Ketamine-Assisted Buprenorphine Initiation:  A Pilot Case Series

AbstractBackground:Many people with opioid use disorder who stand to benefit from buprenorphine treatment fail to initiate it due to experience with or fear of both spontaneous opioid withdrawal and buprenorphine-precipitated opioid withdrawal (BPOW). An effective means of minimizing withdrawal symptoms would reduce patient apprehensiveness, lowering the barrier to buprenorphine initiation. Ketamine, approved by the FDA as a dissociative anesthetic, reduced opioid dependence in preclinical studies. It completely resolved BPOW in case reports when infused at a sub-anesthetic level, yet dissociation, which is an altered cognitive state, occurred. However, most patients undergo buprenorphine initiation in the outpatient setting where altered mental status is undesirable. We explored the potential of short-term use of ketamine, self-administered sublingually at a lower, sub-dissociative dose to assist ambulatory patients undergoing transition to buprenorphine from pure mu-opioid agonists.Methods:Patients prescribed ketamine were either 1) seeking transition to buprenorphine from illicit fentanyl and highly apprehensive of BPOW or 2) undergoing transition to buprenorphine from illicit fentanyl or methadone and experiencing BPOW. We prescribed 4-8 doses of sublingual ketamine 16 mg (each dose bioequivalent to 3-6% of an anesthetic dose), monitored patients daily or near-daily, and adjusted buprenorphine and ketamine dosing based on patient response and prescriber experience.Results:37 patients were prescribed ketamine over 14 months. Ketamine reliably abolished fentanyl withdrawal symptoms for up to 72 hours, often prevented severe BPOW when used prophylactically, and often reduced or abolished BPOW. Of the 24 patients who confirmed trying ketamine, 16 (67%) completed buprenorphine initiation, including 12 (75%) of the last 16 patients. Of the last 12 patients who completed initiation, 11 (92%) achieved 30-day retention in treatment. We developed a ketamine protocol that allowed four of the last patients to undergo a smooth buprenorphine initiation over four days. Adverse effects including dissociation did not occur within the effective ketamine dose range.ConclusionsKetamine at a sub-dissociative dose was useful to prevent, reduce and/or treat painful opioid withdrawal symptoms during buprenorphine initiation in the outpatient setting. Further research is warranted to confirm these results and develop reliable protocols for a range of treatment settings.