Moderation of baclofen response by a GABA<sub>B</sub> receptor polymorphism: results from the BacALD randomized controlled trial

Morley, Kirsten C.; Luquin, Natasha; Baillie, Andrew; Is, Fraser; Trent, Ronald J.; Dore, Glenys; Phung, Nghi; Haber, Paul

doi:10.1111/add.14373

Cited by 19 publications

(10 citation statements)

References 22 publications

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“…It is possible that genetic factors may contribute to the variability in PK and PD effects of baclofen. For example a polymorphism in the ABC transporter gene A BCC9 is associated with greater clearance of baclofen (75), and the GABBRI polymorphism, rs29220, has been reported to modulate response to baclofen, with CC carriers deriving greater benefit with fewer side-effects compared with G-carriers (76, 77). Unfortunately we did not genotype our participants.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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“…N-type calcium channel deletions and GABA B receptor gene variations alter alcohol reward and consumption behavior [37,36]. Moreover, GABA B receptor polymorphisms influence the response to baclofen and its adverse effects in the treatment of alcohol dependence [38]. Thus, N-type calcium channel and GABA B receptor gene polymorphisms may also contribute to phenibut dependence.…”

Section: Eventmentioning

confidence: 99%

Safety and Tolerability of the Anxiolytic and Nootropic Drug Phenibut: A Systematic Review of Clinical Trials and Case Reports

et al. 2020

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Phenibut is a nootropic drug that exerts anxiolytic and antinociceptive effects by acting on the GABAB receptor and the α2-δ subunit of voltage-dependent calcium channels. An increased number of reports of dependence to and intoxication by phenibut purchased online on the one hand and the wide prescription of phenibut in Eastern Europe for more than half a century on the other hand have resulted in a number of controversies regarding its use. In this review, we have summarized currently available information from case reports of phenibut dependence and intoxication and safety data from clinical trials. We included 14 dependence and intoxication case reports (16 patients) and reviewed 11 phenibut clinical trials (583 patients). The clinical symptoms in the case reports included cardiovascular effects, insomnia, anxiety and agitation, hallucinations, and depressed level of consciousness. In addition, the doses used (0.5–100 g/day) were much higher than the recommended daily dose (0.25–2 g/day). An analysis of phenibut side effects described in the clinical trials showed adverse events in only 5.66% of patients, and the most reported side effect was somnolence (1.89%). There are discrepancies in the reported side effects of phenibut in clinical trials compared to those reported in cases of online-purchased phenibut dependence and intoxication. The current systematic review provides evidence that, at therapeutic doses, phenibut is safe and well tolerated with minor adverse effects, but questions regarding the quality of phenibut obtained online and the contribution of alcohol and other drug abuse to phenibut dependence and intoxication remain open.

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“…In der BacALD-Studie wurde für Baclofen die Relevanz des RS29220-SNP im GABAB-Rezeptor für den Therapieerfolg und möglicherweise auch für Unverträglichkeitsreaktionen für Baclofen gezeigt [68].…”

Section: Pharmakogenetikunclassified

Pharmakotherapie der Alkoholentwöhnung: Update und neue Entwicklungen

Soyka

Rösner

2020

Nervenarzt

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Bislang sind nur wenige Medikamente zur pharmakologischen Rückfallprophylaxe der Alkoholabhängigkeit zugelassen. Neben dem in Deutschland nicht mehr vertriebenen Disulfiram sind es die Opioidantagonisten Naltrexon und Nalmefen sowie das vermutlich über glutamaterge Neurone wirkende Acamprosat. Baclofen und γ‑Hydroxybutyrat (GHB) sind in einzelnen Ländern zugelassen. Wirkstoffe wie z. B. Vareniclin, Gabapentin und Topiramat können für die Rückfallprophylaxe der Alkoholabhängigkeit von Interesse sein, jedoch ist bislang keine Zulassung erfolgt. Vor dem Hintergrund der zur Revision anstehenden S3-Leitlinie zur Diagnose und Behandlung alkoholbezogener Störungen wird der heutige Kenntnisstand zur Pharmakotherapie der Alkoholabhängigkeit dargestellt.

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Moderation of baclofen response by a GABA_B receptor polymorphism: results from the BacALD randomized controlled trial

Abstract: The GABBR1 rs29220 polymorphism may influence treatment response and possibly predict adverse effects to baclofen in the treatment of alcohol dependence.

Cited by 19 publications

References 22 publications

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

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

Safety and Tolerability of the Anxiolytic and Nootropic Drug Phenibut: A Systematic Review of Clinical Trials and Case Reports

Pharmakotherapie der Alkoholentwöhnung: Update und neue Entwicklungen

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Moderation of baclofen response by a GABAB receptor polymorphism: results from the BacALD randomized controlled trial

Abstract: The GABBR1 rs29220 polymorphism may influence treatment response and possibly predict adverse effects to baclofen in the treatment of alcohol dependence.

Cited by 19 publications

References 22 publications

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

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

Safety and Tolerability of the Anxiolytic and Nootropic Drug Phenibut: A Systematic Review of Clinical Trials and Case Reports

Pharmakotherapie der Alkoholentwöhnung: Update und neue Entwicklungen

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Moderation of baclofen response by a GABA_B receptor polymorphism: results from the BacALD randomized controlled trial