analgesia for an acute medical or surgical condition," he added.

According to Dr. Gunderson, one consideration for physicians in interpreting the study is that patients were inducted on buprenorphine at a dosage of 12 to 16 mg/day.

"To fully determine the validity of the study findings, it is crucial to examine how abrupt the transition was between induction dose and placebo implant," he said.

"A sudden drop from 16 mg to 0 mg could lead to substantial opioid withdrawal, and we need to know whether they were tapered or had access to rescue doses during the transition off active medication."

The presentation was funded by the study sponsor, Titan Pharmaceuticals. Dr. Beebe is an employee of Titan Pharmaceuticals. Dr. Gunderson has disclosed no relevant financial relationships.

American Society of Addiction Medicine (ASAM) 43rd Annual Medical-Scientific Conference. Poster 33, presented April 20, 2012.

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