Dr. Bisaga is currently overseeing three research projects focusing on developing novel medication interventions for individuals with Opioid Use Disorder (OUD). New treatment approaches are needed to help address the epidemic of opioid overdose deaths in the US.

Evaluation of Safety and Pharmacokinetics of Naltrexone Implant

Currently available medications to treat OUD are highly efficacious, but their effectiveness in practice is limited by poor adherence, with many patients stopping treatment prematurely and relapsing. Currently available formulation of extended-release (XR) naltrexone provides sufficient amount of medication to last up to 1 month after a single injection. However, up to 50% of patients started on XR-naltrexone discontinue treatment in the first 6-months, and this limits its effectiveness for long term OUD treatment and overdose prevention

The goal of this study is to develop an innovative long acting subcutaneous implanted formulation of naltrexone, the O’Neil Long-Acting Naltrexone Implant (OLANI), with the goal of FDA approval. OLANI is expected to produce therapeutic naltrexone blood levels for 6 months after implant circumventing the need for adherence to monthly XR-naltrexone injections while protecting against the relapse.

OLANI is a biodegradable implant that gradually dissolves releasing naltrexone for many months after the insertion. OLANI is inserted under the skin on the abdomen using a minor surgical procedure under a local anesthesia. This naltrexone implant has been developed and used in Australia for 20 years with several prototypes evaluated in controlled clinical trials and used clinically. The current OLANI formulation has been used clinically in over 800 patients, giving confidence that the product can be successfully developed in the US.

In the current study we evaluate the safety and the duration of naltrexone release from OLANI in a diverse group of healthy volunteers that are monitored for up to 18 months after the implantation. In the fall of 2020, we expect to begin the recruitment of participants with OUD seeking relapse prevention with naltrexone after completing detoxification. Over the 12-month study they will receive two OLANI administrations, in addition to medical and psychological treatment, while naltrexone blood level and clinical outcomes are being monitored. If OLANI is shown to provide a safe, feasible and effective method of delivery of naltrexone at therapeutic levels for at least 6 months, it would represent a major advance in the field of OUD treatment providing effective long-term relapse-prevention treatment to individuals that have undertaken opioid detoxification.

Improving the Real-World Effectiveness of Injection Naltrexone for Opioid Use Disorder (SWIFT-CTN0097)

Extended-release naltrexone (XR-naltrexone) is a medication administered monthly by injection approved by the FDA for the relapse prevention treatment after detoxification in patients with opioid use disorder (OUD). However, XR-naltrexone remains under-utilized because of the difficulty initiating this medication in patients presenting for treatment with active opioid use. Starting naltrexone requires a 4-5 day long detoxification and 7-10 day wait-period to assure that the first injection is well tolerated. However, this involves patients tolerating protracted opioid withdrawal symptoms and a substantial delay carrying the risk of dropout and relapse. Shorter methods that last 5-7 days minimize the drop-out rate during the wait period and increase the induction success rate. These “rapid” protocols have been developed but have been rarely used in practice.

This multi-center study conducted at six community treatment programs around the country compares the novel rapid procedure for initiating treatment with XR-NTX with the standard procedure that requires a long wait period. In the course of this study we will develop a training package and the implementation strategy that can support widespread adoption of rapid XR-naltrexone initiation across inpatients and residential treatment facilities.

A Strategy to Improve Success of Treatment Discontinuation in Buprenorphine Responders

Buprenorphine is the primary medication used in the community for treatment of OUD. Buprenorphine is effective for approximately 50-70% of patients and better results are achieved with the longer duration of treatment. However, the prospect of long-term opioid maintenance is not acceptable to some patients and they eventually request to stop treatment or discontinue it on their own. As many patients who had good treatment response desire to discontinue buprenorphine there is a need to collect evidence about the best strategy to accomplish discontinuation while minimizing the risk of relapse following it.

We suggest that naltrexone may be used for patients who wish to discontinue buprenorphine maintenance and be protected from relapse and we are conducting an open-label randomized outpatient trial to evaluate feasibility and efficacy of rapid BUP discontinuation followed by brief course of treatment with XR-naltrexone and to compare it to the standard method of gradual BUP taper. Individuals with OUD (N=55) who have successfully completed at least 6 months of buprenorphine treatment and do not wish to remain in a long-term buprenorphine maintenance program are recruited. The first treatment phase includes a 4-week period of stabilization on buprenorphine 4-8 mg followed by randomization to: 1) buprenorphine discontinuation and rapid outpatient transition to XR-naltrexone with 3 monthly injections, or 2) buprenorphine discontinuation using a gradual, 5-week long taper. In both groups participants receive weekly relapse prevention therapy and are monitored for the duration of the trial, which is 6 months post randomization.

We hypothesize that more patients will successfully discontinue buprenorphine long-term in the group that received XR-naltrexone. A positive signal that transition from maintenance buprenorphine to XR-naltrexone is feasible and prevents relapse would encourage a larger trial to replicate and perhaps extend to multiple community-based treatment settings. A feasible, well-tolerated, and effective method of helping patients wishing to discontinue treatment with buprenorphine has the potential to expand the population of opioid--dependent individuals benefitting from treatment.