Aims: To test the safety of new buprenorphine oral lyophilisate wafer ("bup-lyo") versus standard sub-lingual buprenorphine ("bup-SL"). Design: Randomised (2: 1) openlabel study; opioid-dependent subjects; subsequent partial cross-over. Settings: Specialised clinical trials facility and addictions treatment facility. Participants: Opioid-dependent subjects (n = 36) commencing buprenorphine maintenance (personalised dose-titration) including patients cousing alcohol, cocaine and benzodiazepines (below thresholds). Measurements: Respiratory function (respiratory rate, pulse-oximetry); medication hold and dose adequacy; opiate withdrawal signs and symptoms; tablet disintegration times; treatment retention. Pharmacokinetics (PK) for plasma buprenorphine and norbuprenorphine (n = 11). Findings: Oral lyophilised buprenorphine ("bup-lyo") completely dissolved within 2 min for 58 vs. 5% for "bup-SL." Dose titration resulted in similar maintenance dosing (10.8 vs. 9.6 mg). There were no significant between-group differences in opiate-withdrawal phenomena, craving, adequacy of "hold," respiratory function. No serious adverse events (AEs), nor "severe" AEs, although more AEs and Treatment-Emergent AEs with "bup-lyo" (mostly "mild"). PK found greater bioavailability of buprenorphine with "bup-lyo" (but not norbuprenorphine). Conclusions: Orally disintegrating buprenorphine oral lyophilisate wafer disintegrated rapidly. No increased respiratory depression was found and clinically no difference between medications was observed. PK found substantially increased bioavailability of buprenorphine (but not of nor-buprenorphine) with "buplyo" relative to "bup-SL." In supervised dosing contexts, rapidly disintegrating formulations may enable wider buprenorphine prescribing. (C) 2017 S. Karger AG, Basel