February 19, 2019

WSU's Dr. Mark Greenwald helps conceptualize collaborative study proving effectiveness of once-a-month medication for opioid use disorder

Wayne State University School of Medicine Professor of Psychiatry and Behavioral Neurosciences Mark Greenwald, Ph.D.
Wayne State University School of Medicine Professor of Psychiatry and Behavioral Neurosciences Mark Greenwald, Ph.D.

Physicians treating patients with moderate or severe opioid use disorder now have another treatment option that eliminates the need for daily medication.

BUP-XR is a subcutaneously injected monthly dose of extended-release buprenorphine for opioid use disorder. This formulation can be useful for patients with concerns about adherence, diversion or misuse; as well as those at a high risk for taking intentional days off from treatment to get high; those with occasional unintentional delays in dosing; those with children present in the home; or those with concerns about treatment confidentiality or medication theft.

The U.S. Food and Drug Administration approved BUP-XR, known commercially as Sublocade and produced by UK-based Indivior PLC, on Nov. 30, 2017. It is the only extended-release BUP injection product available in the United States.

Efficacy and safety of a monthly buprenorphine depot injection for opioid use disorder: a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial, a study outlining the clinical trial of BUP-XR, is included in the Feb. 18 issue of The Lancet.

Wayne State University School of Medicine Professor of Psychiatry and Behavioral Neurosciences Mark Greenwald, Ph.D., helped conceptualize the study, which he talks about on this week's episode of The Lancet Podcast. (Listen here, or download from your favorite podcast provider).

The Lancet also published a commentary, Opioid addiction: long-acting formulations for a long-term disorder, in the Feb. 18 issue.

This is a herculean and truly important clinical trial, based on an innovative approach. I am extremely proud to have played a pivotal role during the development of this effective medication, Dr. Greenwald said. It required enormous planning and effort to enroll all participants within 10 months, and then follow each participant weekly over six months. The data collected ranged from medication blood levels to retention and opioid abstinence, as well as global outcomes such as employment and quality of life.

Dr. Greenwald accompanied the Indivior team to present the study results to National Institute on Drug Abuse Director Nora Volkow, M.D. He directs the universityâs Substance Abuse Research Division and is the corresponding author of the study, as well as one of two academic collaborators with the pharmaceutical company. He also serves on the Wayne State University Task Force for Prescription Drug and Opioid Abuse, which in 2016 proposed curriculum changes that would better prepare health professions students to work with those who have substance abuse disorders, including more treatment education and tools to address increased challenges in prescribing controlled substances.

Opioids such as hydrocodone, oxycodone, morphine, codeine and heroin relieve pain by activating opioid receptors in the brain. They have high abuse potential. Opioid drug overdose deaths in the U.S. have increased from 8,048 in 1999 to 47,600 in 2017.

The study is exceptionally timely in addressing the toll that the opioid epidemic is exacting on the United States population, and worldwide. The number of people who are overdosing and dying daily from opioids is unprecedented, Dr. Greenwald said.

Although effective treatments for opioid use disorder exist, only an estimated 20 percent of individuals are receiving treatment, Dr. Greenwald said. BUP-XR offers patients a positive choice 12 times each year to take a medication that can safely help them become abstinent from opioids, while controlling withdrawal and drug craving, and to engage in other aspects of treatment that promote longer-term recovery.

Indivior's medication development plan was developed from Dr. Greenwald's work, launched in the late 1990s. He shared original data from his NIDA-funded studies of sublingual BUP, which mapped relationships between brain and blood levels produced by buprenorphine and how these translated into clinical effects. The Phase 3 clinical trial publication in The Lancet translates that earlier foundational work into actual patients.

Based on an algorithm generated from my data, we analyzed their Phase 1 BUP-XR data to predict what doses should be put into the depot injection formulation. We generated a pharmacokinetic/pharmacodynamic model that accurately predicted what we needed, he said.

The current study involving 36 treatment centers in the U.S. assessed the efficacy of two dosing regimens of BUP-XR in treatment-seeking individuals with opioid use disorder. Eligible participants were between the ages of 18 and 65 who, by medical history, met the criteria for moderate or severe opioid use disorder for the three months immediately before signing the informed consent form and seeking treatment. Participants who completed the study were offered entry into a long-term safety study of BUP-XR, contingent on the medical judgment of the investigator, as well as on each participant meeting inclusion and exclusion criteria for that study.

Eligible participants were randomly assigned to receive BUP-XR 300 mg monthly for six months, BUP-XR 300 mg for the first two months followed by 100 mg for the next four months, or volume-matched placebo for six months, and individual drug counseling weekly, provided by a qualified and trained staff member who remained masked to study treatment and urine drug screen results. At each session, counselors' responsibilities included inquiring whether the study participant had used illicit drugs since the last session; inquiring about any urgent problems that needed attention and, if so, addressing those; and discussing the recovery topic most relevant to the participantâs stage in recovery and needs in treatment.

The primary efficacy endpoint was participants' percentage abstinence from opioid use, defined as the percentage of each participantâs negative urine samples and self-reports of illicit opioid use among 20 weekly opioid use assessments from week five to week 24. The key secondary endpoint was each participant's treatment success, defined as achieving at least 80 percent opioid abstinence across weeks five to 24.

Data showed that both monthly dosing regimens of BUP-XR led to substantial proportions of participants achieving abstinence from opioids, relief of withdrawal symptoms and control of opioid craving, without the need for daily medication adherence or supplemental buprenorphine. The low mean opioid craving and withdrawal scores across weeks in the placebo group were not surprising, because more than 90 percent of placebo participants were using illicit opioids throughout the study. Treatment retention was nearly twice as high with BUP-XR than with placebo. No compensatory non-opioid drug use was observed during BUP-XR treatment. Furthermore, increased employment and medication satisfaction among participants treated with BUP-XR provide evidence to support patient-focused benefits of abstinence as participants progressed toward recovery.

Patients interested in comprehensive treatment should first undergo careful screening to establish a diagnosis of moderate or severe opioid use disorder and other medical and psychiatric conditions to evaluate safety for the individual.

Once the physician believes it is appropriate for the patient to receive this formulation, the physician should first conduct a run-in period with sublingual BUP to ensure the patient can tolerate BUP, which was at least seven days in our study, but research is underway to determine whether that period can be shorter, Dr. Greenwald said. If BUP is well tolerated, the physician administers BUP-XR in the office and can immediately release the patient. Again, this is designed to be part of comprehensive treatment for opioid use disorder, per the Substance Abuse and Mental Health Administration and American Society of Addiction Medicine guidelines, so there should be consistent follow-up care with counseling and other interventions, as needed, for each patient.

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