Abstract
Background and Objectives:
Fentanyl, and other highly potent synthetic opioids, are the leading cause of opioid overdose deaths in the US.
Methods:
In an open-label, uncontrolled 12-week outpatient clinical trial to test the feasibility of a single day induction onto extended-release buprenorphine injection (BXR) treatment for five adults with opioid use disorder using heroin containing fentanyl. Participants were planned to receive three monthly BXR injections (300 mg-300 mg-100 mg).
Results:
After receiving 24 mg sublingual buprenorphine, all five participants received the BXR 300 mg injection on the first day of induction. All five participants were retained for the full 3-month study period post-induction and received all three scheduled BXR injections.
Discussion and Conclusion:
This study provides preliminary evidence supporting the feasibility of inducting users of heroin containing fentanyl onto BXR 300 mg in a single day.
Scientific Significance:
The ability to administer a long-acting injection of buprenorphine that assures therapeutic serum levels for a month on the first day of treatment contact is a promising development for the treatment of OUD.
INTRODUCTION
Opioid use disorder (OUD), affecting approximately 2 million Americans,1 is a major US public health problem. From 2014 to 2017, the overdose death rate due to highly potent synthetic opioids (HPSO) increased dramatically,2,3 and are now the most common cause of fatal opioid overdoses in the US.4 In 2017, 47,600 US persons died of an opioid overdose, with 60% of those deaths due to HPSO.4 The most recent epidemiologic data available show that the rate of overdose deaths involving HPSO continue to increase, demonstrating that the public health problem of fatal HPSO overdose is a substantial public health problem.5 Despite HPSO use being the leading cause of overdose deaths in the US, there are very limited clinical trial data available to provide guidance as to the most effective treatment approaches.
HPSO are synthetic full agonists at the µ-opioid receptor that include fentanyl and fentanyl analogues (e.g., sufentanil, alfentanil, remifentanil, and carfentanil), as well as other novel synthetic opioids (e.g., AH-7921, U-47700, and MT-45).6 Paul Jannsen synthesized fentanyl in 1960 with the goal of developing a highly lipophilic derivative of meperidine that would act as a rapid analgesic, resulting in a drug that is approximately 50–100 times more potent than morphine.7,8 Carfentanil, the most potent HPSO, is estimated to be 10,000 times the potency of morphine.6 The greater potency of fentanyl compared to morphine is not explained by binding affinity or half-life,9–13 but rather the differential lipophilicity.14
Pharmacotherapy with either methadone, buprenorphine or long-acting injectable naltrexone is the standard of care for the treatment of OUD in the US. However, since the emergence of HPSO becoming the main driver of opioid overdose deaths is a relatively recent phenomenon, there are limited data regarding the efficacy of available pharmacotherapies for HPSO-using patients. In 2018, the first extended-release buprenorphine (BXR) for injection (Sublocade™; Indivior)15 formulation became commercially available in the US and a second BXR product (Brixadi™, Braeburn)16 will likely become available in the near future. Long-acting depot medications offer advantages in terms of compliance and serum drug level reliability, and these new formulations of buprenorphine may offer advantages over sublingual administration.
Faced with the reality that in our New York City-based research clinic approximately 90% of heroin users (unpublished data on file) were testing positive for HPSO (primarily fentanyl), and that fentanyl was the leading cause of New York City overdose death,17 we began a clinical development program to determine the best treatments for this at-risk population. We hypothesized that the advantage that BXR offers, enhanced treatment compliance with reliable serum buprenorphine levels, would potentially provide benefit for OUD patients using heroin containing fentanyl. However, the Sublocade BXR formulation FDA labeling instructions recommends stabilization for seven days on a minimum of 8 mg of sublingual (SL) buprenorphine, which presents a barrier to treatment for patients not yet stabilized with SL buprenorphine. One of the main potential advantages of the use of BXR for treating OUD is the rapid achievement of a consistent therapeutic serum level of buprenorphine, which should facilitate rapid stabilization of a patient’s clinic condition. As a test of the feasibility of BXR treatment for OUD patients using heroin containing fentanyl, we conducted a small uncontrolled pilot study proceeding to BXR treatment after 2–3 days of SL buprenorphine induction, which demonstrated the feasibility of the approach.18 We then planned a second phase of this exploratory clinical research, which would administer BXR on the first day of sublingual buprenorphine induction for OUD outpatients using heroin containing fentanyl.
METHODS
The Institutional Review Board of the New York State Psychiatric Institute approved this research protocol and all participants provided informed consent prior to study enrollment. Participants were recruited by local advertising (internet, print, radio, television, and subway) or by clinical referrals to the research clinic in the New York City metropolitan area. Participants were recruited through advertising directed at potential participants seeking treatment for an opioid use problem. The MINI International Neuropsychiatric Interview,19 a clinical psychiatric evaluation, medical history, physical and laboratory examination were conducted to evaluate eligibility. Five participants were planned to be enrolled in this second phase of the study; five participants had been enrolled in the first phase of this study, the results of which have been already been published.18
Participants were outpatients 18 years of age or older, were voluntarily seeking treatment for heroin use, met DSM-5 criteria for OUD, and had a urine sample that tested positive for morphine (metabolite of heroin) and fentanyl or norfentanyl. Potential participants were excluded for: a substance use disorder other than opioid as the primary diagnosis; having a psychiatric diagnosis that might interfere with study participation; methadone or buprenorphine maintenance treatment; having an allergy to buprenorphine; pregnancy or lactation; unstable medical conditions; or being physiologically dependent on alcohol or sedative-hypnotics. The study was conducted from July 29, 2019 through November 18, 2019. Recruitment progress is described in figure 1. The planned sample size was five participants. Participants were treatment seeking, but did not need to commit to abstinence or any clinical goal other than receiving the BXR injection.
figure 1.
CONSORT diagram. HPSO, highly potent synthetic opioids
Sublingual (SL) buprenorphine treatment is required prior to administering BXR to confirm that the participant has an adequate opioid tolerance to tolerate buprenorphine. Based on the positive results of the first phase of our clinical development program,18 we further modified our approach to immediately proceed to the BXR 300 mg injection after a participant received and tolerated at least 24 mg of SL buprenorphine in a single day.
While it was not required by the protocol, we preferred to schedule the outpatient induction earlier in the week to maximize the number of in clinic visits following the injection. Participants were instructed to abstain from opioid use for at least 16 hours prior to arriving at the clinic on the first day of the induction period. The outpatient SL buprenorphine induction was initiated once participants achieved a COWS score > 6 to limit the risk of precipitated withdrawal. As a further measure to reduce the risk of precipitated withdrawal, the first dose of SL buprenorphine administered was 2 mg. The threshold of a COWS score > 6 was based on our prior experience with OUD clinical trials both before and during the fentanyl era.18,20 Sublingual buprenorphine was administered in divided doses until a total dose of 24 mg was reached. The typical hourly SL buprenorphine dosing schedule was 2 mg-6 mg-8 mg-8 mg. The Ramsay Sedation Scale (RSS)21 was conducted before and 1 hour after each SL buprenorphine dose, including immediately prior to administering the BXR injection. One hour after receiving the last buprenorphine dose, the RSS score must have been 2 or lower to proceed to the BXR injection. No additional SL buprenorphine was provided after the BXR injection was administered. After completing the in-clinic single day induction onto BXR 300 mg, as needed ancillary medications (clonidine 0.1 mg 3x/day, clonazepam 0.5 mg 3x/day, zolpidem 10 mg at bedtime) were provided to participants for up to 2 weeks. Participants were discharged from the research clinic one-hour after receiving the BXR injection.
The total study period was 12 weeks. Participants were scheduled to receive three monthly injections of BXR (300 mg-300 mg-100 mg) and were monitored for 4 weeks following the third injection. During the first week of the study period (induction) participants were scheduled to attend the clinic for the first four days. For the remaining 11 weeks of the study participants were scheduled to attend the clinic twice per week. At one of the weekly study visits, participants had a weekly supportive behavioral treatment session with the study psychiatrist. The Medical Management treatment developed for the COMBINE study was modified for OUD.22 At the end of the study period participants were provided community referrals for continuation of buprenorphine treatment.
RESULTS
The participant demographics and outcomes are reported in Table 1. All 5 participants had urine toxicology positive for morphine and fentanyl at the time of screening. All 5 participants were heroin users who tested positive for fentanyl. All 5 participants received the 24 mg of sublingual buprenorphine and received the BXR injection on the first day of the induction. No patients had elevated Ramsay Sedation Scale scores during the induction. COWS scores at the conclusion of the induction on BXR 300 mg on day 1 ranged from 0 to 15. COWS scores on study days 2–4 ranged from 0 to 7.
Table 1:
Participant Demographics and Treatment Outcomes
| Participant | Day 1 | Day 2 | Day 3 | Day 4 | Clinical Status |
|---|---|---|---|---|---|
| #1 41 y/o Hispanic Male Intravenous heroin 13 bags/day Utox: +Fentanyl/+Morphine |
• COWS = 11 at the start of the induction • Total BUP-SL = 24 mg in divided doses • BXR 300 mg injection • COWS = 9 at the end of the induction • Ancillary Meds Dispensed Clonazepam 0.5 mg #3 Clonidine 0.1 #3 Prochlorperazine 10 mg #3 Zolpidem 10 mg #1 |
• Missed Visit |
• COWS = 0 • Ancillary Meds Dispensed Clonazepam 0.5 mg #3 Clonidine 0.1 mg #3 Prochlorperazine 10 mg #3 Zolpidem 10 mg #1 |
• COWS = 1 • Ancillary Meds Dispensed Clonazepam 0.5 mg #3 Clonidine 0.1 mg #3 Zolpidem 10 mg #1 |
• Received 3 BXR injections • Completed Trial • No heroin use in the first 4 days post-induction • 4 days heroin use in first 28 days post-induction • 5 days heroin use in 28 day period after 2nd injection • 4 days heroin use in 28 day period after 3rd injection • Longest continuous heroin using period was 2 days |
| #2 33 y/o White Male Intranasal heroin 15 bags/day Utox: +Fentanyl/+Morphine |
• COWS = 9 at the start of the induction • Total BUP-SL = 24 mg in divided doses • BXR 300 mg injection • COWS = 4 at the end of the induction • Ancillary Meds Dispensed Clonazepam 0.5 mg #2 Clonidine 0.1 #2 |
• COWS = 2 • Ancillary Meds Dispensed Clonazepam 0.5 mg #3 Clonidine 0.1 mg #3 Zolpidem 10 mg #1 |
• COWS = 0 • Ancillary Meds Dispensed Clonazepam 0.5 mg #3 Clonidine 0.1 mg #3 Zolpidem 10 mg #1 |
• COWS = 2 • Ancillary Meds Dispensed Clonazepam 0.5 mg #3 Clonidine 0.1 mg #3 |
• Received 3 BXR injections • Completed Trial • No heroin use after receiving 1st BXR injection for remainder of the study |
| #03 26 y/o White Male Intravenous heroin 15 bags/day Utox: +Fentanyl/+Morphine |
• COWS = 8 at the start of the induction • Total BUP-SL = 24 mg in divided doses • BXR 300 mg injection • COWS = 11 at the end of the induction • Ancillary Meds Dispensed Clonazepam 0.5 mg #3 Clonidine 0.1 #3 Prochlorperazine 10 mg #3 Zolpidem 10 mg #1 |
• COWS = 7 • Ancillary Meds Dispensed Clonazepam 0.5 mg #3 Clonidine 0.1 mg #3 Zolpidem 10 mg #1 |
• COWS = 5 • Ancillary Meds Dispensed Clonazepam 0.5 mg #3 Clonidine 0.1 mg #3 Zolpidem 10 mg #1 |
• COWS = 0 • Ancillary Meds Dispensed Clonazepam 0.5 mg #3 Clonidine 0.1 mg #3 Zolpidem 10 mg #1 |
• Received 3 BXR injections • Completed Trial • No heroin use during the first 4 days post induction • 2 days heroin use in first 28 days post-induction • Longest heroin continuous using period was 1 day • No heroin use after receiving 2nd BXR injection for the remainder of the study |
| #4 29 y/o White Female Intravenous heroin 8 bags/day Utox: +Fentanyl/+Morphine |
• COWS = 18at the start of the induction • Total BUP-SL = 24 mg in divided doses • BXR 300 mg injection • COWS = 9 at the end of the induction • Ancillary Meds Dispensed Clonazepam 0.5 mg #3 Clonidine 0.1 #2 Zolpidem 10 mg #1 |
• COWS = 3 • Ancillary Meds Dispensed Clonazepam 0.5 mg #6 Clonidine 0.1 mg #6 Zolpidem 10 mg #2 |
• Missed Visit |
• COWS = 7 • Ancillary Meds Dispensed Clonazepam 0.5 mg #3 Clonidine 0.1 mg #3 Zolpidem 10 mg #1 |
• Received 3 BXR injections • Completed Trial • Used heroin daily during first 4 days post-induction • 14 days heroin use in first 28 days post-induction • 8 days heroin use in 28 day period after 2nd injection • 3 days heroin use in 28 day period after 3rd injection • Longest continuous heroin using period was 5 days |
| #5 40 y/o Black Male Intranasal heroin 8 bags/day Utox: +Fentanyl/+Morphine |
• COWS = 17 at the start of the induction • Total BUP-SL = 24 mg in divided doses • BXR 300 mg injection • COWS = 15 at the end of the induction • Ancillary Meds Dispensed Clonazepam 0.5 mg #3 Prochlorperazine 10 mg #2 Clonidine 0.1 #3 Zolpidem 10 mg #1 |
• COWS = 0 • Ancillary Meds Dispensed Clonazepam 0.5 mg #3 Prochlorperazine 10 mg #1 Clonidine 0.1 mg #3 Zolpidem 10 mg #1 |
• COWS = 0 • Ancillary Meds Dispensed Clonazepam 0.5 mg #6 Clonidine 0.1 mg #6 Zolpidem 10 mg #2 |
• Missed Visit |
• Received 3 BXR injections • Completed Trial • Used heroin on days #1 and #2 of the first 4 days post-induction • 9 days heroin use in first 28 days post-induction • 7 days heroin use in 28 day period after 2nd injection • Longest heroin continuous period was 3 days • No heroin use after 3rd injection |
All 5 participants were retained for the entire 12-week study period and received all three scheduled BXR injections. The acceptability of the single-day induction onto BXR was high as evidenced by all five participants opting to receive all 3 monthly injections of BXR and remaining in the study for the entire 12-week study period. The longest continuous heroin using period for any of the participants was 5 days (range: 0–5).
At the conclusion of the study, all 5 participants were transitioned to sublingual buprenorphine 16 mg per day. Four participants completed the month post-study SL buprenorphine treatment and accepted clinical referrals; one participant was lost to follow up during the post-study SL buprenorphine phase.
DISCUSSION
While this is a small, uncontrolled pilot study, the results of this preliminary research are promising for this approach, as all five participants were successfully inducted in a single day, received all three scheduled injections, and were retained for the entire three-month study period. There was intermittent heroin use by the participants during the study, but overall retention in treatment for the entire 12-week study period and receipt of all three schedule BXR injections are important markers of clinical stability.
Three of the five participants used heroin/fentanyl during the 4-day induction period. This use of opioid-agonists may have had an effect on COWS scores. We did not collect subject effect data on whether participants using heroin/fentanyl were unable to determine if participants were able to override the blockade provided by buprenorphine. However, as all 5 study participants received all three injections and completed the 12-week trial, heroin/fentanyl use during the induction period did not appear to affect clinical outcome.
Limitations of this study include a small sample size, uncontrolled and open-label design and therefore limited conclusions of the generalizability of this approach should be drawn from these results. An additional limitation is that heroin users testing positive for fentanyl were enrolled. The amount of fentanyl used is unknown and the generalizability of the results collected to primary fentanyl users is unknown. Participants spent at least 5 hours in the clinic on the day of the induction and this will not be feasible in many clinical settings. This small pilot study is promising but needs to be followed up with larger controlled studies before evidence-based recommendations for clinical practice can be made.
A concern with rapidly replacing a high potency full opioid agonist (e.g., fentanyl) with a partial agonist (e.g., buprenorphine) is that precipitated withdrawal symptoms will emerge. In this sample of five participants using heroin and testing positive for HPSO, using the above described single-day induction protocol, did not result in a protracted period of precipitated withdrawal, as evidenced by both generally low COWS scores post-injection and the participants’ willingness to remain in the study and receive additional BXR injections. Given that some degree of irreducible discomfort when transitioning from high-potency opioid agonists to a partial agonist such as buprenorphine is to be expected, the method described in this study was generally well tolerated. It is unlikely that heroin use post-induction affected opioid withdrawal symptom severity as the BXR 300 mg dose provides a rapid blockade of non-buprenorphine agonist effects.{Nasser, 2016 #3812} All participants were offered and accepted ancillary medications for the treatment of withdrawal during the first two weeks of the study period, and these medications very likely reduced opioid withdrawal symptom severity to some degree. The use of ancillary medications by study participants may limit the generalizability of the results.
Patients testing positive for HPSO have an inherently high opioid tolerance and therefore a lower risk of buprenorphine overdose, and the preliminary results of this study suggest that a single day SL dosing of 24 mg is may be a predictor of tolerability for the BXR 300 mg dose. Within 24 hours after BXR administration, withdrawal symptoms were generally well controlled. This pattern is consistent with the known pharmacokinetics of this BXR formulation, that leads to a serum blood level spike approximately 24 hours after administration.21,22 We chose a 24 mg SL buprenorphine dose to determine readiness to receive the BXR 300 mg injection. It is possible that a lower dose could be an adequate predictor of readiness to receive the BXR 300 mg injection, as was tested in the Brixadi pivotal trial,16 where a 4 mg sublingual dose was provided before initiating the BXR injection. However, the BXR serum level peak does not occur for 24 hours and receiving a robust dose of SL buprenorphine on the first day may help relieve withdrawal symptoms in the first 24 hours, particularly for patients using fentanyl.
Anecdotally, our experience with performing sublingual buprenorphine inductions during the HPSO-era is that patients using heroin containing fentanyl do not develop withdrawal symptoms predictably within 12–16 hours as heroin-only users typically do. What instead emerges is a more protracted withdrawal time course where SL buprenorphine administration tends to precipitate withdrawal symptoms, resulting in patients and clinicians abandoning the induction attempt. Patients with withdrawal symptoms precipitated by an abandoned SL buprenorphine induction are at risk of returning to heroin/fentanyl use. The primary clinical advantage of BXR over SL buprenorphine is the depot administration and assurance of medication treatment adherence. Providing this definitive treatment earlier in the induction process may decrease the risk of a failed induction. Simply put, providing the BXR injection on the first day of the induction sharply reduces the ability of either the patient or clinician to abandon the induction due to emerging withdrawal symptoms or clinical uncertainty.
The method of single day induction to BXR for OUD patients using heroin containing fentanyl requires further study in larger controlled trials. An inherent advantage of extended-release buprenorphine injection formulations is that once administered, neither the patient nor the clinician can abandon the induction and treatment plan in response to opioid withdrawal symptoms. While we did not provide SL buprenorphine after the BXR injection, nor found it necessary, supplemental buprenorphine could be provided with minimal risk. The main risk of a single day induction onto BXR is that the abrupt administration of a large dose of buprenorphine could precipitate withdrawal to a greater degree than would occur with a more graduated introduction of buprenorphine. There is also a risk that the BXR 300 mg dose will be too high and lead to adverse effects than if a SL dose of buprenorphine were more gradually adjusted to an individual’s symptoms.
The next logical step in this line of clinical research would be testing the single day induction onto BXR injection as compared to standard SL buprenorphine treatment for OUD patients using heroin containing fentanyl. However, other BXR induction strategies should be studied as well, including no pre-injection SL buprenorphine dosing. The single day induction approach would also have value for other OUD subpopulations as well and should be studied in a variety of clinical settings, such as emergency departments or walk-in clinics. The ability to deliver a therapeutic dose of buprenorphine22 on the first day of treatment that lasts for a full month solves the problem of needing to find immediate referrals for patients who present in urgent care settings, as well eliminating the risk of diversion or non-adherence with therapy. The results of this case series suggest that providing an effective treatment that relieves symptoms can promote treatment engagement, as all 5 participants received all 3 planned injections. The emergence of fentanyl and other HPSO has been a deadly development for people using opioids in the US. The newly available extended-release buprenorphine injection formulations may be an important potential treatment option for this at-risk population.
Table 2.
Induction Day Timeline
| Participant | Time | COWS Score | Buprenorphine Dosing |
|---|---|---|---|
| FRP-007 | 1241 | 6 | |
| 1340 | 9 | ||
| 1410 | 11 | Buprenorphine 2 mg SL | |
| 1517 | 5 | Buprenorphine 8 mg SL | |
| 1550 | 3 | Buprenorphine 14 mg SL | |
| 1605 | XR-Buprenorphine 300 mg SC | ||
| 1640 | 9 | ||
|
| |||
| ACP-008 | 1150 | 6 | |
| 1240 | 9 | Buprenorphine 2 mg SL | |
| 1330 | 5 | Buprenorphine 6 mg SL | |
| 1415 | 5 | Buprenorphine 8 mg SL | |
| 1500 | 4 | Buprenorphine 8 mg SL | |
| 1530 | 5 | XR-Buprenorphine 300 mg SC | |
|
| |||
| RPM-009 | 1045 | 4 | |
| 1135 | 5 | ||
| 1235 | 8 | ||
| 1315 | 8 | Buprenorphine 2 mg SL | |
| 1430 | 5 | Buprenorphine 6 mg SL | |
| 1515 | Buprenorphine 8 mg SL | ||
| 1600 | 9 | Buprenorphine 8 mg SL | |
| 1620 | XR-Buprenorphine 300 mg SC | ||
| 1740 | 11 | ||
|
| |||
| NLP-010 | 1035 | 18 | Buprenorphine 2 mg SL |
| 1125 | 14 | Buprenorphine 8 mg SL | |
| 1155 | Buprenorphine 8 mg SL | ||
| 1235 | 17 | Buprenorphine 6 mg SL | |
| 1340 | 9 | XR-Buprenorphine 300 mg SC | |
|
| |||
| CXG-011 | 0945 | 17 | |
| 1020 | Buprenorphine 2 mg SL | ||
| 1110 | 8 | Buprenorphine 8 mg SL | |
| 1145 | 9 | Buprenorphine 8 mg SL | |
| 1230 | 15 | Buprenorphine 6 mg SL | |
| 1245 | XR-Buprenorphine 300 mg SC | ||
ACKNOWLEDGMENTS
Funding for this research was provided by the National Institute on Drug Abuse (NIDA). NIDA grant U54DA037842-01 (Dr. Levin). NIDA had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. Dr. Mariani had full access to all of the data of the study and takes full responsibility for the integrity of the data and for the accuracy of the data analysis.
We would like to thank the staff of the Substance Treatment and Research Service (STARS) of the Columbia University Irving Medical Center/New York State Psychiatric Institute for their clinical support.
Footnotes
DECLARATION OF INTERESTS
Dr. Mariani has served as a consultant to Indivior and Novartis. Dr. Levin receives grant support from the NIDA, SAMHSA and US World Meds and has been an unpaid member of a Scientific Advisory Board for Alkermes, Novartis and US WorldMeds. Drs. Brezing, Naqvi, and Luo reported no biomedical financial interests or potential conflicts of interest. Also, Ms. Mahony, Mr. Brooks, and Mr. Podell reported no biomedical financial interests or potential conflicts of interest. The authors alone are responsible for the content and writing of this paper.
Trial Registration:clinicaltrials.gov identifier: NCT03861338
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