Strategies for identifying problematic codeine use are needed. Identifying codeine dependence in clinical settings is often delayed, contributing to serious morbidity. Commonly described approaches for managing codeine dependence include opioid taper, opioid agonist treatment, and psychological therapies. These approaches are consistent with published evidence for pharmaceutical opioid dependence treatment and with broader frameworks for treating opioid dependence. PROSPERO registration: CRD42016052129.

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Introduction: Benzodiazepines (BZDs) are used in the management of anxiety and sleep disorders; however, chronic use is associated with tolerance and dependence. During withdrawal, symptoms of anxiety are often severe and problematic for patients and may lead to relapse or maintenance on low doses of BZDs. Low, continuous doses of flumazenil reduce BZD withdrawal symptoms in several studies; however, bolus doses are known to induce anxiety and precipitate panic. Accordingly, this study aimed to determine whether continuous low-dose flumazenil is anxiogenic like bolus doses. Method: In a randomised control cross over design, participants received a continuous low-dose flumazenil infusion for eight days at an approximate rate of 4 mg/24 h or placebo before crossing over to the alternate study arm. Participants were able to request diazepam as needed. The primary outcome was the change in state anxiety levels. Trait anxiety was also recorded at baseline and one month after the flumazenil/placebo infusion period. Results: BZD use was significantly reduced in both groups. There were no significant differences between state anxiety and the 95% confidence interval showed no evidence of a clinically significant anxiogenic effect from low-dose flumazenil. Trait anxiety was significantly reduced one month after the infusion period. Conclusion: There is no evidence that continuous low-dose flumazenil infusion significantly increases state anxiety levels to a clinically significant level. Interestingly, flumazenil may decrease state anxiety during BZD withdrawal, unlike bolus doses of flumazenil. Flumazenil may have an anxiolytic effect on trait anxiety, which was evident one month after treatment.