Robert MacLaren, MPH, PharmD
University of Colorado Skaggs School of Pharmacy
Aurora, CO
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Richard Radcliffe, PhD
Professor
University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, United States
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.jpg "Edward Van Matre, BCCCP, MS, PharmD photo")
Edward Van Matre, BCCCP, MS, PharmD
Assistant Professor
University of Tennessee College of Pharmacy
Memphis, Tennessee
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Scott Mueller, PharmD, BCCCP,FCCM
Associate Professor
University of Colorado Skaggs School of Pharmacy, United States
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Nichole Reisdorph, PhD
Professor
University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, United States
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Rick Reisdorph, PhD
Associate Professor
University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, United States
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Kevin Quinn, PhD
Senior Research Associate
University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, United States
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Katrina Doenges, MS
Senior Research Associate
University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, United States
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Title: Symptom Control and Metabolomics of Diazepam, Ketamine and Dexmedetomidine in Alcohol Withdrawal
Introduction: Conventional therapies for managing alcohol withdrawal target gamma-aminobutyric acid (GABA) mediated neuro-inhibition. Dexmedetomidine (dex) and ketamine reduce neuro-excitation by stimulating alpha-2 (A2) and inhibiting N-methyl-D-aspartate (NMDA), respectively. Using a murine model, this study assessed symptom control and metabolomics of brain structures after drug combinations that modulate GABA (diazepam), A2 (dex), and NMDA (ketamine).
Methods: To induce dependence, 72 mice received an alcohol-rich diet. Nine mice served as control. On day 13, mice received intraperitoneal injections of diazepam 2mg/kg or placebo four hours after the alcohol diet was stopped followed by dex 50microg/kg or placebo and ketamine 10mg/kg or placebo an hour later for a total of eight intervention groups. Symptom control was assessed hourly in 42 mice for 12 hours using the tailspin method (peak severity score of 17). Tukey-Kramer test analyzed withdrawal scores at each time point and area under the withdrawal curve (AUCw) for 12 hours across all groups. Unbiased and targeted metabolomics were performed on the frontal lobe (FL), hippocampus (HC), and locus coerulus (LC) in 30 mice that were sacrificed three hours after the last study drug. Comparisons between groups used ANOVA with FDR correction.
Results: Groups receiving diazepam exhibited less severe alcohol withdrawal than other groups (mean peak scores of 3.3-6.5 vs. 7-7.8, p< 0.05). The addition of dex to diazepam further reduced the severity of withdrawal although not significantly more than diazepam alone. AUCw values were significantly lower across all groups receiving diazepam. Normalized intensity values of epinephrine were higher in the FL (p=0.022), HC (p=0.016), and LC (p=0.076) in groups receiving dex. Norepinephrine intensity values were higher only in the HC (p=0.016) for groups receiving dex. Metabolomics of dopamine, GABA, glutamine, NMDA, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, and acetylcholine were similar between groups for each brain structure.
Conclusions: GABA modulation is critical for managing alcohol withdrawal. A2 stimulation with dex may provide additional symptom control by centrally modulating epinephrine and norepinephrine. Studies should ascertain optimal combinations of these therapies.