(27) Pilot Study Comparing Traditional to Low-Dose Initiation with Buprenorphine

Background & Introduction: Buprenorphine is one of three FDA-approved medications for treatment of opioid use disorder (OUD) and is commonly used for patients treated in the telehealth setting. Buprenorphine is a partial agonist with high binding affinity at the mu-opioid receptor. If a patient is using a full agonist opioid, until it clears fully, administering buprenorphine may cause displacement of the full agonist from the receptor and induce rapid onset of precipitated withdrawal (1). In traditional initiation, patients must abstain from opioids until withdrawal is experienced prior to starting buprenorphine. Barriers to traditional initiation include the required withdrawal period, fear of withdrawal, and intolerable withdrawal, all which may discourage patients from treatment (2). Introduced in 2016 as the “Bernese Method”, low-dose initiation is an alternative approach that uses small but escalating doses of buprenorphine over a period of several days to weeks, such that buprenorphine slowly overcomes the effect of the opioid agonist at the receptor (3). This and other similar protocols do not require a period of withdrawal, but they do require the patient to concurrently use a full agonist opioid until cravings cease (4). To date, no study has compared these two approaches in a prospective randomized trial.

Methods: This is a quasi-experimental randomized trial evaluating patients entering treatment with a telehealth OUD provider. To be eligible, patients were 18 years or older, had OUD by DSM-5 criteria, had no or mild withdrawal at the time of intake, had used a full agonist opioid not directly from a pharmacy in the prior 24 hours, and were deemed appropriate for telehealth treatment. Trained providers (either MD, PA or NP) consented patients after assessment but prior to determining a buprenorphine initiation plan. Patients were randomized to either traditional initiation, in which a patient waited until a self-administered withdrawal scale indicated moderate withdrawal and they took 4-16 mg of buprenorphine on day 1 depending on symptoms, or the Manitoba low-dose protocol, escalating from 1 mg to 12 mg over the course of 7 days while still using their full agonist opioid. The study was quasi-experimental because patients randomized to low-dose had the choice to withdraw from the study and choose traditional initiation. Patients were asked to complete a daily survey for 10 days that included a Subjective Opiate Withdrawal Scale (SOWS) score, and clinical outcomes were followed prospectively through day 30.

Results: Between March 5 and October 3, 2023, 32 patients were consented. Three patients had not yet reached the 30-day study endpoint and were excluded from analysis. Seven patients withdrew from the study (1 return to full-agonist opioid use, 1 had provider change from traditional induction to low-dose because of precipitated withdrawal, 1 changed their mind about participation, 2 left the program for financial reasons, and 2 did not attend any follow-up visits). Therefore, data from 22 patients were included for analysis, 13 (59.1%) in the low-dose arm and 9 (40.9%) in the traditional arm.

Overall mean age was 36.0 (SD 7.9) years, range 22-60. Thirteen patients (59.1%) were male. Enrollees came from 8 U.S. states. Ten patients (45.5%) had commercial insurance, 7 (31.8%) had Medicaid, and 5 (22.7%) self-paid. Primary substances used were fentanyl (n=9, 40.9%), heroin (n=4, 18.2%), and oxycodone (n=9, 40.9%). Nine patients (40.9%) had prior experience with buprenorphine and 8 (36.3%) had history of precipitated withdrawal. Six patients (27.3%) reported prior history of unsuccessful induction. There were no significant differences in age (p=0.47), gender (p=0.14), experience with buprenorphine (p=0.78), history of precipitated withdrawal (p=0.25), or unsuccessful induction (p=0.16) between the two arms. However, patients in the traditional initiation arm were more likely to report oxycodone as their primary substance (78.8% vs. 15.4%, p=0.01) compared with the low-dose arm.

For the first 10 days after starting buprenorphine, patients completed their daily survey a mean of 4.5 times in the low-dose arm and 4.4 times in the traditional arm, p=0.47. At the most recent report, patients in the low-dose arm were more likely to still have cravings for opioids (88.9% vs. 11.1%, p=0.007). Low-dose patients were more likely to still use other opioids in the prior 24 hours (69.2% vs 0%, p=0.001), and to have either relapse or evidence of continued opioid use at 30 days (76.9% vs. 22.2%, p=0.01). Patients in the traditional arm appeared to be more likely to still be in treatment at 30 days, but the results were not statistically significant (88.9% vs. 53.9%, p=0.08). Fifteen patients reported SOWS scores on day 8, 9 and/or 10, 10 patients in the low-dose arm and 5 in the traditional arm. The most recent day’s report was analyzed for these 15 patients, and the mean SOWS scores were 24.4 (SD 19.9) in the low-dose arm vs. 8.2 (SD 7.0) in the traditional arm, p=0.02.

Conclusion & Discussion: In this preliminary analysis of an in-progress randomized study comparing traditional vs. low-dose buprenorphine initiation protocols, the traditional protocol appeared to be associated with less cravings of opioids, less use of full agonist opioids, and less rate of relapse at 30 days. Additionally, after a week of treatment, self-reported withdrawal scores were significantly lower for patients treated with traditional initiation. This result was unexpected, especially as low-dose initiation should be associated with less withdrawal. However, the results must be considered in the context of more fentanyl and heroin use in the low-dose arm compared with the traditional arm, which more commonly used oxycodone. Additionally, the low-dose protocol we chose for the study may be either too short or patients may require either more or less buprenorphine than the protocol specified. The study is ongoing, and results may change when target enrollment is met, but preliminary results demonstrate superiority of traditional initiation in the telehealth setting.

References: 1) De Aquino, J. P., Parida, S., & Sofuoglu, M. (2021). The Pharmacology of Buprenorphine Microinduction for Opioid Use Disorder. Clinical drug investigation, 41(5), 425–436.
2) Hewell, V. M., Vasquez, A. R., & Rivkin, I. D. (2017). Systemic and individual factors in the buprenorphine treatment-seeking process: a qualitative study. Substance abuse treatment, prevention, and policy, 12(1), 3.
3) Hämmig, R., Kemter, A., Strasser, J., von Bardeleben, U., Gugger, B., Walter, M., Dürsteler, K. M., & Vogel, M. (2016). Use of microdoses for induction of buprenorphine treatment with overlapping full opioid agonist use: the Bernese method. Substance abuse and rehabilitation, 7, 99–105.
4) Hardy, M., Grable, S., Otley, R., & Pershing, M. (2023). Survey of Buprenorphine Low-dose Regimens Used by Healthcare Institutions. Journal of addiction medicine, 17(5), 521–527.