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Topiramate Pharmacotherapy for Alcohol Use Disorder and Other

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CE: ; JAM-D-16-00049; Total nos of Pages: 16; JAM-D-16-00049 REVIEW Topiramate Pharmacotherapy for Alcohol Use Disorder and Other Addictions: A Narrative Review Ajay Manhapra, MD, Anirban Chakraborty, MBBS, and Albert J. Arias, MD, MS 08/15/2018 on pR0X8mps8emMFe6SSjULcOvZdU7Lq92sVezWUqbDpikBtBa8dPs+x8jFMo+CspZ5E+TY5YMZQKrQAwY1b8dC/CITypGBtyI/TuXrHp5+MNSsd6YOAns1MMj9Atc5CqXrWirhh/uUTYs= by https://journals.lww.com/journaladdictionmedicine from Downloaded Downloaded from Patra, 2010). SUDs are often chronic diseases with complex https://journals.lww.com/journaladdictionmedicine Topiramate is a non-benzodiazepine anticonvulsant medication with neurobiological underpinnings resulting in varied behavioral multi-faceted pharmacologic action. It has emerged as an efficacious and psychosocial problems posing significant treatment chal- pharmacotherapeutic option for the treatment of addiction, especially lenges to clinicians. Investigations into pharmacological treat- alcohol use disorder (AUD). We present a broad narrative review of ment of SUDs have not yielded a ‘‘magic bullet,’’ but led to the putative mechanism of action and clinical utility of topiramate the development of multiple pharmacotherapeutic agents, with regard to AUD and other substance use disorders. Collective putatively targeting different components of the disease pro- evidence suggests topiramate is an effective treatment option in cess (ie, craving, euphoria from the substance). AUD, with notable efficacy in reducing harmful drinking patterns Non-benzodiazepine anticonvulsant medications with by pR0X8mps8emMFe6SSjULcOvZdU7Lq92sVezWUqbDpikBtBa8dPs+x8jFMo+CspZ5E+TY5YMZQKrQAwY1b8dC/CITypGBtyI/TuXrHp5+MNSsd6YOAns1MMj9Atc5CqXrWirhh/uUTYs= in AUD. Though not currently approved by the United States Food their effects on glutamatergic and GABAergic neurotransmis- and Drug Administration for the indication of AUD, topiramate sion, have broad therapeutic benefits in the treatment of AUD should be considered as a pharmacological treatment option with with regard to both withdrawal and relapse prevention, and high utility among AUD patients. Early pharmacogenetic studies with varying degrees of effectiveness (Hammond et al., 2015; raise the intriguing possibility of identifying patients likely to Pani et al., 2014). Topiramate appears to be an effective respond to topiramate using genetic testing, and initial studies show treatment option in AUD, and is emerging as a possible option that topiramate may also be useful in treating cocaine use disorder, in the management of other SUDs (Johnson and Ait-Daoud, smoking cessation and behavioral addictions. However, further 2010). Here we provide a narrative review of the possible research is needed in all these areas. utilities of topiramate in AUD and other SUDs. Key Words: alcohol dependence, alcohol use disorder, alcoholism, SEARCH METHODOLOGY anticonvulsant, medication treatment, Topiramate We conducted a series of English-language medical (J Addict Med 2018;xx: xxx–xxx) literature searches using the PubMed, Cochrane Library, and PsycINFO databases using the following search terms: lcohol and other substance use disorders (AUD, SUDs) ‘‘topiramate,’’ ‘‘topiramate þ substance abuse/substance use A are highly prevalent in the United States and also disorder/addiction/withdrawal/side-effects/alcohol/alcohol globally, imposing a tremendous burden on society (Meri- use disorder/alcohol dependence/cocaine/nicotine/smoking/ kangas and McClair, 2012; Sacks et al., 2015; United Nations gambling/eating disorder.’’ Studies involving humans only, Office on Drugs and Crime, 2017). AUD is a significant health published up to September 2017 were included in the review. problem in the United States with a 13.9% 12-month and All study designs, namely meta-analysis, randomized control 29.1% lifetime prevalence (Grant et al., 2015). The 12-month trials, open trials, case series and case reports were included prevalence for AUD reported globally is up to 16% (Rehm and for review. We manually searched the reference lists of pertinent original research articles, review articles, and text- books for additional relevant citations. From the VA Hampton Medical Center, Hampton, VA (AM); VAConnecticut Healthcare System, West Haven (AM, AJA); Department of Psychiatry, MECHANISM OF ACTION Yale School of Medicine, New Haven (AM, AC, AJA); VA New England Mental Illness Research and Education Center, West Haven, CT (AM, Topiramate is a fructose-1,6-diphosphate analogue and AJA). was initially developed as an anti-diabetic drug but was later Received for publication March 1, 2016; accepted June 1, 2018. developed as an anti-convulsant due to its similarity with Ajay Manhapra was supported by the VA/OAA Interprofessional Advanced acetazolamide. Topiramate acts as a positive allostatic mod- Fellowship in Addiction Treatment, and Research in Addiction Medicine on ulator at GABAA receptors, which are activated causing 08/15/2018 Scholars (RAMS) Program, R25DA033211 from the National Institute on Drug Abuse. VA New England Mental Illness Research and Education increased chloride ion influx into neurons, thus increasing Center, West Haven, CT supported this review. overall GABA mediated inhibition (White, 2003). These activ- The authors have no financial or other conflicts of interests to report. ities are probably mediated through non-benzodiazepine bind- Send correspondence to Albert J. Arias, MD, MS, 950 Campbell Rd #116A, ing sites on GABAA receptors (White et al., 2000). GABA West Haven, CT 06516. E-mail: [email protected]. levels in the brain are also increased. Topiramate is a non- Copyright ß 2018 American Society of Addiction Medicine ISSN: 1932-0620/16/0000-0001 competitive antagonist of a-amino-3-hydroxy-5-methyl-4-iso- DOI: 10.1097/ADM.0000000000000443 xazolepropionic acid (AMPA)/kainate mediated glutamate J Addict Med Volume 00, Number 00, Month/Month 2018 1 Copyright © 2018 American Society of Addiction Medicine. Unauthorized reproduction of this article is prohibited. CE: ; JAM-D-16-00049; Total nos of Pages: 16; JAM-D-16-00049 Manhapra et al. J Addict Med Volume 00, Number 00, Month/Month 2018 receptors causing blockage of glutamate-mediated neuroexci- side effect. Carbonic anhydrase (CA) activity inhibition has tation, but has no effect on NMDA-sensitive glutamate recep- been implicated in several of these adverse effects. CA tors (Angehagen et al., 2005). In addition, topiramate limits inhibition in the kidneys is the obvious driver of metabolic depolarization and excitability at voltage-activated Naþ chan- acidosis associated with topiramate and Type 3 renal tubular nels, causing inhibition of high and repetitive action potential acidosis which has also been reported in association with CA discharges. Topiramate also inhibits L-type Ca2þ channels inhibition (Garris and Oles, 2005; Sacre´ et al., 2006). CA reducing neurotransmitter release and Ca2þ-dependent second inhibition locally and preferentially at sensory neuronal end- messenger systems (Zhang et al., 2000). Consistent with its ings leading to acidosis and resulting ectopic activation of structural similarity to acetazolamide, it also inhibits Types II sensory neurons has been implicated in parasthesias (unpleas- and IV carbonic anhydrase, leading to inhibition of hydrogen ant tingling in extremities) associated with topiramate (Fujii ion secretion by renal tubules, and increasing secretion of Naþ, et al., 1993; Spitzer et al., 2002; Swietach et al., 2003). Renal þ À K , HCO3 , and water (Dodgson et al., 2000). calculi occur at a 2- to 4-fold higher rate among those on The effects of topiramate on pathways involved in topiramate, and are thought to be due to an increase in urinary addiction have been elucidated to some extent, but hypotheses pH caused by increased excretion of bicarbonates and about how it affects the addicted brain remain largely specu- decreased citrate excretion that promotes precipitation of lative and have not been fully explored in the context of calcium salts (calcium phosphate) (Welch et al., 2006). translational studies (Johnson, 2005; Johnson and Ait-Daoud, Oligohydrosis is a rare but serious risk of topiramate 2010; Johnson, 2008). Topiramate is thought to alter the treatment. Oligohydrosis (insufficient sweating associated reinforcing properties and subjective experience of drugs with heat or exercise) has been attributed to CA inhibition and alcohol, and probably helps to normalize and restore (Cerminara et al., 2006) and inhibition of aquaporin 5 recep- balance in the reward circuits of the brain, thus restoring tors in sweat glands (Ma et al., 2007). Topiramate is preg- proper hedonic function and stress response among chroni- nancy category D, and cleft palate can occur with fetal cally drug or alcohol using persons. Topiramate putatively exposure. Due caution should be exercised with topiramate exerts it effects on midbrain dopaminergic (DA) pathways use in women of childbearing potential; a reliable form of projecting from ventral tegmental area (VTA) to the nucleus birth control should be used as well. accumbens (NAcc) by enhancing GABAergic neurotransmis- Acute visual disturbance, myopia and acute angle clo- sion and antagonizing glutamatergic neurotransmission, lead- sure glaucoma all occur infrequently among those receiving ing to suppression of dopaminergic surges at the NAcc. These topiramate, mostly at the beginning of the treatment (Shank proposed effects have not yet been thoroughly investigated in and Maryanoff, 2008). Cognitive impairment
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