Using baclofen to explore GABA-B receptor function in alcohol dependence: insights from pharmacokinetic and pharmacodynamic measures

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Title: Using baclofen to explore GABA-B receptor function in alcohol dependence: insights from pharmacokinetic and pharmacodynamic measures
Authors: Lingford-Hughes, A
Durant, C
Paterson, L
Turton, S
Venkataraman, A
Wilson, S
Myers, J
Muthukumaraswamy, S
Mick, I
Paterson, S
Jones, T
Nahar, L
Cordero, R
Nutt, D
Item Type: Journal Article
Abstract: Background: The role of GABA-B neurotransmission in addiction has recently received increased attention, with clinical trials indicating that baclofen, a GABA-B receptor agonist, may reduce alcohol consumption, craving and promote abstinence. However, the optimal dose to treat alcohol dependence is unclear with patients requesting and tolerating much higher doses of baclofen, compared with other clinical uses. We assessed the pharmacokinetics and pharmacodynamics (PK/PD) of baclofen to provide insight into GABA-B sensitivity in this patient group, relative to controls. Methods: Male healthy volunteers (controls, n = 12) and abstinent alcohol dependent individuals (AD, n = 8) received single oral doses of baclofen or placebo in a 3-way crossover design. Controls received placebo/10 mg/60 mg baclofen in a randomized, double-blind design, AD received placebo/60 mg/90 mg baclofen in a single-blind design. PK/PD measures were recorded at baseline and multiple time-points up to 6 h post-dosing, including plasma baclofen, plasma growth hormone (GH), Subjective High Assessment Scale (SHAS) and biphasic alcohol effects scale (BAES). Repeated measures ANOVA analysis explored “change from baseline” dose, time, group, and interaction effects, t-tests compared peak effects. Results: Dose-dependent effects of baclofen on PK and PD measures were observed in both control and AD groups. Whilst there were no significant group differences in any baclofen PK parameters (t1/2, tmax, Cmax, AUC), marked differences in PD effects were clearly evident. In controls, 60 mg baclofen significantly increased total SHAS and BAES scores, and significantly increased plasma GH levels compared with placebo, with peak effects at 60–120 min, in line with its PK profile. In AD, 60 mg baclofen had limited effects on these parameters; SHAS scores, BAES scores and plasma GH levels were significantly blunted compared with controls (significant group*time interactions P = 0.0014, 0.0015 and P < 0.0001, respectively). Conclusions: Our study shows blunted sensitivity to baclofen in AD relative to controls, with no difference in PK suggesting a lower GABA-B receptor sensitivity. This may explain why higher baclofen doses are requested and tolerated in the treatment of alcohol dependence. Our data has implications for choice of dose in future clinical trials in AD and possibly other substances of dependence.
Issue Date: 14-Dec-2018
Date of Acceptance: 19-Nov-2018
URI: http://hdl.handle.net/10044/1/66465
DOI: https://dx.doi.org/10.3389/fpsyt.2018.00664
ISSN: 1664-0640
Publisher: Frontiers Media
Journal / Book Title: Frontiers in Psychiatry
Volume: 9
Copyright Statement: © 2018 Durant, Paterson, Turton, Wilson, Myers, Muthukumaraswamy, Venkataraman, Mick, Paterson, Jones, Nahar, Cordero, Nutt and Lingford-Hughes. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Sponsor/Funder: Medical Research Council (MRC)
Funder's Grant Number: G1002226
Keywords: Science & Technology
Life Sciences & Biomedicine
Psychiatry
baclofen (PubChem CID: 2284)
addiction
pharmacodynamic (PD)
pharmacokinetic (PK)
alcohol use disorder (AUD)
GABA-B receptor
EEG
growth hormone
HIGH-DOSE BACLOFEN
GROWTH-HORMONE RESPONSE
DOUBLE-BLIND
INTRAVENOUS BACLOFEN
CLINICAL TOLERANCE
ORAL BACLOFEN
GH SECRETION
PLACEBO
DRUG
SAFETY
EEG
GABA-B receptor
addiction
alcohol use disorder (AUD)
baclofen (PubChem CID: 2284)
growth hormone
pharmacodynamic (PD)
pharmacokinetic (PK)
Publication Status: Published
Article Number: ARTN 664
Appears in Collections:Department of Medicine
Faculty of Medicine



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