Using Baclofen to Explore GABA-B Receptor Function in Alcohol Dependence: Insights From Pharmacokinetic and Pharmacodynamic Measures

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.

Is R(+)‐Baclofen the best option for the future of Baclofen in alcohol dependence pharmacotherapy? Insights from the preclinical side

“…The Cagliari Consensus statement suggested that RS(±)‐Baclofen's superiority over placebo is yet to be established, and further knowledge of dose‐response relationships is required 11 . Controversial data about RS(±)‐Baclofen efficacy in AD may come from numerous parameters such as the optimal dose, highly variable plasma levels of RS(±)‐Baclofen, levels of comorbid anxiety, clinical endpoints (abstinence versus intake reduction), lack of identification of responder characteristics, and AD severity 12‐15 . Regarding highly variable plasma levels of RS(±)‐Baclofen in AD patients, no study has been able to identify factors explaining inter‐individual variability 16,17 …”

Genome-wide association study for circulating FGF21 in patients with alcohol use disorder: Molecular links between the SNHG16 locus and catecholamine metabolism

“…The iPSC-derived brain organoids are composed of multiple brain cell types, including neurons, oligodendrocytes, astrocytes, and microglia, and the cell composition varies over time during differentiation. It should also be emphasized that the concentrations of drugs used in our cell culture studies were within the range of clinical use concentrations [ [19] , [20] , [21] , [22] , [23] , 40 ]. Obviously, further study will be needed to perform full dose–response curves and a time course to verify optional treatment conditions.…”

“…This concentration is considered physiologically relevant for EtOH use, with 25 mM EtOH being slightly higher than the 0.08% blood alcohol concentration often used as a measure of intoxication [ 18 ]. The concentrations of naltrexone (30 nM) [ 19 ], acamprosate (5 μM) [ 19 ], nalmefene (70 nM) [ 20 ], baclofen (1 μM) [ 21 ], topiramate (5 μM) [ 22 ], and gabapentin (30 μM) [ 23 ] used to conduct these experiments were selected to fall within the range of blood drug concentrations in patients taking standard clinical doses of these drugs. Cells were treated with drugs for 7 days, with a daily medium change.…”

Unraveling Autocrine Signaling Pathways through Metabolic Fingerprinting in Serous Ovarian Cancer Cells

“…Our results, presented here indicate that the antagonists of these metabolism-derived ligands can effectively disrupt the autocrine signaling loop and inhibit ovarian cancer cell proliferation ( Figure 7 , Figure 8 , Figure 9 , Figure 10 and Figure 11 ). In this context, it should be noted here that baclofen, a selective agonist for GABA B receptor [ 83 ], has been shown to inhibit cell proliferation in SKOV3 cells [ 84 ], a cell line that represent clear cell carcinoma of the ovary [ 51 ]. Contrary to this observation, our studies indicate that the GABA B -antagonist inhibit cell proliferation in multiple ovarian cancer cell lines representing HGSOC ( Figure 7 ).…”