Gabapentin for the treatment of alcohol use disorder

Mason, Barbara J.; Quello, Susan; Shadan, Farhad F.

doi:10.1080/13543784.2018.1417383

Cited by 85 publications

(88 citation statements)

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“…Because of the structural similarities between gabapentinoids and GABA, and the known influence of the M-current in many of the disease states responsive to gabapentinoids (epilepsy, pain, anxiety, alcohol withdrawal) (Blackburn-Munro et al, 2005; Kang et al, 2017;Mason et al, 2018), we hypothesized that gabapentinoids might modulate KCNQ2/3 channels. Here, using This article has not been copyedited and formatted.…”

Section: Introductionmentioning

confidence: 99%

“…We found that, like the anticonvulsant retigabine (Kim et al, 2015;Schenzer et al, 2005), GABA binds to a conserved tryptophan (W265) on KCNQ3 to activate KCNQ3 homomers and KCNQ2/3 heteromers (Manville et al, 2018) (Fig. 1B-D).Because of the structural similarities between gabapentinoids and GABA, and the known influence of the M-current in many of the disease states responsive to gabapentinoids (epilepsy, pain, anxiety, alcohol withdrawal) (Blackburn-Munro et al, 2005; Kang et al, 2017;Mason et al, 2018), we hypothesized that gabapentinoids might modulate KCNQ2/3 channels. Here, using This article has not been copyedited and formatted.…”

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confidence: 99%

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Gabapentin Is a Potent Activator of KCNQ3 and KCNQ5 Potassium Channels

Manville

Abbott

2018

Mol Pharmacol

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IntroductionGabapentin (Neurontin) and pregabalin (Lyrica) are synthetic antiepileptic and antinociceptive gabapentinoid compounds originally designed as analogues of the neurotransmitter γ-aminobutyric acid (GABA), and both are in widespread clinical use (Calandre et al., 2016). However, the mechanisms of action of gabapentinoids, exemplified by gabapentin and pregabalin, are incompletely understood. [ 3 H]-gabapentin binding was first described in membrane fractions from rat brain homogenates, and the target protein identified as the α2-δ subunit of voltage-gated calcium (CaV) channels. The findings were later recapitulated using porcine brain tissue, heterologously expressed α2-δ, and also with pregabalin; binding was found to be exclusive to α2-δ1 and 2 isoforms (Brown and Gee, 1998; Field et al., 2006; Fuller-Bicer et al., 2009; Gee et al., This article has not been copyedited and formatted. The final version may differ from this version.Molecular Pharmacology Fast Forward. Published on as DOI: 10.1124 at ASPET Journals on April 27, 2019 molpharm.aspetjournals.org Downloaded from MOL #112953 4 1996). Gabapentin and pregabalin are generally considered inactive against canonical GABAA and GABAB receptors, despite their structural similarity to GABA (Ben-Menachem, 2004; Jensen et al., 2002; Lanneau et al., 2001;Stringer and Lorenzo, 1999;Taylor, 1997), although some investigators contend that there are some subtype-specific effects on GABAB receptors (Bertrand et al., 2003a;Ng et al., 2001;Parker et al., 2004). Binding of gabapentin and pregabalin to α2-δ is suggested to act therapeutically via impairment of Cav channel activity, thus reducing neuronal calcium currents (Stefani et al., 1998;Stefani et al., 2001), although others observed no evidence for gabapentin-induced changes in neuronal Cav activity (Rock et al., 1993;Schumacher et al., 1998).We recently made the unexpected discovery that GABA can activate voltage-gated potassium (Kv) channels composed of heteromeric assemblies of KCNQ2 (Kv7.2) and KCNQ3 (Kv7.3) poreforming α subunits (Manville et al., 2018). KCNQ (Kv7) channels comprise tetramers of α subunits, each containing six transmembrane (S) segments, organized into the voltage-sensing domain (VSD, S1-4) and the pore module (S5-6) ( Fig. 1 A, B). In vertebrate nervous systems, KCNQ2/3 (Kv7.2/3) heteromers are the primary molecular correlate of the M-current, a muscarinicinhibited Kv current essential for regulating excitability of a wide range of neurons throughout the nervous system (Brown and Adams, 1980;Marrion et al., 1989;Wang et al., 1998). We found that, like the anticonvulsant retigabine (Kim et al., 2015;Schenzer et al., 2005), GABA binds to a conserved tryptophan (W265) on KCNQ3 to activate KCNQ3 homomers and KCNQ2/3 heteromers (Manville et al., 2018) (Fig. 1B-D).Because of the structural similarities between gabapentinoids and GABA, and the known influence of the M-current in many of the disease states responsive to gabapentinoids (epilepsy, pain, anxiety, alcohol withdrawal) (Bla...

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Section: Introductionmentioning

confidence: 99%

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confidence: 99%

Gabapentin Is a Potent Activator of KCNQ3 and KCNQ5 Potassium Channels

Manville

Abbott

2018

Mol Pharmacol

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“…• It reduces the release of glutamate, a key component of the excitatory system 16 • It increases the concentration of gammaaminobutyric acid (GABA), the main inhibitory neurotransmitter in the brain 7 • By binding the alpha-2-delta type 1 subunit of voltage-sensitive calcium channels, 8,[15][16][17] it inhibits excitatory synapse formation independent of calcium channel activity 16 • By blocking excitatory neurotransmission, it also may indirectly increase the concentration of GABA in the central nervous system 16,17 • It modulates action of glutamic acid decarboxylase (involved in the synthesis of GABA) and glutamate synthesizing enzyme to increase GABA and decrease glutamate. 17…”

Section: ■ Gabapentin Reduces Excitationmentioning

confidence: 99%

“…18 Alpha-2-delta type 1 subunits of calcium channels are upregulated in the reward centers of the brain by addictive substances, including alcohol. 16 Alcohol interacts with corticotropin-releasing factor and several neurotransmitters, 18 and specifi cally affects neuropathways involving norepinephrine, GABA, and glutamate. 19 Alcohol has reinforcing effects mediated by the release of dopamine in the nucleus accumbens.…”

Section: Modesto-lowe and Colleagues ■ Alcohol's Actionsmentioning

confidence: 99%

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Gabapentin for alcohol use disorder: A good option, or cause for concern?

Modesto‐Lowe

Barron

Aronow

et al. 2019

CCJM

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P erceptions regarding the use of gabapentin for alcohol use disorder (AUD) have shifted over time. 1-4 Early on, the drug was deemed to be benign and effective. 4-6 But more and more, concerns are being raised about its recreational use to achieve euphoria, 7 and the drug is often misused by vulnerable populations, particularly those with opioid use disorder. 7-9 Given the large number of gabapentin prescriptions written off-label for AUD, it is incumbent on providers to understand how to prescribe it responsibly. 7-9 To that end, this article focuses on the benefi tsand concerns-of this treatment option. We describe the effects of gabapentin on the central nervous system and how it may mitigate alcohol withdrawal and increase the likelihood of abstinence. In addition, we review clinical trials that evaluated potential roles of gabapentin in AUD, discuss the drug's misuse potential, and suggest a framework for its appropriate use in AUD management. ■ ALCOHOL USE DISORDER IS COMMON AND SERIOUS AUD affects about 14% of US adults and represents a signifi cant health burden, 1 often with severe clinical and social implications. It manifests as compulsive drinking and loss of control despite adverse consequences on various life domains. 10 It is generally associated with cravings, tolerance, and withdrawal symptoms upon cessation. Alcohol withdrawal is characterized by tremors, anxiety, sweating, nausea, and tachycardia, and in severe cases, may involve hallucinations, seizures, and delirium tremens. Untreated, alcohol withdrawal can be fatal. 10

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Gabapentinoids for treatment of alcohol use disorder: A systematic review and meta‐analysis

Cheng

Huang

2020

Human Psychopharmacology

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Objective Gabapentin (GBP) and pregabalin (PGB) have been used to treat alcohol use disorder (AUD) and alcohol withdrawal, but with inconsistent results. In this meta‐analysis, we explored the effects of GBP/PGB treatment on AUD and their effects on withdrawal, craving, depression, and sleep disturbance in AUD patients. Methods We carried out a systematic review and meta‐analysis of randomized controlled trials comparing the effects of GBP/PGB on AUD with those of a placebo or control treatment. Electronic databases were searched for relevant articles published before September 2019. The primary outcome was defined as the efficacy measure on achieving abstinence or reducing alcohol consumption in a hierarchical order. We included 16 studies in our meta‐analysis. Results Overall, GBP had no significant benefit comparing to placebo or control treatment (Hedges' g = 0.0725, p = 0.6743). For specific alcohol‐related outcome, GBP had significant effect on percentage of heavy drink (Hedges' g = 0.5478, p = 0.0441) and alcohol withdrawal symptoms (Hedges' g = 0.2475, p = 0.0425). GBP/PGB did not have significant beneficial effect on craving, depressive symptoms, or sleep disturbance. Instability was shown in sensitivity analyses of some above results. Conclusions GBP may be helpful to reduce AUD patients' heavy drinking behavior and withdrawal, but more studies are needed for drawing conclusions.

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Gabapentin for the treatment of alcohol use disorder

Cited by 85 publications

References 97 publications

Gabapentin Is a Potent Activator of KCNQ3 and KCNQ5 Potassium Channels

Gabapentin Is a Potent Activator of KCNQ3 and KCNQ5 Potassium Channels

Gabapentin for alcohol use disorder: A good option, or cause for concern?

Gabapentinoids for treatment of alcohol use disorder: A systematic review and meta‐analysis

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