Characterizing Baclofen Withdrawal: A National Survey of Physician Experience.

OBJECTIVE: We studied physicians' opinions and experiences concerning clinical concerns, perceived severity, occurrence, and management of baclofen withdrawal due to abrupt discontinuation. METHODS: A nationwide 26-question electronic survey was distributed via e-mail to physicians (N = 952) representing varying specialties who manage spasticity with baclofen. A total of 110 physicians provided responses to the survey (response rate = 11.6%). Results were evaluated using descriptive statistics. RESULTS: Withdrawal from both oral and intrathecal (IT) baclofen was recognized as a significant concern and was observed by most respondents. However, approximately 75% and 35% of respondents or their clinic sites lack established management protocols for managing anticipated interruption of oral or IT baclofen, respectively. CONCLUSIONS: These findings highlight the need for further research on and the development of guidelines for the prevention and treatment of baclofen withdrawal. The results of this survey, along with a systematic literature review and multidisciplinary stakeholder input, may be helpful in establishing guidelines for the treatment and prevention of baclofen withdrawal.

A Randomized Dose Escalation Study of Intravenous Baclofen in Healthy Volunteers: Clinical Tolerance and Pharmacokinetics.

BACKGROUND: Abrupt discontinuation of baclofen can result in a potentially severe withdrawal syndrome. The current treatment for baclofen withdrawal is inadequate, resulting in a critical need to develop an alternative method to prevent or treat this withdrawal syndrome. OBJECTIVE: To evaluate the safety profile and pharmacokinetics of oral (PO) and investigational intravenous (IV) baclofen formulations at clinically relevant doses. DESIGN: Randomized, open-label, dose-escalation, crossover study. SETTING: Contract Research Organization (CRO). METHODS: Three cohorts of 12 healthy adults received single doses of PO baclofen (10 mg, 15 mg or 20 mg) and 10-minute infusions of IV baclofen (7.5 mg, 11.5 mg, or 15 mg) with a minimum 48-hour wash-out period. The third cohort also received a 60-minute infusion of 15 mg IV baclofen after an additional 48-hour wash-out period. MAIN OUTCOME MEASURES: Subjects were observed in a CRO for 24 hours after each dose of baclofen, and were assessed for nystagmus, ataxia, and sedation. Blood samples were collected from 0 to 24 hours and analyzed for baclofen concentration using high-performance liquid chromatography-mass spectroscopy. Noncompartmental pharmacokinetic analyses were performed. Dose linearity and proportionality was assessed using 2-way repeated-measures analysis of variance and a power model analysis. RESULTS: None of the PO or IV doses resulted in significant sedation compared to baseline. All subjects could perform tandem gait after each baclofen dose. The most common side effect, transient mild nystagmus, was noted in 4 of 36 and in 13 of 36 subjects after PO and IV administration, respectively. This was likely related to increased maximum concentrations (Cmax). After the 20 mg PO and 15 mg IV doses, mean Cmax levels were 255 and 722 ng/mL and half-lives were 5.24 and 5.79 hours for PO and IV baclofen, respectively. The mean oral bioavailability for the 20-mg PO dose was approximately 80%. CONCLUSIONS: All PO and IV doses of baclofen were well tolerated clinically. The 80% bioavailability suggests that a 20% reduction in IV dose will produce comparable total drug exposures to that of the PO dose. When PO therapy is interrupted, bridging with IV baclofen may be feasible. LEVEL OF EVIDENCE: II.