Treatment-refractory substance use disorder: Focus on alcohol, opioids, and
cocaine

Michael Soyka, Jochen Mutschler

PII: S0278-5846(15)30057-9
DOI: doi: 10.1016/j.pnpbp.2015.11.003
Reference: PNP 8850

To appear in: Progress in Neuropsychopharmacology & Biological Psychiatry

Received date: 14 September 2015

Revised date: 23 October 2015
Accepted date: 11 November 2015

Please cite this article as: Soyka Michael, Mutschler Jochen, Treatment-refractory sub-
stance use disorder: Focus on alcohol, opioids, and cocaine, Progress in Neuropsychophar-
macology & Biological Psychiatry (2015), doi: 10.1016/j.pnpbp.2015.11.003

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 ACCEPTED MANUSCRIPT

Treatment-refractory substance use disorder: Focus on alcohol, opioids, and

cocaine
Michael Soyka, MD a, b Jochen Mutschler, MD c

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a
Department of Psychiatry and Psychotherapy
Ludwig Maximilian University

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Nussbaumstrasse 7
80336 Munich, Germany

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b
Privatklinik Meiringen

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Postfach 612
CH – 3860 Meiringen, Switzerland

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c
Center for Addictive Disorders
Department of Psychiatry, Psychotherapy and Psychosomatics
Psychiatric Hospital, University of Zurich
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Selnaustrasse 9
8001 Zurich, Switzerland
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Corresponding author:
Michael Soyka, MD
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Privatklinik Meiringen
Postfach 612
CH–3860 Meiringen
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Switzerland
Tel: +41 33 972 82 95
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Fax: +41 33 972 82 91

Email: michael.soyka@privatklinik-meiringen.ch
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Submitted to: Progress in Neuro-Psychopharmacology & Biological Psychiatry for inclusion in

the Special Issue “Neurobiological understanding and treatment options for treatment-refractory
psychiatric disorders”

Short title: Treatment of substance use disorders

 ACCEPTED MANUSCRIPT

Abstract
Substance use disorders are common, but only a small minority of patients receive adequate
treatment. Although psychosocial therapies are effective, relapse is common. This review
focusses on novel pharmacological and other treatments for patients with alcohol, opioid, or

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cocaine use disorders who do not respond to conventional treatments.

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Disulfiram, acamprosate, and the opioid antagonist naltrexone have been approved for
the treatment of alcoholism. A novel, “as needed” approach is the use of the mu-opioid antagonist

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and partial kappa agonist nalmefene to reduce alcohol consumption. Other novel pharmacological

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approaches include the GABA-B receptor agonist baclofen, anticonvulsants such as topiramate
and gabapentin, the partial nicotine receptor agonist varenicline, and other drugs. For opioid

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dependence, opioid agonist therapy with methadone or buprenorphine is the first-line treatment
option. Other options include oral or depot naltrexone, morphine sulfate, depot or implant
formulations, and heroin (diacetylmorphine) in treatment-refractory patients. To date, no
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pharmacological treatment has been approved for cocaine addiction; however, 3 potential
pharmacological treatments are being studied, disulfiram, methylphenidate, and modafinil.
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Pharmacogenetic approaches may help to optimize treatment response in otherwise

treatment-refractory patients and to identify which patients are more likely to respond to
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treatment, and neuromodulation techniques such as repeated transcranial magnetic stimulation

and deep brain stimulation also may play a role in the treatment of substance use disorders.
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Although no magic bullet is in sight for treatment-refractory patients, some novel

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medications and brain stimulation techniques have the potential to enrich treatment options at
least for some patients.
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Key words: alcoholism, opioid dependence, baclofen, brain stimulation, nalmefene

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1. Introduction
ICD-10 and DSM-IV follow a categorical approach and classify substance use disorders (SUDs)
as abuse (harmful use) or dependence. Substance abuse/harmful use is characterized by somatic
or psychiatric problems (and social problems in DSM-IV but not ICD-10). These classifications

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define dependence by a cluster of somatic, psychological, and behavioral symptoms (APA, 2000;

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WHO, 1992). The recently published DSM-5 has abandoned the categorical distinction between
abuse and dependence and introduced a dimensional approach (APA, 2013). Substance-related

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and addictive disorders are specified by 11 symptoms: 6 or more positive symptoms constitute a

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severe substance use disorder; 4 or 5, a moderate one; and 2 to 3, a mild one. SUDs are associated
with high psychiatric and somatic morbidity, a substantial global burden of morbidity and

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premature death (Gowing et al., 2015).
Numerous studies indicate that SUDs, in particular alcoholism, are common. A recent
report on global statistics of addictive behaviors (Gowing et al., 2015) states that 4.9% of the
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world adult population have an alcohol use disorder (7.8% of men and 1.5% of women), 22.5%
of the adult population smoke tobacco products, and 3.5% use cannabis. The use of other illegal
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psychoactive drugs is less than 1% for each class. The prevalence estimates are 0.2% for opioid
use and 0.5% for both cocaine and amphetamines. Recent European data suggest that 1.9% of
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young Europeans (15-34 years old) have used cocaine at least once in the last 12 months, and 1%
of this group have used amphetamines (EMCDDA, 2015). Opioid use is reported in 0.4% of
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adults (15-64 years old).

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Earlier studies estimated the prevalence of alcoholism to be 7%-10% in Europe and the
USA (Grant et al., 2004; Kessler et al., 2005; Pirkola et al., 2006; Rehm et al., 2005). Using
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DSM-5 criteria, the US National Epidemiologic Survey on Alcohol and Related Conditions II
reported a 12-month and lifetime prevalence for alcohol use disorders of 13.9% and 29.1%,
respectively (Grant et al., 2015). Only 19.8% of affected people had ever been treated. Globally,
prevalence estimates of alcoholism range from 0% to 16% (WHO, 2011).
Opioid dependence is a chronic relapsing disorder with a significant mortality rate
(Degenhardt et al., 2011; Degenhardt et al., 2013; Peles et al., 2010). Epidemiological studies
indicate that the worldwide prevalence of opioid use disorders is about 0.4% in individuals aged
15-64 years and that there are 15.5 million opioid-dependent people worldwide (United Nations
Office on Drugs and Crime, 2006). Epidemiological data suggest that in the European Union
prevalence rates for opioid consumption have declined in recent years (EMCDDA, 2014);
however, still about 1.3 million individuals in the EU have problematic opioid use, with a
prevalence of about 0.4%. The drugs of choice have shifted somewhat from heroin towards other

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opioids, including methadone, buprenorphine, and fentanyl (EMCDDA, 2014). In the USA, some
3.7 million individuals have used heroin at least once in their lives, and 750,000 to 1 million
individuals are currently heroin dependent (Kessler et al., 2012; Kleber et al., 2007). The World
Health Organization (WHO) estimates that the burden of harm from opioid use is 11.2 million

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disability-adjusted life years (DALYs; WHO, 2004). The Global Burden of Disease study

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estimated that the burden of harm from opioid dependence is 9.2 million DALYs (Degenhardt et
al., 2014; Degenhardt et al., 2013). In addition, the USA in particular has an epidemic of opioid

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prescription drug use and has recorded multiple deaths associated with an overdose of opioid pain

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killers, including many accidental poisonings in children (Imtiaz et al., 2014).
Cocaine abuse is becoming increasingly prevalent in western countries. Cocaine is the

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second most common illicit drug (after marihuana) in both the USA and in almost all western
industrial societies. The 12-month prevalence for cocaine use is 1% in Europe, and the lifetime
prevalence is 4.6% (EMCDDA, 2015).
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In contrast to other psychiatric disorders, “treatment-refractory” SUDs have no clear or
operationalized definition. In a recent review on heroin treatment in treatment-refractory heroin
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addiction, Strang et al. (2015) reported studies in patients who “repeatedly failed in orthodox
treatment.” This definition may serve well for this review. Usually, treatment of SUDs has 2
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goals: (1) Complete and continuing abstinence, or (2) reduction of substance use (harm reduction
strategy). Agonist drug maintenance plays an important role in the latter, especially in opioid
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dependence. For pharmacological and other reasons, agonist maintenance treatment is not
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suitable for all drugs of abuse. A recently published excellent and insightful comment on this
topic is provided by Darke and Farrell (2015). Since alcohol, opioid, and cocaine use plays the
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most important role in substance use treatment and causes significant psychiatric and somatic
complications, this narrative will focus on these types of drugs and in particular on new or
emerging treatment options. We identified relevant publications from the years 2005-2015
through a Medline/PubMed search with the terms “pharmacotherapy,” “therapy,” and “brain
stimulation.”

2. Alcoholism
2.1 Neurobiology
The neurobiological basis of alcoholism is complex and has been the subject of intensive research
in recent years (for a review see Noronha et al., 2014). In brief, the neural substrates and
neurocircuitry of alcohol dependence and other drugs of abuse include the limbic system (ventral
tegmentum and nucleus accumbens) and orbito- and prefrontal cortices. Dopamine (DA) release

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in the nucleus accumbens mediates reinforcing effects of drugs of psychoactive drugs (reward
processing); the prefrontal cortex is of relevance for cognitive control and the orbitofrontal cortex
for motivation (Nutt and Nestor, 2013).
Other variables mediating the vulnerability for alcohol dependence are stress or

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sensitivity to stress and neuroendocrine function, especially the hypothalamic-pituitary-adrenal

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(HPA) axis, among others (Heilig and Koob, 2007; Spanagel et al., 2014a; Stephens et al.,
2014).

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Alcohol has different molecular targets and a low affinity to many neuroreceptors. There

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is no specific alcohol receptor or molecular target. Neurotransmitters affected by alcohol include
inhibitory gamma-aminobutyric acid (GABA), the opioid endorphin system, glutamate, the

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endocannabinoid system, noradrenaline, DA, and serotonin (Koob et al., 2014; Spanagel and
Vengeliene, 2013).
There are 3 major classes of opioid receptors: mu (µ), kappa (κ), and delta (δ)
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(Gianoulakis, 2004). Recent research has viewed the opioidergic system as a “hedonic” system. It
is implicated in the development of alcohol use disorders (Nutt, 2014) and mediates the
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reinforcing effects of alcohol by indirectly modulating DA release (Gianoulakis, 2004; Koob et

al., 2014), especially via the mu-opioid receptor subtype (Narita et al., 2001).
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Alcohol stimulates the release of the endogenous opioid receptor ligands beta-endorphin,
enkephalins, and dynorphin (Dai et al., 2005; Marinelli et al., 2005; Marinelli et al., 2006;
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Marinelli et al., 2004). Opioid receptors on GABAergic neurons interact with dopaminergic
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neurons and thus mediate DA release (Koob et al., 2014). Functional neuroimaging data suggest a
negative correlation between mu-opioid receptor binding and alcohol craving (Bencherif et al.,
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2004; Heinz et al., 2005).

3.2 Approved medications

Beside psychosocial therapies, medications can be used to lower relapse risk to heavy drinking,
although pharmacotherapy for alcoholism is still a widely neglected area and few
pharmacotherapies have been approved for treatment of alcoholism to date (Heilig and Egli,
2006; Soyka et al., 2011a; Soyka and Rosner, 2010; Spanagel and Kiefer, 2008).

3.2.1 Disulfiram
For decades, the acetaldehyde dehydrogenase inhibitor disulfiram was the only available drug to
treat alcohol dependence. Disulfiram is described as an aversively-acting agent and induces
negative states through an unpleasant alcohol-disulfiram reaction, mediated by acetaldehyde

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inhibition of hepatic aldehyde dehydrogenase (Ehrenreich and Krampe, 2004; Mutschler et

al., 2011; Soyka et al., 2011a; Soyka and Lieb, 2015). However, evidence for efficacy is
limited, at least in non-supervised settings; supervised treatment with disulfiram produces high
effect sizes, making it an effective and well-established form of pharmacotherapy for relapse

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prevention in alcohol dependence (Skinner et al., 2014). The use of disulfiram has become

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controversial for various reasons, including the safety profile of the drug, patient adherence to
treatment, methodological limitations of former studies, and mainly the psychologically aversive

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nature of the treatment approach itself (Mutschler and Kiefer, 2013).

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3.2.2 Acamprosate

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In the 1990s, the putative N-methyl-D-aspartic acid (NMDA) modulator acamprosate (Maisel et
al., 2013; Rosner et al., 2010a) was introduced into clinical practice for the treatment of
alcoholism. The mechanism of action of acamprosate is not fully understood, but some data
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suggest that modulation of the glutamatergic NMDA receptors is of relevance (Littleton and
Zieglgansberger, 2003). Recent data indicate that the calcium part of the molecule is the only
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active compound, but these findings need to be replicated (Spanagel et al., 2014b). The efficacy
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of acamprosate was hypothesized to be linked to glutamatergic hyperactivity in the CNS

(Gueorguieva et al., 2011).
Clinically, acamprosate is usually safe and well tolerated. A Cochrane analysis suggests
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that the only frequent side effect is diarrhea (Rosner et al., 2010a). Acamprosate is given as 3
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tablets of 333 mg 3 times a day in patients with a bodyweight ≥ 60 kg and 2 tablets twice a day
in patients weighing ≤ 60 kg. The comparatively high number of tablets needed may limit the
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acceptance of acamprosate treatment. Numerous randomized controlled trials (RCTs) on

acamprosate have been performed in more than 4000 patients in total (Rosner et al., 2010a).
Furthermore, several recent meta-analyses have evaluated acamprosate (Jonas et al., 2014;
Rosner et al., 2010a), including 1 Cochrane analysis (Rosner et al., 2010a). Although there are
some important negative studies (Anton et al., 2006; Mann et al., 2013b), the overall data show
moderate but significant effects of acamprosate on abstinence rates or relapse to heavy drinking,
a finding that is supported also by a recent Japanese study (Higuchi, 2015). Studies to date
suggest that acamprosate is associated with a reduction of the risk of returning to alcohol drinking
(Jonas et al., 2014). Unfortunately, acamprosate has not found much acceptance in clinical
practice (Knudsen and Roman, 2014; Zindel and Kranzler, 2014).

3.2.3 Naltrexone

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The opioid antagonist naltrexone (Maisel et al., 2013) was introduced into clinical practice also in
the 1990s. Opioid antagonists have been studied extensively in alcoholism. The nonselective
opioid antagonist naltrexone is orally active and administered as a 50 mg tablet once a day.
Naltrexone is licensed and covered by health insurance in many countries. In the USA, naltrexone

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is also available in a depot formulation (Lobmaier et al., 2011). Naltrexone reduces the
“pleasant,” rewarding effects of alcohol. Numerous studies have been performed on naltrexone

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(Rosner et al., 2010b), especially in combination with psychotherapy (Jarosz et al., 2013). Similar

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to acamprosate, oral naltrexone reduces the risk of returning to drinking alcohol (Donoghue et

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al., 2015; Jonas et al., 2014); however, it also is not well accepted in clinical practice (Knudsen
and Roman, 2014; Zindel and Kranzler, 2014). There also are some recent conflicting data

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(O'Malley et al., 2015). Recently, the combination of naltrexone with the alpha adrenergic
antagonist prazosin as an daily or “as needed” treatment was studied, with some
encouraging results in the animal model (Froehlich et al., 2013; Rasmussen et al., 2015).
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3.3. New pharmacological developments

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A substantial number of preclinical and clinical compounds are currently under investigation for
the treatment of alcoholism (for a review see Davies et al., 2013; Franck and Jayaram-Lindstrom,
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2013; Litten et al., 2014; Muller et al., 2014; Spanagel and Vengeliene, 2013; Zindel and
Kranzler, 2014), although progress is slow (Litten et al., 2014). Some medications have been
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approved recently or are particularly useful in otherwise refractory or difficult-to-treat patients.

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3.3.1. Nalmefene
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Nalmefene was approved in the US in the 1990s for the treatment of opioid overdose. In 2012, it
became the first medication explicitly approved by the European Medicines Agency for the
reduction of alcohol intake (EMA, 2014). It is an antagonist at the mu- and delta-opioid receptor
(Emmerson et al., 1994; Niciu and Arias, 2013) and a partial agonist at the kappa receptor (Bart
et al., 2005). The functional relevance of the kappa receptor in alcoholism is somehow unclear,
but evidence suggests that it may be of relevance for motivational aspects (Walker and Koob,
2008; Walker et al., 2012; Walker et al., 2011). The oral bioavailability of nalmefene is 40%
(EMA, 2014; Ingman et al., 2005).
Neuroimaging data indicate a slow dissociation of nalmefene from the mu-opioid
receptor (Dixon et al., 1987; Ingman et al., 2005), effective binding to central opioid receptors
(Emmerson et al., 1994; Ingman et al., 2005), and a higher bioavailability (Dixon et al., 1987)
compared to naltrexone. There is no evidence for a dose-dependent association with liver toxicity

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(Mason et al., 1999). Preclinical findings suggest that nalmefene is effective in alcoholism (June
et al., 1998; Koob et al., 2003; Walker and Koob, 2008; Walker et al., 2011). Similar to
naltrexone, nalmefene reduces the reinforcing effects or subjective “high” feeling after alcohol
consumption (Drobes et al., 2003; 2004). To date, 6 RCTs have been published on nalmefene

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(Anton et al., 2004; Gual et al., 2013; Karhuvaara et al., 2007; Mann et al., 2013a; Mason et al.,

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1994; Mason et al., 1999), subsequent to some pilot studies with limited statistical power (Mason
et al., 1994; Mason et al., 1999).

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Anton et al. (2004) evaluated 3 doses of nalmefene (5, 20, and 40 mg) in a double-blind

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comparison with placebo over a 12-week treatment period (N=270). Both the nalmefene and
placebo groups showed a reduction in heavy drinking days, and no differences were found

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between the groups on any relevant measures. In contrast, a multicenter, placebo-controlled RCT
by Karhuvaara et al. (2007) in 403 heavy drinkers found significant effects of nalmefene
compared to placebo on the mean number of heavy drinking days. The most common adverse
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events associated with nalmefene were nausea, insomnia, fatigue, and dizziness, all of which are
typical for opioid antagonists.
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Two major placebo-controlled RCTs that explicitly focused on the efficacy of

nalmefene in reducing alcohol use were conducted in Europe (Gual et al., 2013; Mann et al.,
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2013a). Both studies used a novel “as needed” design (i.e. the patients could decide to take the
drug on a daily basis or not) and compared 18 mg nalmefene with placebo.
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Mann et al. (2013a) compared nalmefene with placebo over 6 months in 579 patients
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with alcohol dependence. The study found a significant reduction of total daily alcohol
consumption and heavy drinking days in the nalmefene group. However, the number of patients
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who discontinued treatment was significantly higher in verum group. Again, the main treatment-
emergent adverse events relevant for discontinuation were nausea, dizziness, fatigue, and
headache. Gual et al. (2013) evaluated as-needed use in 718 patients. Patients took study
medication on 65% of the days in the main treatment period. From baseline to month 6, alcohol
consumption decreased and heavy drinking days were reduced significantly in the nalmefene
group compared to the placebo group. In contrast to the Mann et al. (2013a) study, the incidence
of adverse events leading to drop-out was similar in both groups. A subsequent pooled analysis of
the 2 studies (van den Brink et al., 2013) showed that nalmefene was effective in patients who did
not reduce their consumption after the initial assessment.
The novel “as needed” approach used in some of the studies may be attractive for
patients who are “treatment refractory” in other treatment settings and not yet motivated or

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suitable for abstinence-oriented treatment. However, to date the use and clinical efficacy of
nalmefene is still somewhat controversial (Braillon, 2014; Spence, 2014; Swift, 2013).

3.3.2. Topiramate

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Topiramate is an antiepileptic medication approved for the treatment of epilepsy (French et al.,

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2004; Wenzel et al., 2006). Topiramate facilitates the inhibitory action of GABA at its non-
benzodiazepine receptor and reduces the glutamate excitatory action at the α-amino-3-hydroxy-

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5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors (Angehagen et al., 2005;

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White et al., 2000). Its mechanism of action in alcoholism is not entirely clear (Guglielmo et al.,
2015), but it is assumed to decrease the reward effects of alcohol by reducing the mesolimbic

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cortical activity of dopamine (Johnson et al., 2004). Topiramate has a bioavailability of at least
80% and a half-life of about 19 to 23 hours. The most common adverse events include
paresthesia, anorexia, difficulty with memory or concentration, and taste perversion (Johnson and
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Ait-Daoud, 2010). Most side effects are mild to moderate (Johnson, 2005; 2008). Cognitive
impairment may occur (Biton et al., 2001; Johnson, 2005) and has been described also in studies
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in patients with alcoholism (Batki et al., 2014).

A systematic review (Blodgett et al., 2014) included 7 RCTs (N = 1,125 participants)
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that compared topiramate to placebo for the treatment for alcohol use disorders. Overall, this
meta-analysis showed small to moderate effects of topiramate. The largest effect was found on
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abstinence and heavy drinking. Additional studies are available, including a negative one
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(Likhitsathian et al., 2013). Batki et al (2014) studied the effects of topiramate in veterans with
post-traumatic stress disorder (PTSD) and alcohol use disorder; the group reported topiramate to
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be effective in reducing alcohol consumption and craving as well as PTSD symptom severity.
Kranzler et al. (2014a; 2014b) reported moderating effects of a single nucleotide
polymorphism (rs2832407) in GRIK1 that encodes the glutamatergic kainate GluK1 receptor
subunit. The effect on heavy drinking days was significantly greater than for placebo only in the
subgroup of rs2832407 C-allele homozygotes.
In a recent review, Guglilmo et al. (2015) concluded that topiramate shows a greater
beneficial effect in patients with a typology of craving, characterized by drinking obsessions and
automaticity of drinking. The group recommended topiramate (75-300 mg/d) as a first-line
treatment option for alcohol use disorders. A Cochrane review by Pani et al (2014) confirmed the
effects of topiramate on alcohol intake.
Topiramate may be used off label as a second-to-third-line medication in otherwise
treatment-refractory people.

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3.3.3. Gabapentin
Gabapentin is used and approved for the treatment of epilepsy and neuropathic pain. The drug
inhibits presynaptic voltage-gated Na+ and Ca2+ channels (Rogawski and Loscher, 2004) and

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prevents the release of various neurotransmitters, including glutamate (Bonnet et al., 1999;

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Bozikas et al., 2002; Myrick et al., 1998; Rustembegovic et al., 2004; Watson et al., 1997). It may
reduce CNS hyperexcitability and anxiety during alcohol withdrawal (Watson et al., 1997).

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The database on gabapentin in alcohol use disorders is limited. In a recent Cochrane

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review (Pani et al., 2014), it was found to have statistically significant positive effects on heavy
drinking (n=183 participants).

3.3.4. Baclofen
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Baclofen was promoted by the deceased cardiologist Olivier Ameisen, who reported and
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published his experiences of using it in to treat his own alcohol dependence (Ameisen, 2005;
2008). It is an agonist at the B subunit of GABA receptor (GABA-B) and was originally
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approved for use in spasticity associated with neurologic disorders (for a review see Soyka and
Lieb, 2015). GABA neurotransmission is also known to be an important factor in the control of
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anxiety. Following these lines of evidence, activation of GABA-B receptors might reduce anxiety
(Addolorato et al., 2009). Baclofen inhibits dopaminergic neurotransmission via GABA-B
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activation (Addolorato and Leggio, 2010).

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A series of RCTs conducted in Italy and an RCT conducted in the US generated

conflicting results for 30 mg/day baclofen (Addolorato et al., 2000; Addolorato et al., 2002;
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Addolorato et al., 2011; Addolorato et al., 2007; Garbutt et al., 2010; Morley et al., 2014).
Since baclofen has a low ability to cross the blood brain barrier, dosing may be a crucial
issue, because the drug must be titrated to reach higher doses. Previous studies used baclofen in
doses of 30-80 mg. An important but small RCT of high-dose baclofen up to 270 mg, funded by
the Deutsche Forschungsgemeinschaft, was published recently (N=56, Muller et al., 2015); this
study showed a higher abstinence rate and abstinence duration during the high-dose phase. Two
important French studies are currently under way. Baclofen has a temporary approval in France
for the treatment of alcohol-dependent patients for dosages up to 300 mg/d (see Muller et al.,
2015). In contrast to the positive findings, a recent 12-week RCT (N=64, Ponizovsky et al.,
2015) showed negative results. The use of baclofen in this area is not undisputed (Akosile and
Klan, 2015). Safety issues and interactions with alcohol, for example, are of relevance. Sedation
may be an important side effect: Clinical data indicate that the level of sedation in alcohol-

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dependent patients appears directly depended on the immediate doses of alcohol and baclofen
(Rolland et al., 2015). Baclofen has been viewed as a partial substitution in alcoholism (Rolland
et al., 2013). However, withdrawal symptoms or alcohol-like effects have not been reported in
the relevant studies (Addolorato et al., 2002; Garbutt et al., 2010; Muller et al., 2015). Anti-

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craving effects have been described (Imbert et al., 2015). On the basis of the relatively high rate

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of acceptance of baclofen in patients with alcoholism, influenced by the Ameisen monography
and expressed in “baclofen forums” on the web, the drug may be viewed as an alternative strategy

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in otherwise treatment-refractory patients with alcoholism with the main goal of abstinence.

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3.3.5. Varenicline

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Most alcohol-dependent people also smoke (Ait-Daoud et al., 2006; Nocente et al., 2013).
Varenicline is an approved medication for smoking cessation and was reported to lower alcohol-
consumption in smokers (Mitchell et al., 2012); for a review, see Erwin et al. (2014).
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Varenicline is a partial agonist at the α4β2 and full agonist at the α7 nicotinic
acetylcholine receptor in the ventral tegmental area, indirectly modulating dopaminergic
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pathways (Crunelle et al., 2010; Crunelle et al., 2011; Muller et al., 2014; Nocente et al., 2013). It
probably modulates rewarding effects associated with alcohol intake (Ait-Daoud et al., 2006;
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Crunelle et al., 2010; Crunelle et al., 2011; Litten et al., 2013; Mitchell et al., 2012; Nocente et
al., 2013). Nausea is a common adverse effect (Erwin and Slaton, 2014). In a recent systematic
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review, Erwin and Slaton (2014) identified 7 double-blind, placebo-controlled RCTs and 1 open-
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label study assessing the efficacy of varenicline on alcohol intake. In brief, there is some modest
evidence for improved in alcohol consumption, not only in smokers (Plebani et al., 2013).
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The data suggest that varenicline does not increase the percentage of days on which
participants abstain from alcohol but rather limits alcohol consumption after relapsing to alcohol.
The most commonly reported adverse effects are nausea, abnormal dreams, and constipation, all
of which are generally mild (Erwin and Slaton, 2014).
To date, the drug may be recommended for smokers who also want to quit alcohol.

3.3.6. Other medications

In Austria and Italy, sodium oxybate (gamma-hydroxy butyric acid, GHB) is approved for the
treatment of alcohol withdrawal syndrome and alcohol dependence (Keating, 2014). The drug
(“liquid ecstasy”) is a GABA-B agonist and has a significant risk for abuse, diversion, and use as
a “rape drug.” Few studies have been performed in alcohol withdrawal syndrome, but craving for
and abuse of sodium oxybate have been reported in alcohol use disorders (Skala et al., 2014).

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Because of its apparent risks (addictions), the drug cannot be recommended for widespread use in
alcoholism. The WHO (2012) warns against the use of GHB.
A few larger studies have been conducted on the serotonin 5-HT3 receptor antagonist
ondansetron. Johnson et al. (2000) performed a double-blind placebo-controlled RCT in 321

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patients with alcoholism (271 randomized) and found that drinking was reduced only patients

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with early-onset alcoholism. Johnson et al. (2011) reported also that the serotonin transporter
gene may be of relevance for the effects of ondansetron. Individuals with the LL genotype who

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received ondansetron had a lower mean number of drinks and a higher percentage of abstinent

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days than those who received placebo.
The neuroleptic aripiprazole, a partial D2, D3, and 5-HT1a agonist and 5-HT2a

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antagonist, may be of future interest for alcohol use disorders (Anton et al., 2008a; Edwards et
al., 2011). Aripiprazole may reduce alcohol craving and increase abstinence rates, as shown in a
clinical laboratory paradigm (Voronin et al., 2008). Anton et al. (2008a) failed to demonstrate
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superiority of aripiprazole over placebo in the primary endpoints (alcohol consumption, only on
subjective treatment effects).
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Because stress tolerance, cortisol dysregulation, and the HPA stress axis and related
systems play a very significant role in the development of alcoholism (Emsley et al., 2013;
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Heilig and Koob, 2007), these systems may be targets for novel drugs in the treatment of
alcoholism. Corticotrophin releasing factor (CRF) antagonists or other drugs affecting
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neuropeptide Y (NPY) or ghrelin are of potential interest. Clinical trials are ongoing with CRF 1
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antagonists in anxious alcoholics (Zorrilla et al., 2013). Again, the clinical perspective is vague.
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4. Opioid dependence
4.1 Approved medications
4.1.1 Opioid agonists
Opioid maintenance treatment is a well-established first-line approach for opioid dependence.
Methadone, buprenorphine, and the combination of buprenorphine and naloxone (in a 4:1 ratio)
are frequently used (Kleber et al., 2007; Lingford-Hughes et al., 2012; Mammen and Bell, 2009;
Mattick et al., 2009a; 2014; New South Wales Department of Health, 2006; Soyka, 2015; Soyka
et al., 2011a; Soyka et al., 2011b). These treatments have proven efficacy in reducing opioid
consumption and psychosocial and medical morbidity and in increasing treatment retention rates
and social functioning in people with opioid dependence (Mattick et al., 2009b; 2014).

4.1.2 Opioid antagonists

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Oral and (monthly) depot naltrexone are also available for the treatment of opioid-dependent
patients who are clearly abstinence oriented (Adi et al., 2007; Syed and Keating, 2013; Taylor et
al., 2011). However, both formulations are rarely used in opioid-dependent patients. Compliance
to treatment is rather low, at least for the oral formulation. Oral naltrexone appears to have some

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limited benefit in helping formerly opioid-dependent individuals to remain abstinent, as stated in

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a comprehensive review by Adi et al. (2007). Depot naltrexone has been tested in Russia, where
methadone treatment is not available (Krupitsky et al., 2011). During or after naltrexone

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treatment, patients no longer have an increased opioid tolerance, which may result in relapse to

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heroin, opioid overdose, and fatal intoxications. Other concerns include liver damage (Taylor et
al., 2011). Novel opioid antagonists are currently being developed and tested (Giuliano et al.,

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2015).

4.2 Alternative and novel treatments

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Most importantly, the dose of the agonist treatment must be adequate, because doses of
methadone or buprenorphine that are too low often provoke relapse to opioid use. Some alternate
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pharmacological treatments are available for treatment-refractory patients who do not respond to
methadone or buprenorphine treatments.
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To improve compliance, depot or implant formulations of buprenorphine are currently

being developed. They have been tested in RCTs (Ling et al., 2010; Rosenthal et al., 2013) but
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are not yet approved.

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A possible alternative treatment is an injectable opiate, either methadone or heroin

(diacetylmorphine). This approach has been studied predominantly in the UK in patients
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“persistently failing in orthodox treatment,” with encouraging results (Strang et al., 2010). Client
satisfaction seems to be quite good with this kind of approach (Groshkova et al., 2013). Both
injectable methadone and injectable heroin were found to be more cost effective than
optimized oral methadone in chronic refractory heroin users (Byford et al., 2013). In several
European countries, heroin maintenance is legal for patients not responding to conventional
treatment. A number of RCTs and clinical studies have been conducted, 6 of which were
included in a recent meta-analysis (Strang et al., 2015); see also Dursteler et al. (2015). Injectable
doses typically range between 150-250 mg per injection. The authors concluded that the overall
outcome improved in patients who did not respond to oral methadone treatment. An earlier
Cochrane analysis on this issue (Ferri et al., 2011) included 8 studies involving a total of 2007
patients. The analysis concluded that heroin has an added value alongside flexible doses of
methadone for long-term, treatment-refractory opioid users but also a higher rate of serious

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adverse events. Because injectable heroin treatment is less safe than conventional agonist
maintenance treatment and requires more clinical attention, its use is clearly limited to a small
subgroup of patients and can be considered a second-line option for treatment-refractory patients
(Garcia-Portilla et al., 2014). Legal regulations for heroin use vary significantly between

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countries.

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Oral slow-release morphine is another treatment option. The drug has been studied as an
alternative to methadone for opioid detoxification (Madlung-Kratzer et al., 2009) and in

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particular maintenance (Beck et al., 2014; Hammig et al., 2014). The Cochrane review was based

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on 3 RCTs only (Ferri et al., 2013). The authors stated that none of the studies included people
with a documented poor response to other maintenance treatment and that medical adverse events

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were consistently higher in people in slow-release morphine treatment. The drug is available in
some European countries and may be an alternative treatment for patients not responding to or
tolerating methadone because of side effects such as QTc prolongation.
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5. Cocaine Addiction
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5.1 New pharmacological developments

Cocaine abuse and dependence have a wide range of adverse somatic and psychiatric health
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consequences (Kaye and Darke, 2004; Marzuk et al., 1998; Marzuk et al., 1992). However, there
is still no specific approved pharmacological treatment for cocaine addiction, although recent
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advances in the neurobiology and pathophysiology of cocaine addiction have suggested several
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promising pharmacodynamic targets (Hulka et al., 2014; Kalivas and Volkow, 2011; Preti, 2007).
In addition to modafinil, methylphenidate, and disulfiram, which so far have the best
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evidence for the pharmacological treatment of cocaine addiction and thus are discussed in
more detail below, other medications have been tested for cocaine dependence in clinical
studies. Phase II and III studies have provided first evidence also for levodopa-carbidopa
and dextroamphetamine (dopaminergic agents); doxazosin and nepicastat (SYN 117;
noradrenergic agents); and topiramate, baclofen, N-acetylcysteine, and vigabatrin
(GABAergic agents) (Shorter et al., 2015). Finally, a cocaine vaccine (TA-CD) has been
investigated as a novel immunologic medication in a Phase III study for the treatment of
cocaine dependence (Kosten et al., 2014). However, this study did not find a significant
reduction in cocaine use among those receiving vaccination, compared to the placebo group.

5.1.1 Disulfiram

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Despite the fact that conclusive evidence supporting one specific compound is still lacking, at the
present time disulfiram seems to be the most promising agent for the treatment of cocaine
addiction (Suh et al., 2006). This conclusion is supported by about a dozen methodologically
sound RCTs of disulfiram use in cocaine-dependent patients (Baker et al., 2007; Carroll et al.,

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2004; Carroll et al., 2000; Carroll et al., 1998; Grassi et al., 2007; Kosten et al., 2013; McCance-

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Katz et al., 1998; Oliveto et al., 2011; Petrakis et al., 2000; Pettinati et al., 2008; Schottenfeld et
al., 2014; Shorter et al., 2013; Spellicy et al., 2013). Besides the inhibition of aldehyde

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dehydrogenase (see 3.2.1), inhibition of brain DA-beta-hydroxylase (DBH) and subsequent

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monoaminergic modulation has been discussed recently as another possible direct
pharmacological effect in the central nervous system (Faiman et al., 2013; Mutschler et al., 2009;

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Weinshenker, 2010). These significant changes in dopaminergic and noradrenergic
neurotransmission have been suggested to be the pharmacological mechanism of action of
disulfiram in the treatment of addictive disorders such as cocaine dependence and pathological
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gambling (Mutschler et al., 2010; Mutschler et al., 2009). However, it is unclear whether the
inhibition of DBH reported in animal studies leads to clinically relevant changes in dopaminergic
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transmission in the human brain. Furthermore, disulfiram is not specifically classified as a

stimulant medication, although dopaminergic and noradrenergic changes as a direct consequence
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of acute disulfiram administration have been shown in animal studies. In clinical studies,
disulfiram has shown initial promise in the treatment of cocaine addiction alone and in patients
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with a dual diagnosis of substance abuse, e.g., alcohol and cocaine.

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5.1.2 Methylphenidate
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Methylphenidate (MPH), when used as a stimulant medication, has been shown to have potential
as a treatment for cocaine addiction (Dursteler, 2015). The initial idea behind the use of MPH and
other stimulant medications (such as modafinil) in the treatment of cocaine addiction was based
on the replacement-substitution therapy approach (Dursteler, 2015). This approach has been very
successful in reducing drug-related harm in treatments for opioid and nicotine dependence (Batra,
2011; Nordt and Stohler, 2009).
Both cocaine and MPH target the DA system by inhibiting the presynaptic DA
transporters and thus have very similar pharmacodynamic properties (Calipari et al., 2014). Like
cocaine, MPH acts as a monoamine reuptake inhibitor, thereby increasing extracellular
catecholamine concentrations (Calipari et al., 2014). Inhibition of the presynaptic DA transporters
results in increased extracellular DA levels within the mesolimbic reward system (Ritz et al.,
1987). However, cocaine dependence not only alters the DA system; the reinforcing effects of

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cocaine are mediated also via serotonin, norepinephrine, and other neurotransmitters (Hulka et
al., 2014; Rocha, 2003; Weinshenker and Schroeder, 2007).
MPH is approved and mainly indicated for the treatment of attention-
deficit/hyperactivity disorder (ADHD), but it is used also in the treatment of excessive daytime

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sleepiness and narcolepsy (Epstein et al., 2014; Leonard et al., 2004). When used as indicated,

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MPH is well tolerated and has a good safety profile, as reported in many studies (Epstein et al.,
2014). However, MPH is known also to have reinforcing effects similar to those of cocaine

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(Kollins et al., 2001; Parran and Jasinski, 1991). This means that MPH has a potential for abuse

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and dependence and thus has been classified as a schedule II controlled substance in the USA.
The illicit use of MPH has also expanded because of (mis)use as a cognitive enhancer to improve

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intellectual performance (Maier et al., 2015).
To date, only a small number of studies have considered MPH as a treatment for
cocaine-dependent patients. Notably, positive studies have primarily consisted of case reports and
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open-label trials. A recently published review by Dürsteler et al. (2015) found that 4 out of 5
published case reports and all 3 open-label studies (N=83) reported positive effects for MPH. By
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contrast, investigation of the effects of MPH on cocaine dependence in the 5 double-blind

placebo-controlled RCTs published to date produced a quite different picture: 4 out of 5 found no
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benefit for MPH compared to placebo (N=363; Dursteler, 2015). Only one study, by Levin et al.
(2007), reported a reduced likelihood of cocaine use over time in cocaine-dependent patients with
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comorbid ADHD.
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In summary, current evidence for the use of MPH in the treatment of cocaine abuse and
dependence is still very weak, and such evidence as there is derives mainly from case reports.
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Case studies tend to focus on positive outcomes and show other methodological limitations,
meaning that general conclusions on possible effects cannot be derived from this type of study.
Studies with a high level of scientific evidence (RCTs) failed to find significant benefits for MPH
in reducing cocaine use compared to placebo. In addition, the reported risks of MPH beyond the
approved usage suggest potential for abuse, due to both the reinforcing effects of MPH and the
performance-enhancing effects on cognition. An increasing number of students reportedly abuse
MPH, and some patients show MPH dependence (Bjarnadottir et al., 2015; Gahr et al., 2014;
Peles et al., 2015). A recent study by Harel-Fisch et al. (2013) amongst youth aged 17-18 years
found a 0.9 % rate of non-prescribed use of MPH. Much higher rates of MPH abuse were
reported by Peles et al. (2015) in a recent cross-sectional study of patients on methadone
maintenance treatment. These investigators found a 14.7% (n=45/306) prevalence of MPH abuse
in urine tests in Tel Aviv. However, in the same study none of the 190 patients tested in Las

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Vegas showed positive MPH results (Peles et al., 2015). Potential contributory factors to high
rates of MPH use could be easy accessibility or the high MPH prescription rates seen in some
countries. These striking differences in reported misuse of MPH call for further research to better
understand the factors contributing to national variation and higher rates of MPH abuse in certain

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countries.

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Prospective studies have reported an elevated comorbidity of substance dependence and
ADHD (van de Glind et al., 2014; Wilens et al., 1994). Because of the overlapping

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pathophysiological aspects of both disorders (e.g. dopaminergic deficits, executive dysfunction,

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common genetic risk factors), some patients may self-treat their ADHD symptoms with cocaine
(“self-medication theory”) (Khantzian, 1983). This comorbidity suggests that patients with

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ADHD are more vulnerable to the development of substance dependence. Treatment of ADHD
may very well reduce the risk for substance abuse or dependence (Paslakis et al., 2010).
However, MPH study results are unambiguous in this regard: A recent meta-analysis of 15
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studies found no protective effects of MPH on the development of later SUDs (Humphreys et al.,
2013).
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Thus far, it is unclear whether particular subgroups of cocaine-dependent patients show a

better response to MPH, although leading candidates may be patients with comorbid ADHD. We
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therefore suggest that pharmacological substitution therapy with MPH should be considered for
treatment-resistant cocaine dependence and comorbid ADHD (Paslakis et al., 2010). Treating
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physicians should regularly interview and monitor patients regarding their condition (e.g. craving,
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consumption), with a particular emphasis on increasing the dosage of MPH. The evidence
supporting MPH treatment of cocaine-dependent patients without comorbid ADHD is in our
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opinion too weak to allow recommendation of the therapy and would probably even be dangerous
in some cases. Thus, we recommend caution regarding MPH use when treating patients with a
history of cocaine dependence.

5.1.3 Modafinil
Modafinil is another promising stimulant medication for the treatment of cocaine abuse and
dependence. Modafinil is an alpha-adrenergic/glutamate agonist that inhibits DA re-uptake. It is
an approved treatment for narcolepsy, shift work sleep disorder, and obstructive sleep apnea
syndrome. In 2 placebo-controlled RCTs in cocaine-dependent patients, modafinil (200 mg – 400
mg/day) was shown to reduce craving and increase cocaine abstinence compared to placebo (total
N=272) (Anderson et al., 2009; Dackis et al., 2005). In an open-label study (N=65) recently
published by Nuijten et al. (2015), adherence to modafinil was very low, with only a 10% rate of

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treatment completion. Furthermore, no significant benefit was found for modafinil as an add-on
treatment to cognitive behavioral therapy (Dackis et al., 2012). Taken together, the few studies
that have investigated modafinil as a treatment for cocaine dependence have produced
inconclusive outcomes. Further research is warranted to identify possible modafinil

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responders/non-responders in the treatment of cocaine dependence. Finally, it is important to

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keep in mind that modafinil is listed as a schedule IV drug in the United States and that the
medication is a potent reinforcer at higher dosages. First case reports of modafinil-associated

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psychosis, withdrawal symptoms, and abuse/dependence have also been reported (Kate et al.,

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2012; Krishnan and Chary, 2015; Mariani and Hart, 2005).

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6. Pharmacogenetics
Pharmacogenetic approaches may help to optimize treatment response in otherwise treatment-
refractory patients and could represent an important strategy to further improve treatment
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effectiveness by allowing responders/non-responders to be identified.
A118G, a common and clinically relevant single nucleotide polymorphism of the
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OPRM1 gene at the mu-opioid receptor, results in an amino acid exchange at position 40 from
asparagine to aspartate (Bond et al., 1998). The OPRM1 118G genotype appears to moderate the
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subjective and neuronal response of opioid antagonists to alcohol and alcohol cue reactivity
(Ashenhurst et al., 2012; Schacht et al., 2013; Setiawan et al., 2012) and treatment response with
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opioid antagonists. Results for naltrexone are mixed and were obtained mainly from post hoc
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analyses (Anton et al., 2008b; Anton et al., 2012; Gelernter et al., 2007; Kim et al., 2009;
Kranzler et al., 2013; Oroszi et al., 2009). A meta-analysis stressed the role of the A118G
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polymorphism of the OPRM1 gene in moderating the effect of naltrexone in patients with alcohol
dependence and treatment response (Chamorro et al., 2012), but there are recent negative findings
(Oslin et al., 2015).
Recently, promising pharmacogenetic studies were published showing an influence of
genetic polymorphisms (e.g., DBH, ADRA1A genes) on the outcome of disulfiram treatment in
cocaine-dependent patients (Kosten et al., 2013; Shorter et al., 2013; Spellicy et al., 2013).

7. Neuromodulation: Repeated Transcranial Magnetic Stimulation and Deep Brain

Stimulation in Substance Use Disorders
SUDs are the result of a complex interaction of genes, environment, and substance effects. As
described above, a variety of treatment options are currently available for patients with SUDs.
However, only a small percentage of patients treated for SUDs remain abstinent in the long term,

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and patients often develop a chronic course with multiple relapses. In one study, only 6% to 30%
of alcohol-dependent patients remained abstinent 2 to 3 years after treatment (Project MATCH
Research Group, 1998). Without further treatment after inpatient detoxification, most patients
with SUDs relapse after discharge, and this relapse is relatively independent of the substance or

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drug used (e.g. opioids, cocaine, nicotine, or alcohol) (Berglund et al., 2003; Dutra et al., 2008).

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One of the underlying causes of relapse might relate to the broad clinical heterogeneity of SUDs,
in terms of symptom dimensions, severity, and psychiatric comorbidity, and the wide variability

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in treatment response. Almost all effective therapeutic interventions interact with the brain

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structures that are known to be involved in reward and motivation pathways. Improving treatment
results calls for effective treatment approaches, especially for SUD patients with multiple relapses

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and a chronic course of addiction. New and innovative electrophysiological treatment options,
including deep brain stimulation (DBS) and repeated transcranial magnetic stimulation (rTMS),
show potential in the direct modulation of dysfunctional brain networks in patients with
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(treatment-refractory) SUDs and may represent a novel tool to supplement pharmacological and
psychosocial/psychotherapeutic approaches.
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7.1 Deep brain stimulation (DBS)

DBS is a neurosurgical technique with proven effectiveness as an additional therapeutic
intervention in the treatment of severe neurological movement disorders (e.g. Parkinson disease,
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dystonia, and essential tremor) (Kern and Kumar, 2007). It involves the delivery of electrical
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pulses via electrodes implanted in defined regions of the brain, which results in direct interactions
with neurons and cortico-striatal circuits. Despite the fact that the exact mechanisms of action of
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DBS still are largely unknown, the growing interest worldwide in DBS for SUDs has resulted in
increasing numbers of publications on the topic. Although still less widely investigated and
implemented than in the field of movement disorders, the application of DBS in psychiatric
illnesses such as depression, schizophrenia, anorexia, obsessive-compulsive disorder, therapy-
resistant Tourette syndrome, and drug addiction has also shown promising results (Bartsch and
Kuhn, 2014; Coenen et al., 2015; de Haan et al., 2015; Greenberg et al., 2008; Kuhn et al.,
2011a; Luigjes et al., 2012; Stephen et al., 2012; Sun et al., 2015; Voges et al., 2013). The
majority of studies of DBS in psychiatric illness have focused on the treatment of therapy-
resistant obsessive-compulsive disorder (OCD) (Greenberg et al., 2008). In this section, we
provide a summary of the available clinical evidence on DBS treatment of patients with SUDs.
The application of DBS in SUDs generally remains at the stage of an experimental
therapy, without official approval. DBS was originally developed in animal research; the only

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evidence in humans derived from case reports (Kravitz et al., 2015). The earliest studies of DBS
were in the 1950s, involving experiments on self-stimulation in rats in which animals with
implanted electrodes robustly sought stimulation of the septal region, resulting in apparent
feelings of pleasure (Olds and Milner, 1954). Subsequent preclinical studies investigated the

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effects of DBS in animal models of addiction to ethanol (Knapp et al., 2009), morphine (Liu et

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al., 2008), and cocaine (Rouaud et al., 2010), affecting target brain areas that included the
subthalamic nucleus, lateral habenula, medial prefrontal cortex, lateral hypothalamus, and

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nucleus accumbens. In a review of DBS in animal studies, Luigjes et al. (2012) concluded that

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stimulation of the nucleus accumbens showed the most robust effects in different models of
addiction.

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To date, only a handful of human studies have been published that describe the use of
DBS in patients with SUDs. In most of these publications, patients were treated with DBS
primarily in relation to other conditions such as Parkinson’s disease, anxiety disorders, or OCD.
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The positive effects on addiction were generally observed secondarily during follow-up. The
most commonly targeted brain areas in patients with SUD were the nucleus accumbens and the
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subthalamic nucleus. Positive therapeutic effects of DBS on these brain regions have been
described for addictions to alcohol (Kuhn et al., 2011b; Kuhn et al., 2007; Muller et al., 2009;
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Voges et al., 2013), nicotine (Kuhn et al., 2009; Mantione et al., 2010; Zhou et al., 2011), and
heroin (Stephen et al., 2012; Valencia-Alfonso et al., 2012; Zhou et al., 2011) and for behavioral
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addictions (Ardouin et al., 2006; Bandini et al., 2007). DBS studies in patients with SUDs are
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summarized briefly in Table 1.

Despite these initial promising results, additional studies are required before definitive
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conclusions can be reached on the efficacy and safety of DBS in SUDs. Almost all currently
available studies on DBS in SUDs have clear limitations, because they were non-randomized,
open-label studies or small case-control series. In some patients, SUDs actually worsened after
DBS. Besides the obvious questions regarding methodological and ethical aspects and regarding
the presently unknown long-term effects of DBS, improving understanding of treatment-resistant
SUDs is also a priority. Available reports also differ in terms of stimulation parameters and
targeted brain areas, emphasizing the need for further research on the application of DBS in
patients with SUDs before these outstanding questions can be resolved.
Another important challenge involves the recruitment of patients with SUDs for DBS
RCTs. One recent report described this as being much more difficult than recruiting patients with
OCD (Luigjes et al., 2015). Two registered DBS RCTs are currently recruiting SUD patients
(Cologne, Germany, and Amsterdam, Netherlands), but both research groups are experiencing

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problems in obtaining sufficient numbers of patients, and it is not clear whether these studies will
eventually recruit the originally envisaged number of study participants (Luigjes et al., 2015).
These problems mean that current evidence supporting DBS is limited to that derived from
preclinical studies, human case reports, or case series. However, despite these reservations,

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patients with treatment-refractory SUDs could be eligible for DBS as a possible therapeutic

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option in severe cases (preferably within the setting of an RCT), thus effectively extending
current therapeutic options in patients with SUDs.

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7.2 Repeated Transcranial Magnetic Stimulation (rTMS)
rTMS is another electrophysiological therapeutic approach to treating patients with SUDs

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(Bellamoli et al., 2014; Sousa, 2013). In contrast to DBS, rTMS is a non-invasive method with
many advantages over DBS in the treatment of patients with SUDs that therefore has much
greater potential to become an established therapy for SUDs (Bellamoli et al., 2014; Sousa,
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2013). rTMS is based on magnetic field pulses delivered via a stimulation coil close to the head;
the magnetic field induces an electrical field in the brain, thereby activating cortical neurons
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(Fitzgerald et al., 2009). rTMS can induce sustained changes in cortical excitability and brain
activities and may affect the HPA axis (Baeken et al., 2009). Furthermore, rTMS has been shown
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to induce DA release in subcortical and cortical brain areas (Strafella et al., 2001). The main brain
target for rTMS in the treatment of SUDs is the prefrontal cortical network, in particular the
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dorsolateral prefrontal cortex (DLPFC) and the orbitofrontal cortex (Gorelick et al., 2014;
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Mishra et al., 2015). These brain regions have important functions in the inhibitory control of
addictive substances, a mechanism often impaired in patients with SUDs (Herremans et al.,
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2015; Kravitz et al., 2015; Prikryl et al., 2014; Protasio et al., 2015). Increased activity of the
prefrontal cortex could be one major mechanism of action of rTMS in patients with SUDs (Feil
and Zangen, 2010). Other possible mechanisms of action include the reduction of craving, the
modulation of the dopaminergic and HPA systems, and the modulation of decision-making
processes, leading to a reduction in risk-taking behavior (Knoch et al., 2006).
Many studies have been published on rTMS, and the technique is considered safe
(Levkovitz et al., 2007; Rossi et al., 2009). Depending on the location and parameters of
stimulation, a range of changes in behavior can be induced. High-frequency rTMS (5-20 Hz) is
thought to increase synaptic transmission, whereas low-frequency rTMS (0.2-1 Hz) is thought to
decrease synaptic transmission (Fitzgerald et al., 2006). Repetition of TMS is required to induce
the long-term synaptic changes that are important for prolonged therapeutic effects, and effects
may last for weeks (Fitzgerald et al., 2006). rTMS can be applied safely and painlessly to

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patients, and the technique can be used in addition to other treatments (as an augmentation
therapy). rTMS is rarely the only (standard) treatment.
Despite modest therapeutic effects in the majority of studies, rTMS reportedly achieves
therapeutic-like effects in major depression. Consequently, the FDA recently approved rTMS for

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depressed patients (Daskalakis et al., 2008). In principle, any psychiatric disorder that includes

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cortical dysfunction may benefit from rTMS. Therefore, rTMS has been investigated in
conditions such as mania, OCD, PTSD, and schizophrenia (Burt et al., 2002; Dunlop et al.,

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2015; Grammer et al., 2015; Hasan et al., 2015).

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To date, studies on the application of rTMS for SUDs have most frequently investigated
alcohol, nicotine, and cocaine SUDs (Table 2 gives a brief summary of the studies on alcohol

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and cocaine). In addition, preliminary reports of promising rTMS interventions in other addictive
diseases, including opiates, 3,4-methylenedioxymethamphetamine (MDMA), and gambling (Barr
et al., 2011), also have been published recently. Taken together, studies on rTMS as a treatment
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for SUDs suggest efficacy, particularly in the reduction of craving in patients dependent on
alcohol, nicotine, and cocaine. Furthermore, there seems to be a potential for high frequency
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rTMS to reduce not only craving, but also the consumption of alcohol, nicotine, and cocaine.
However, the limitations of the available studies should be recognized, the main issues being the
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absence of reporting of long-term effects in most studies and the short-lived nature of effects on
craving and consumption. Moreover, some studies reported inconsistent outcomes for craving and
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consumption measures, illustrating the difficulties in the operationalization of the concept

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“craving” and the verification of “consumption.” Objective measures of consumption, e.g. hair
analysis for drugs (Madry et al., 2014), could provide better evidence for the effectiveness of
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rTMS in SUDs. Furthermore, studies differed in technical and stimulation standards, making it
difficult to comment on the optimal hemisphere and rTMS parameters for the treatment of SUDs.
The studies reviewed in Table 2 support the efficacy of high frequency rTMS stimulation of the
right and/or left DLPFC. Further studies should investigate larger sample sizes, identify ideal
stimulation standards and, finally, investigate rTMS in further SUDs.
In conclusion, rTMS is a safe, non-invasive therapeutic method with demonstrably
positive effects on craving and consumption in patients with SUDs. In addition, rTMS could be
easily applied together with other SUD treatments as an augmentation therapy, without a risk of
side effects.

Conclusion

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Treatment-refractory substance use disorders require multidimensional therapeutic

approaches. In this review, we focus on novel pharmacological and brain stimulation
techniques that have the potential to enrich treatment outcomes, at least for some patients.
However, pharmacological and stimulation techniques always have to be combined with

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psychosocial/psychotherapeutic treatments. Further studies are needed to find new

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therapeutic strategies/targets and to further elucidate the discussed treatment options.

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Acknowledgements

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The authors thank Jacquie Klesing, Board-certified Editor in the Life Sciences (ELS), and Dr. J.
P. Bayley (Medactie), for editing assistance with the manuscript.

Statement of interest
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No funding was used to prepare this narrative. For the past 5 years, M.S. has worked as a
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consultant or has received research grants from Sanofi Aventis, Novartis, Mepha, Reckitt
Benckiser, and Lundbeck. J.M. has received travel expenses and consultant fees from Lundbeck
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and Takeda.
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Table 1
Studies of Deep Brain Stimulation in Substance Use Disorders

Target brain Stimulation

Reference N Substance DBS effects
area Frequency
Mantione et al.
1 nicotine Bilateral NAc 180 Hz 1 resolved

T
(2010)
Kuhn et al. 5 bilateral, 5 3 resolved, 7

IP
10 nicotine 130-145 Hz
(2007) unilateral NAc unchanged
Müller et al. 2 resolved, 1

R
3 alcohol Bilateral NAc 130 Hz
(2010) improved
Kuhn et al.

SC
1 alcohol Bilateral NAc 130 Hz 1 improved
(2009)
Zhou et al.
1 heroin Bilateral NAc 145 Hz 1 resolved
(2011)

NAc: Nucleus accumbens

NU
MA
D
TE
P
CE
AC

24
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Table 2
Studies of repeated transcranial magnetic stimulation (rTMS) in Substance Use Disorders

Target
Stimulation Sham
Reference N Substance brain rTMS effects

T
frequency condition
area

IP
Reduction in
Ceccanti et
18 alcohol MLPFC 20 Hz Yes craving and
al. (2015)
alcohol intake

R
No effect on

SC
Herremans et Right immediate or
36 alcohol 20 Hz Yes
al. (2012) DLPFC long-term
craving
Höppner et 10, 9 Left No reduction

NU
alcohol 20 Hz Yes
al. (2011) (females) DLPFC in craving
Reduction in
immediate
MA
Mishra et al. Right craving, but
30, 15 alcohol 10 Hz Yes
(2010) DLPFC no effect on
craving after
4 weeks
D

Yes (right Reduction in

Mishra et al.
20 alcohol DLPFC 10 Hz vs. left craving in
TE

(2015)
DLPFC) both groups
Reduction in
craving and
P

1 (48-year- consumption
de Ridder et
CE

old alcohol dACC 1 Hz No (but relapse

al. (2011)
woman) after 3 months
with increased
craving)
AC

Reduction in
craving (right
DLPFC),
reduction in
anxiety,
Right and increase in
Camprodon
6 cocaine left 10 Hz No mood after
et al. (2007)
DLPFC right-sided
and in
unhappiness
after left-
sided
stimulation
0.03–0.08 Increased safe
Yes (right
Gorini et al. mA/cm2 behavior after
18,18 cocaine DLPFC vs. left
(2014) when used right DLPFC
DLPFC)
with a current stimulation,

25
 ACCEPTED MANUSCRIPT

of 1.5 mA risk-taking
behavior
increased
after left
DLPFC
stimulation

T
Politi et al. Left Reduction in
36 cocaine 15 Hz No
(2008) DLPFC craving

IP
DLPFC: Dorsolateral prefrontal cortex; dACC: Dorsal anterior cingulated cortex; MLPFC:

R
Medial prefrontal cortex

SC
NU
MA
D
P TE
CE
AC

26
 ACCEPTED MANUSCRIPT

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Highlights

- Nalmefene is an as-needed medication for reduction of alcohol intake.

- Depot/implant buprenorphine, i.v. methadone may be options for opioid use disorder.

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- Neuromodulation techniques such as TMS and DBS are emerging treatment options.
- Disulfiram, methylphenidate, modafinil are being studied for cocaine use disorder.

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