Upon initial database and manual searches, we identified 1825 citations after duplicates were removed (see Additional file 1: Fig. S1). After citation screening, we reviewed 253 articles at the full text level. Fifteen articles met our inclusion criteria and were included in the systematic review, all of which were case series or case reports.
We evaluated risk of bias for each article (see Additional file 2: Appendix Table S1). The domains of selection and causality has most weaknesses. None of the articles described selection methods and if other patients had attempted the described protocol. Despite length of follow up being adequate in all reports, we judged “no” for ruling out potential alternative causes of withdrawal in all reports because they either provided supportive medications that could have influenced withdrawal symptoms, or did not comment whether supportive medications were given or not. Seven articles (47%) used adequate methods to ascertained exposures and outcomes, which we considered to be medical records and validated tools to measure withdrawal severity, respectively, as opposed to patient reported information. All but one article reported cases with sufficient detail to replicate them.
Twenty-four unique patient cases met our inclusion criteria (Additional file 2: Table S1). Two cases within the 15 articles were excluded because they did not report the presence or absence of withdrawal symptoms during buprenorphine initiation, our primary outcome [4, 11]. Most reports came from the United States or Canada and represented both genders of adults ranging from 19 to 72 years. In most cases, buprenorphine was initiated for OUD alone or in combination with pain in both inpatient and outpatient settings. There was a range of initiation strategies represented amongst the 24 cases including micro-dosing, bridging with a transdermal opioid, or a combination of multiple strategies. The most utilized strategy was the Bernese method of micro-dosing , followed by bridging with a buprenorphine patch. Rapid micro-dosing, bridging with a fentanyl patch, and combination strategies compromised a small fraction of cases.
Our primary outcome of interest was the number of cases that experienced any level of withdrawal during the initiation period; 14 of the 24 cases (58.3%) reported withdrawal symptoms and 2 of the 24 cases (8.3%) experienced withdrawal severity that was at least moderate (Additional file 2: Table S2). Three cases (12.5%) did not successfully transition from full opioid to buprenorphine monotherapy and continued full opioid agonists. Further synthesis of data is provide based on the specific initiation strategy.
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 . 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).
Buprenorphine patch bridging
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.
Fentanyl patch bridging
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.