Initiating buprenorphine to treat opioid use disorder without prerequisite withdrawal: a systematic review

We completed this systematic review consistent with the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidance [17]. We conducted a systematic literature search of MEDLINE and Cochrane Central Register of Controlled Trials from 1996 through April 10, 2020 (see Additional File 3). To augment our bibliographic database search, we searched Google Scholar on April 13, 2020 and reviewed potentially relevant citations from the prior year as well as forward citation tracking of relevant citations. We also reviewed the references of included studies. Finally, we searched www.​clinicaltrials.​gov for completed studies with results or ongoing studies to evaluate results that may be informative in the future.

Two investigators independently screened the title and abstract of each citation identified by the search and subsequently reviewed the full-text manuscript for final inclusion into the review. Discrepancies were resolved by discussion or a third investigator. A study (any design) was included if it (1) evaluated an alternative buprenorphine initiation strategy that aimed to avoid prerequisite opioid withdrawal, (2) was in patients with substance use disorder or chronic pain that were taking a full opioid agonist and (3) reported presence or absence of withdrawal during the initiation phase. Traditional initiation of buprenorphine includes an opioid-free period to establish mild to moderate prerequisite withdrawal, considered to be a minimum score of 5 or more on the Clinical Opiate Withdrawal Scale (COWS) [18‐20]. Such studies were excluded. We defined alternative strategies aimed to avoid prerequisite withdrawal as those that either (1) overlapped the full opioid agonist and buprenorphine (omitting the opioid free period and thus omitting prerequisite withdrawal) or (2) reported a baseline COWS score of less than 5 (documenting lack of withdrawal symptoms). In the absence of a reported baseline COWS score, we estimated the maximal possible score using symptoms reported prior to the first buprenorphine dose and included reports with a score less than 5. In addition to withdrawal, additional outcomes of interest included severity of withdrawal, number of patients that fully transitioned from full opioid agonist to buprenorphine monotherapy, duration of the initiation period, number of patients with a deviation from the initiation protocol, and patient satisfaction. Post-initiation outcomes included the duration buprenorphine was continued and the number of patients that experienced the following: illicit drug use, overdose, and cravings.

Using a standardized data collection tool, two investigators independently collected the following data from included studies: patient characteristics including age, gender, substance use history, indication for buprenorphine; initiation regimen characteristics including the method used, setting, medication dosing details, duration of initiation period, use of ancillary medications; and information to assess risk of bias and our outcomes of interest.

We assessed the internal validity of included studies using a tool designed for case reports [21]. The tool includes eight questions across four domains: selection, ascertainment, causality and reporting. We answered each question as “yes” or “no” and summarize assessments. We omitted two of the original eight questions regarding challenge/re-challenge phenomenon and dose–response relationships intended for reporting of adverse events because this was not applicable to our topic. Internal validity was assessed for each study by two separate investigators with conflicts resolved through discussion.

Microdosing was the most common initiation strategy reported (n = 13) (see Additional file 2: Appendix Table S2), more specifically the Bernese method (n = 10). All cases overlapped full opioid agonist with buprenorphine (median 7 days range 2 to 120 days) and four cases also reported baseline COWS scores less than 5 (range 0 to 4). Seven of the 13 cases utilized an initial buprenorphine dose of 0.5 mg while the other 6 cases utilized smaller initial buprenorphine doses, as low as 0.2 mg. While exact doses and rates of titration varied between cases, the majority followed a general framework of increasing the total daily buprenorphine dose by 50–100% per day. Fewer than half of the cases achieved a buprenorphine dose of 16 mg or greater at the end of initiation, a dose that has been associated with long term retention [22]. Most cases (85%) completed initiation within 2 weeks (median 8 days, range 3 to 120 days). Seven of 13 cases (54%) reported withdrawal symptoms of any severity during initiation. One case experienced withdrawal of moderate severity. The frequency of withdrawal was similar, regardless if the initial buprenorphine dose was ≥ 0.5 mg or < 0.5 mg (approximately 50% in each group).

The second most common initiation strategy was bridging with the buprenorphine patch (10 or 20 ug/hr) to sublingual buprenorphine (n = 7) (see Additional file 2: Appendix Table S3). The first sublingual buprenorphine dose ranged from 2 to 8 mg and was given between days 2 and 4 (median day 3). The patch was removed between days 2 and 6 (median day 5) corresponding to an overlap with the full opioid in all cases (median 3 days, range 1 to 5 days). Initiation was completed within 1 week (median 5 days; range 4 to 7 days) and all patients fully transitioned from their full opioid agonists to buprenorphine monotherapy. Three cases achieved a buprenorphine dose of 16 mg or greater at the end of initiation. Four cases (57.1%) experienced withdrawal of any severity during the initiation process. No cases experienced moderate to severe withdrawal.

One inpatient case used a fentanyl patch (25 mcg/hr for 5 days) to bridge to sublingual buprenorphine (see Additional file 2: Appendix Table S4). The buprenorphine doses began shortly after the fentanyl patch was removed, when the COWS score was zero. The initial buprenorphine dose was 1 mg with repeat doses of 1 mg and 2 mg to a total dose of 8 mg that day. No symptoms of withdrawal were reported during initiation but eight days post initiation the patient tested positive for opioids, buprenorphine, and methamphetamine and subsequently died from an overdose.

One case combined micro-dosing with buprenorphine patch bridging while 2 cases combined micro-dosing with Sustained Release Oral Morphine (SROM) bridging (see Additional file 2: Appendix Table S5). All cases occurred in the outpatient setting.

In the case evaluating combination micro-dosing and buprenorphine patch bridging, a 5mcg/hr buprenorphine patch was applied on day 1 and continued for days 2 and 3. On day 4, the patient transitioned to buprenorphine microdosing with an initial dose of 0.5 mg. The initiation process took 12 days and mild withdrawal was reported during initiation.

In the 2 cases evaluating combination micro-dosing and SROM bridging, initial doses of buprenorphine were 0.5 mg and 0.2 mg. Only one case was able to completely transition to buprenorphine monotherapy after 24 days and there were several protocol deviations that did lead to mild to moderate withdrawal. The second case did not complete the transition to buprenorphine and continued concurrent use of diacetylmorphine for > 250 days. Mild to moderate withdrawal symptoms occurred four times during initiation.

This systematic review aimed to evaluate the efficacy and safety of buprenorphine initiation strategies that omit the traditional approach of waiting for opioid withdrawal symptoms. Evidence is limited to case reports, no controlled studies were identified. The most common strategies reported in cases included microdosing and bridging with transdermal therapies. Approximately half of cases still reported withdrawal symptoms during initiation, albeit mild in severity. Given the lack of controlled studies, evidence is insufficient to determine the efficacy or safety of alternative initiation strategies presently.

Current case reports suggest it may be reasonable to expect some patients will successfully transition to sublingual buprenorphine with little to no symptoms of withdrawal while using an alternative approach, something that isn’t possible with traditional initiation of buprenorphine. On the other hand, initiation using alternative strategies may take longer to complete. Traditional initiation appears to be a quicker process (2–4 days) [23‐25] whereas the median time to complete alternative initiation in the included cases was 1 week. Prior research suggests initiation that is too gradual is associated with high rates of drop-out among patients with OUD [24] and it is unclear if this would apply to these alternative strategies of initiating buprenorphine.

Despite a lack of current evidence, there are also practical challenges to implementation of alternative initiation strategies for buprenorphine. Insurance coverage for off-label use may be a barrier to successful implementation of certain strategies [26]. Traditional initiation typically occurs in the outpatient setting, whereas many of the included cases describe inpatient initiation which has direct implications to resources and costs of care. In general, many of the alternative initiation methods require manipulation of prescription products to achieve small enough doses to be consistent with published protocols. For example, manipulation of buprenorphine/naloxone to execute a microdosing protocol requires using scissors, razors, or folding and ripping buprenorphine/naloxone films to achieve the desired dose [27]. In the outpatient setting, patients are left to manipulate the dosage forms themselves. In the inpatient setting, some institutions may choose not to operationalize these practices based on the available evidence or may have policies and procedures that prohibit certain strategies [28, 29].

While eliminating prerequisite withdrawal is well intentioned, how it impacts the overall success of OUD treatment is left to be determined. For patients with OUD, these strategies may be a last line effort to initiate a mortality-reducing medication. As a result, there is a critical need for future research to inform the efficacy and safety of differing initiation strategies using buprenorphine. Anecdotal evidence suggests varying institutions may be already developing internal guidelines and protocols of novel dosing strategies, which further supports the need for validation [14, 30]. Ideally, studies are needed to compare alternative strategies to traditional initiation and include not only short-term outcomes of initiation, but also long-term indicators of success, such as retention, and mortality. Ongoing studies may begin to inform this topic soon (NCT04228250, NCT04234191).

For future directions, investigators should consider prospective randomized trials comparing novel dosing strategies to traditional buprenorphine initiation using validated tools to measure withdrawal outcomes. No comparative studies exist evaluating withdrawal severity between varying buprenorphine initiation strategies. While cases suggest alternative strategies may result in less withdrawal during the initiation process, this observation needs evaluation in a controlled, prospective trial. Additionally, investigators should take into consideration long term outcomes such as buprenorphine retention, which is approximately 45–50% at 24 weeks [31, 32].

Based on the data available, it may be reasonable to consider an alternative buprenorphine initiation strategy if patients cannot tolerate traditional prerequisite withdrawal and thus would otherwise preclude them from being a candidate for buprenorphine. While some patients did experience withdrawal with alternative strategies, most experienced mild symptoms and some experienced no withdrawal; this would be unattainable with traditional buprenorphine initiation. Buprenorphine microdosing and buprenorphine patch bridging were the most common strategies and were executed in patients with a wide variety of historical opioid use. Clinicians should be cognizant that the impact of omitting prerequisite withdrawal on long term outcomes is unknown.

We aimed to include all types of studies and despite this, only case reports and case series exist, which have very low internal and external validity. However, case reports can provide valuable insight into novel treatment strategies for a known condition that may be further explored [21]. We assessed internal validity of included cases and cannot rule out selection bias towards favorable outcomes because case selection was unclear. We were limited by reporting within the cases; at times we were unable to confirm the presence or absence of an outcome simply because there wasn’t enough information reported. We were left to rely on qualitative statements describing withdrawal outcomes in some cases, and it is unknown if these statements were founded on validated tools or were the opinion of the patient or provider. Finally, in order to focus on initiation strategies that omit traditional prerequisite withdrawal, we did not consider other possible strategies such as those that may use an opioid free window that is shorter than current recommendations, which may be an additional approach to balancing the benefits and risks of buprenorphine initiation.