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Purpose To review the efficacy and safety of transitioning from dexmedetomidine to clonidine to facilitate weaning of patients from sedation with dexmedetomidine. There is a paucity of data describing dexmedetomidine withdrawal syndrome (DWS) as well as clonidine’s place in therapy for DWS. This review will describe and analyze current literature to provide clinical recommendations. Summary A MEDLINE literature search was performed to identify original research articles describing DWS and/or transitioning from dexmedetomidine to clonidine for the purpose of weaning patients from sedation with dexmedetomidine. Four case reports describing DWS, 3 case reports describing the use of clonidine to treat DWS, and 3 observational studies describing the use of clonidine to facilitate dexmedetomidine weaning were identified. The incidence of and risk factors for DWS are unknown; factors including patient age and dexmedetomidine infusion rate, loading dose, and discontinuation strategy have inconsistent associations with DWS. All cases of DWS have been associated with infusion durations greater than 72 hours. While there are limited data describing clonidine use for the treatment of dexmedetomidine withdrawal, clonidine appears to be beneficial for dexmedetomidine weaning and its use for that purpose has been well described. Clonidine dosages that have been assessed for discontinuing dexmedetomidine vary from 0.1 to 0.3 mg orally or enterally every 6 to 8 hours; one study assessed use of transdermal clonidine (100 µg/24 h patch). Patients with extensive cardiac comorbidities may be more susceptible to adverse effects of clonidine, which may limit the drug’s use for DWS intervention. Conclusion Despite limited supportive data, clonidine provides a promising option for sedation management in adult ICU patients, with successful transitions from dexmedetomidine reported within 24 hours after clonidine initiation.