The World Journal of Biological Psychiatry, 2008; 9(1): 623 World Federation of Societies of Biological Psychiatry (WFSBP)Guidelines for Biological Treatment of Substance Use and RelatedDisorders, Part 1: Alcoholism MICHAEL SOYKA1, HENRY R. KRANZLER2, MATS BERGLUND3, DAVID GORELICK4,VICTOR HESSELBROCK2, BANKOLE A. JOHNSON5, HANS-JU THE WFSBP TASK FORCE ON TREATMENT GUIDELINES FOR SUBSTANCE USEDISORDERS* 1Psychiatric Hospital Meiringen, Meiringen, Switzerland, 2Department of Psychiatry, University of Connecticut HealthCenter, Farmington, CT, USA, 3Department of Clinical Alcohol Research, University Hospital MAS, Malmo¨, Sweden,4National Institute on Drug Abuse, Baltimore, MD, USA, 5Department of Psychiatric Medicine, University of Virginia,Charlottesville, VA, USA, and 6Department of Psychiatry, Ludwig-Maximilians-University, Munich, Germany AbstractThese practice guidelines for the biological treatment of substance use disorders were developed by an international TaskForce of the World Federation of Societies of Biological Psychiatry (WFSBP). The goal during the development of theseguidelines was to review systematically all available evidence pertaining to the treatment of substance use disorders, and toreach a consensus on a series of practice recommendations that are clinically and scientifically meaningful based on theavailable evidence. These guidelines are intended for use by physicians evaluating and treating people with substanceuse disorders and are primarily concerned with the biological treatment of adults suffering from substance use disorders.
The data used to develop these guidelines were extracted primarily from various national treatment guidelines for substanceuse disorders, as well as from meta-analyses, reviews and randomized clinical trials on the efficacy of pharmacological andother biological treatment interventions identified by a search of the MEDLINE database and Cochrane Library. Theidentified literature was evaluated with respect to the strength of evidence for its efficacy and then categorized into fourlevels of evidence (AD). This first part of the guidelines covers the treatment of alcohol dependence; Part 2 will be devotedto the treatment of drug dependence.
Key words: Alcoholism, pharmacotherapy, acamprosate, naltrexone, topiramate, carbamazepine, disulfiram, ondansetron,benzodiazepine cluster of somatic, psychological and behaviouralsymptoms. In the US, a recent estimate of the 1-year Alcohol dependence is a widespread psychiatric population prevalence of alcohol use disorders (i.e., disorder with lifetime prevalence estimates of 7 alcohol abuse or dependence) was 8.5% (Grant et al.
12.5% in most Western countries (Pirkola et al.
2006; Hasin et al. 2007), though with clear evidence The biological treatment of alcoholism includes of variability of prevalence (Rehm et al. 2005).
therapies for alcohol intoxication, withdrawal symp- Alcohol misuse and dependence are defined by a toms, alcohol-related neuropsychiatric disorders, *Henry R. Kranzler (Chairman; USA), Mats Berglund (Co-Chairman; Sweden), Anne Lingford-Hughes (Co-Chairman; UK), MichaelSoyka (Secretary; Switzerland), Hans-Ju ¨ rgen Mo¨ller (Chairman of the WFSBP Committee on Scientific Publications), Edgard Belfort (Venezuela), Ihn-Geun Choi (Korea), Richard Frey (Austria), Markus Gastpar (Germany), David A. Gorelick (USA), Gerardo M. Heinze(Mexico), Victor Hesselbrock (USA), Bankole A. Johnson (USA), Thomas Kosten (USA), John Krystal (USA), Phillipe Lehert (Belgium),Michel Lejoyeux (France), Walter Ling (USA), Carlos Mendoza (Peru), Michael Musalek (Austria), Toshikazu Saito (Japan), ManitSrisurapanont (Thailand), Hiroshi Ujike (Japan), Ulrich Wittchen (Germany) ISSN 1562-2975 print/ISSN 1814-1412 online # 2008 Taylor & FrancisDOI: 10.1080/15622970801896390 Guidelines for Biological Treatment of Substance Use and Related Disorders and for the initiation and maintenance of abstinence been shown to enhance GABAergic neurotransmis- (i.e., relapse prevention). Over the past two decades, sion. There also is cross-tolerance between alcohol a number of medications have been tested for these and GABAergic drugs. The clinical picture of alcohol intoxication, which includes sedation, ataxiaand drowsiness, can be explained by its effects onGABAergic neurotransmission. PET studies have Alcohol's effects on neurotransmitters revealed reduced GABA-receptor function in alco- Alcohol is metabolized by the alcohol dehydrogenases hol dependence (Lingford-Hughes et al. 2005).
(ADHs) to acetaldehyde, which is rapidly converted Recent genetic studies also show that the vulner- by acetaldehyde dehydrogenases (ALDHs) to ace- ability for alcoholism may be mediated in part tate. Acetaldehyde is a toxic compound that is through variation in the genes encoding GABA responsible for many unpleasant effects of alcohol, receptor subunits (Covault et al. 2004; Dick et al.
especially the ‘flushing response' seen among suscep- 2004; Edenberg et al. 2004; Lappalainen et al. 2005; tible individuals. There are a number of isoforms of Fehr et al. 2006; Soyka et al. 2008). In alcohol both enzymes which significantly modify alcohol withdrawal, GABAergic dysfunction contributes to metabolism, tolerance and risk for development of restlessness, seizures and other signs and symptoms.
alcohol dependence. Blockade of ALDHs by different There is also substantial evidence that alcohol drugs, especially disulfiram (see below), was until enhances dopaminergic transmission in the meso- recently one of the few pharmacological interventions limbic brain (Johnson and Ait-Daoud 2000). The for alcohol dependence. There is now compelling abuse liability of alcohol appears to be mediated by evidence from controlled clinical trials that a variety of dopaminergic pathways that originate in the ventral compounds that interact with the opioid, serotone- tegmental area and progress via the nucleus accum- rgic, and g-aminobutyric acid (GABA)/glutamate bens to the cortex (Weiss and Porrino 2002; Koob systems are safe and efficacious medications for 2003). In addition, alcohol was found to increase treating alcohol withdrawal, alcohol dependence, or serotonin levels and to antagonize glutamatergic neurotransmission (see below). Recently the inter- Alcohol is a simple molecule that affects many action of the endocannabinoid system and alcohol different neurotransmitters systems including, but has attracted more attention (Economidou et al.
not limited to, dopamine, serotonin, glutamate, opioids, and GABA. There is a very substantialbody of literature on the neuropharmacology ofalcohol, including neurochemical and neuroimaging studies. Some of the methodological problems that These guidelines are intended for use in clinical limit interpretation of the results of these studies are practice by clinicians who diagnose and treat patients with substance use disorders. The aim of 1. acute and chronic effects of alcohol may differ these guidelines is to improve the quality of care and to aid physicians in clinical decisions. Although these 2. dose-dependent effects of alcohol are often guidelines are based on the available published evidence, the treating clinician is ultimately respon- 3. changes induced by alcohol's metabolic pro- sible for the assessment and the choice of treatment ducts (e.g., acetaldehyde) and other ingredients options, based on knowledge of the individual of alcoholic beverages are difficult to evaluate; patient. These guidelines do not establish a standard 4. alcohol has clear neurotoxic effects, resulting in of care nor do they ensure a favourable clinical outcome if followed. The primary aim of the guide- 5. few studies have been conducted in long-term lines is to evaluate the role of pharmacological agents abstinent alcoholics or high-risk patients.
in the treatment and management of substance usedisorders, with a focus on the treatment of adults.
Over the last decades considerable efforts have been Because such treatments are not delivered in isola- made to elucidate the neurobiological basis of tion, the role of specific psychosocial and psy- alcoholism. Evidence comes from animal studies as chotherapeutic interventions and service delivery well as from neurochemical and neuroimaging systems is also covered, albeit briefly.
studies in humans (for reviews see Johnson and The aim of these guidelines is to bring together Ait-Daoud 2000; Petrakis 2006; Knapp et al. in different views on the appropriate treatment of press). Alcohol does not act via a single receptor but substance use disorders from experts representing affects multiple neurotransmitter systems and recep- all continents. To achieve this aim, an extensive tors. In brief, acute alcohol intake has consistently literature search was conducted using the Medline M. Soyka et al.
and Embase databases through March 2007, sup- on Addiction Disorders, consisting of 22 interna- plemented by other sources, including published tional experts in the field.
reviews. The guidelines presented here are based ondata from publications in peer-reviewed journals.
Treatment of the alcohol withdrawal syndrome The evidence from the literature research was and delirium tremens summarized and categorized to reflect its suscept-ibility to bias (Shekelle 1999). Daily treatment costs The alcohol withdrawal syndrome (AWS) occurs were not taken into consideration due to the varia- with some frequency among individuals with a tion worldwide in medication costs. Each treatment diagnosis of alcohol dependence. The AWS develops recommendation was evaluated and is discussed within the first hours or days of abstinence or after a with respect to the strength of evidence for its significant reduction of alcohol consumption in an efficacy, safety, tolerability and feasibility. It must individual with severe physical dependence. In many be kept in mind that the strength of recommenda- cases, this condition resolves without complications tion is due to the level of efficacy and not necessarily and does not require pharmacological treatment.
of its importance. Four categories were used to However, in some cases it can progress to a more determine the hierarchy of recommendations (re- serious or even life-threatening condition.
lated to the described level of evidence): Diagnostic and Statistical Manual of Mental Dis- Level A: There is good research-based evidence to orders, 4th edition Text Revision (DSM-IV-TR) support this recommendation. The evidence was (American Psychiatric Association 2000) criteria obtained from at least three moderately large, for alcohol withdrawal are: positive, randomised, controlled, double-blind trials . cessation of or reduction of heavy alcohol use; (RCTs). In addition, at least one of the three studies . two or more of the following symptoms devel- must be a well-conducted, placebo-controlled study.
oping within hours to a few days: Autonomic Level B: There is fair research-based evidence to hyperactivity (sweating, fast pulse); increased support this recommendation. The evidence was hand tremor; insomnia; nausea and vomiting; obtained from at least two moderately large, positive, transient hallucination or illusions; psychomo- randomised, double-blind trials (this can be either tor agitation; anxiety; grand mal seizures.
two or more comparator studies or one comparator- Most symptoms of alcohol withdrawal are non- controlled and one placebo-controlled study) or specific: tremor, elevated pulse rate and blood from one moderately large, positive, randomised, pressure, perspiration, agitation, nervousness, sleep- double-blind study (comparator-controlled or pla- lessness, anxiety, and depression. They occur typi- cebo-controlled) and at least one prospective, mo- cally within the first hours after discontinuation of derately large (sample size equal to or greater than50 participants), open-label, naturalistic study.
alcohol consumption and may last for a few days upto a week, seldom for longer. In addition, more serious symptoms can occur that may warrant evidence to support this recommendation. The specific interventions: hallucinations, delirium tre- evidence was obtained from at least one randomised, mens, alcohol-related psychotic symptoms, and double-blind study with a comparator treatment and seizures. There are a number of rating scales to one prospective, open-label study/case series (with a measure intensity of alcohol withdrawal symptoms.
sample of at least 10 participants), or at least two The most frequently used scale is the Clinical prospective, open-label studies/case series (with a Institute Withdrawal Assessment-Alcohol-Revised sample of at least 10 participants) showing efficacy.
scale (CIWA-Ar, Sullivan et al. 1989). There are a Level D: Evidence was obtained from expert number of detailed evidence-based guidelines con- opinions (from authors and members of the WFSBP cerning management of AWS (Mayo-Smith et al.
Task Force on Addiction Disorders) supported by at 1997; Mundle et al. 2003; Berner et al. 2004; least one prospective, open-label study/case series Lingford-Hughes et al. 2004; American Psychiatric (with a sample of at least 10 participants).
Association 2007).
The treatment of alcohol withdrawal focuses on No level of evidence or Good Clinical Practice the relief of immediate symptoms, prevention of (GCP): This category includes expert opinion- complications, and the initiation of rehabilitation.
based statements for general treatment procedures Although outpatient detoxification is a safe treat- and principles.
ment option for many patients with mild-to-moder- The guidelines were developed by the authors and ate AWS (Soyka et al. 2005, 2006), patients with arrived at by consensus with the WFSBP Task Force severe symptoms, extremely high alcohol intake, Guidelines for Biological Treatment of Substance Use and Related Disorders significant somatic or psychiatric symptoms, or a smoother course of withdrawal, may require less delirium tremens should be treated as inpatients.
frequent dosing, and are more forgiving of a missed Risk factors for severe withdrawal syndromes and dose (Mayo-Smith et al. 1997). BZDs can be delirium tremens are concurrent physical illness, categorised according to their catabolism. Longer- long and intensive consumption of large amounts acting BZDs are oxidized by the hepatic microsomes of alcohol and a previous history of similar condi- into active and inactive metabolites. Shorter-acting BZDs like lorazepam and oxazepam, which are not Supportive care (Whitfield et al. 1978; Shaw et al.
oxidized, but simply conjugated in the liver before 1981) and repletion of nutrient, fluid or mineral excretion, may be preferred in patients with severe deficiencies plays a very important role in the liver disorder in order to avoid cumulative effects or treatment of AWS, but will not be discussed here in detail. Vitamin deficiencies are very common in There are different treatment strategies and tech- patients with heavy alcoholic intake. Supplementa- niques for the use of BZD in the treatment of AWS.
tion, especially of B vitamins including thiamine to In most cases, oral treatment with BZDs is sufficient prevent the development of Wernicke-Korsakoff and effective. In severely disturbed or physically ill syndrome (see Section 7), is recommended. The patients, especially those with delirium tremens, major aims of pharmacotherapy are sedation of intravenous administration of, e.g., diazepam may patients to control increased excitability as mani- be preferable. While many clinicians favour a symp- fested by agitation, anxiety and related symptoms tom-triggered approach and an individualized do- and prevention of cardiovascular complications due sage, Sellers et al. (1983) proposed a fixed dosage to high blood pressure and pulse rate.
scheme with diazepam ‘loading,' involving adminis- Numerous pharmacological agents have been tration of 20 mg every hour until the patient's used for the treatment of alcohol withdrawal, but symptoms subside. Other possible dosage regimens few have sufficient empirical evidence supporting are diazepam 10 mg every 6 h, or lorazepam 2 mg or their efficacy. Results from placebo-controlled stu- chlordiazepoxide 50 mg (Level C). The optimal dies suggest that benzodiazepines (BZDs), b-adre- dosage depends on the severity of AWS.
It should be noted, however, that a major problem blockers, anticonvulsants, and clonidine reduce with the BZDs is their abuse liability. Therefore, a withdrawal symptoms (Berglund et al. 2003). Clo- number of alternate strategies for the treatment of methiazole, which is not available in the US, is also the AWS have been studied. (These are discussed frequently used for the treatment of AWS. The few studies conducted in patients with delirium tremensshow that benzodiazepines, used for treatment of Treatment of alcohol withdrawal delirium. Alcohol- AWS, are also useful for delirium tremens (Mayo- withdrawal delirium is the most serious and danger- Smith et al. 2004).
ous manifestation of the AWS. It has a prevalencerate of approximately 5% (315%) among indivi-duals who manifest withdrawal symptoms (Hansen et al. 2005). It usually lasts 4872 h but can persist Worldwide, benzodiazepines (BZDs) are the drugs for a much longer period. Control of agitation is of first choice in the treatment of AWS. BZDs act via essential in alcohol withdrawal delirium. The patient allosteric effects at the GABA receptor and are cross- should be sedated and kept in light somnolence for tolerant with alcohol. There is good empirical the duration of the delirium. Sedative-hypnotic evidence from a number of placebo-controlled agents, usually BZDs, are recommended for treat- studies of the clinical efficacy of BZDs. They are ment (Level A). A recent meta-analysis of nine also superior to many other drugs for this indication prospective controlled trials found BZDs to be (Berglund et al. 2003; Mayo-Smith 1997). BZDs are more effective than antipsychotics in reducing the clinically effective in reducing key symptoms of the duration of delirium and mortality risk (Mayo-Smith AWS such as anxiety, agitation, and symptoms of et al. 2004). Several different BZDs, most com- autonomic hyperactivity (e.g., perspiration, tremor, monly diazepam or lorazepam, and different dosing palpitations). They also reduce overall withdrawal regimens have been recommended for the treatment severity and the incidence of delirium and seizures.
of delirium. Severe cases of delirium require intra- The most commonly used BZDs are diazepam, venous therapy to ensure adequate dosing. The BZD chlordiazepoxide, oxazepam, lorazepam and alpra- dosage required to treat delirium can be extremely zolam. It is a matter of debate whether short-acting high: up to 1000 mg of diazepam equivalents/day.
or long-acting BZDs are preferable. Many clinicians Although there are no placebo-controlled trials favour the longer-acting agents because they provide available, antipsychotics, especially haloperidol, can M. Soyka et al.
be given in combination with a BZD for treatment of However, it has a substantial abuse potential and a severe agitation (Mayo-Smith et al. 2004, Level C).
relatively narrow therapeutic range, limiting its Less potent antipsychotics may have a greater risk of lowering the seizure threshold. There are no studies should be intensively monitored because of the risk of the utility and risks of second-generation anti- of adverse cardiac effects.
psychotics for the treatment of agitation in the There are few studies comparing the effects of context of the AWS. b-Adrenergic blockers may be clomethiazole with those of BZDs or other drugs.
of value in patients with persistent hypertension.
Despite the conclusion by Majumdar (1990), that Magnesium should be provided in cases of hypo- clomethiazole is safe and equal or superior to BZDs, a recent meta-analysis (Mayo-Smith et al. 2004) didnot favour this medication. Nonetheless, the drug Other GABAergic compounds. Recently, a variety remains well established in Europe for the treatment of other GABAergic compounds have been advo- of AWS (Level B).
cated for treatment of AWS (Johnson et al. 2005).
g-Hydroxybutyric acid (GHB) is a naturally occur- ring short-chain 4-carbon fatty acid that proved tobe of comparable efficacy to BZDs or clomethiazole BZDs have some limitations in clinical use, includ- (Addolorato et al. 1999; Gallimberti et al. 1989; ing abuse liability, pharmacological interaction with Nimmerrichter et al. 2002, Level C). Its role as a so- alcohol, and adverse cognitive and psychomotor called anti-craving drug is less clear (see below).
effects. A number of studies demonstrating the GHB has a relatively short half-life, so that more efficacy and safety of anticonvulsants such as carba- frequent dosing is necessary. The abuse potential of mazepine and valproate suggest that they provide GHB (‘liquid ecstasy') has raised significant concern safe alternatives to benzodiazepines for the treat- (McDonough et al. 2004). In addition, GHB with- ment of alcohol withdrawal. They are considered to drawal can be very severe. Other drugs, such as be relatively safe, free from abuse liability, and gabapentin or baclofen, have not been studied usually do not potentiate the psychomotor or adequately to recommend them for use in the cognitive effects of alcohol (Ait Daoud et al. 2006).
treatment of the AWS (Level D).
Controlled studies have shown CBZ to be superior to placebo (Bjorkquist et al. 1976; Berglund et al.
Glutamatergic compounds. Impairment of glutamater- 2003) and as effective as BZDs (Malcolm et al.
gic neurotransmission has been shown to play a 1989, 2001, 2002; Stuppaeck et al. 2002) or major part in the development of alcohol withdrawal clomethiazole (Ritola and Malinen 1981; Seifert symptoms. There is preliminary evidence that the et al. 2004) for the treatment of the symptoms of glutamate release inhibitor, lamotrigine; the NMDA AWS (Level B). The usual dosage of carbamazepine receptor antagonist, memantine; and the AMPA/ is 6001200 mg/day. There is no evidence that CBZ kainate receptor inhibitor, topiramate may be useful is effective in alcohol withdrawal delirium. CBZ has in the treatment of alcohol withdrawal (Rustembe- also been used in combination with tiapride for govic et al. 2002; Choi et al. 2005; Krupitsky et al.
outpatient treatment of AWS (Soyka et al. 2002, 2007, Level C for topiramate; Level D for lamotrigine 2006, Level C). In addition to reducing symptoms of and memantine).
L-type voltage-gated calcium AWS, carbamazepine reduced drinks per drinking channel antagonists (diltiazem, verapamil, nimodi- day and time to first drink in abstinent alcoholics pine) are probably not effective.
(Mueller et al. 1997; Malcolm et al. 2002) (Level C).
A study of individuals with moderate alcohol Clomethiazole. Clomethiazole, derived from thia- withdrawal showed that sodium valproate treatment mine, was introduced into clinical practice in the was well tolerated, reduced the need for BZD early 1960s. It is a potent anticonvulsant hypnotic treatment, and decreased the likelihood of progres- widely used in Europe to treat the AWS. It is not sion in severity of withdrawal symptoms compared approved for use in the US. Although the drug has with placebo (Reoux et al. 2001).
been used to treat delirium (Majumdar 1990), no Both carbamazepine and valproate are contra- randomized studies have been conducted in full- indicated in patients with comorbid hepatic compli- blown delirium tremens (Berglund et al. 2003).
cations or hematological disorders.
Some studies have shown a substantial decrease in A recent inpatient study showed that topiramate mortality in patients treated with clomethiazole. The was as efficacious as lorazepam at treating alcohol drug has GABA-mimetic and glycine-potentiating withdrawal, while allowing transition of the patient effects, a half-life of only 4 h, and no hepatic toxicity, to outpatient care on the same regimen (Choi et al.
and can be given both orally and intravenously.
2005), without the potential for abuse or the Guidelines for Biological Treatment of Substance Use and Related Disorders increased risk of relapse commonly seen in alco- population. Alcohol consumption acutely increases holics treated with BZDs. An open-label study the seizure threshold. However, following chronic showed topiramate to be efficacious and well toler- heavy drinking, the seizure threshold is lowered ated in the treatment of tonic-clonic seizures asso- upon cessation of drinking. Alcohol seizures typically ciated with alcohol withdrawal (Rustembegovic et al.
occur within the first 648 h following abrupt cessation of heavy drinking. First onset of alcohol-related seizures is typically in middle-aged indivi- Clonidine. In patients with symptoms of severe duals. Most alcohol-related seizures are of the grand- adrenergic hyperactivity, use of a sympatholytic mal type, although partial seizures and epileptiform may be necessary. Under these circumstances, either EEG abnormalities are not uncommon. Some, but clonidine or a b-adrenergic blocker such as atenolol not all, clinical series have also found a high (Kraus et al. 1985; Horwitz et al. 1989) may be effective, especially in patients with a systolic blood (Brathen et al. 1999; Leone et al. 2003).
pressure over 160 mmHg or diastolic over 100 A first seizure should prompt neuroimaging to mmHg. These drugs should be avoided in patients search for a structural cause, i.e., CT or MRI who are dehydrated, have active volume losses, or (Brathen et al. 2005). Since most alcohol-related have evidence of sick sinus syndrome or high-grade seizures are of the grand mal type, any other type of conduction blocks (Level C).
seizure, e.g. focal type or partial-onset seizures, mayindicate underlying pathology such as cerebrovascu-lar disease (intracranial haemorrhage or infarctions), Management of alcohol intoxication or concurrent metabolic, toxic, infectious, trau- The severely intoxicated patient should be mon- matic, or neoplastic disease. A number of pathophy- itored in a safe environment. The presence of other siological mechanisms may explain the increased risk drugs should be assessed by laboratory tests, espe- of seizures in alcoholics, including alcohol's effects cially in severely intoxicated or sedated patients.
on calcium and chloride flux through ion-gated Clinical management includes the administration of glutamate and GABA receptors. Chronic alcohol thiamine and fluids. The obtunded patient may exposure results in adaptive changes in the CNS, require intervention to ensure adequate respiratory including a higher alcohol tolerance. There is no function. High doses (5 mg) of the benzodiazepine clear evidence for a genetic predisposition to alcohol receptor antagonist flumazenil are reported to hasten withdrawal seizures, which likely reflects the diffi- the recovery from ethanol-induced heavy sedation or culty of conducting research in this area. Although coma in open-label case series (Martens et al. 1990; status epilepticus following an alcoholic seizure is rare, Lheureux and Askenasi 1991), but these results its serious consequences warrant prompt treatment require confirmation in controlled clinical trials.
to prevent it.
After an alcoholic seizure, the patient should be observed in a hospital for at least 24 h. For patients Diagnosis and management of alcohol-related with no history of withdrawal seizures and mild- to-moderate withdrawal symptoms, routine drug The relationship between alcohol and seizures is therapy for prevention of seizures is not necessary.
complex (Brathen et al. 1999; Leone et al. 2003).
A meta-analysis of controlled trials for primary According to the recent guidelines of the European prevention of alcohol withdrawal seizures demon- Federation of Neurological Science (EFNS) Task strated a highly significant reduction of seizures with Force on Diagnosis and Treatment of Alcohol- benzodiazepines and epileptic drugs and an in- Related Seizures, alcohol-related seizures account creased risk with antipsychotics (Hillbom et al.
for one-third of seizure-related admissions. Up to 2003). Diazepam and lorazepam are recommended 15% of patients with alcohol dependence suffer from for such preventive efforts (Level A). A meta-analysis seizures (Hillbom et al. 2003). There is little of randomised, placebo-controlled trials for the consensus as to the optimal evaluation and manage- secondary prevention of seizures after alcohol with- ment of alcohol-related seizures (Brathen et al.
drawal showed lorazepam to be effective but pheny- 2005). While the prevalence of epilepsy in alcohol- toin to be ineffective (Hillbom et al. 2003). Because dependent patients is only slightly higher than in the withdrawal seizures typically do not re-occur in general population (Hillbom et al. 2003), the pre- abstinent patients, there is no reason for continuing valence of seizures among alcohol-dependent pa- antiepileptic treatment in these patients. (Hillbom tients is at least three times higher than in the general et al. 2003) (Level C).
M. Soyka et al.
Alcohol psychosis Treatment of alcohol dependence Chronic alcohol consumption can result in a psy- Goals of treatment chotic disorder, most commonly with hallucinatory Alcohol dependence is primarily manifest as im- features. In the older psychiatric literature, this paired control over drinking. Both naturalistic and schizophrenia-like syndrome was called alcohol hal- clinical long-term studies have indicated that relapse lucinosis. Patients suffer from predominantly audi- to heavy drinking can occur even after decades of tory but also visual hallucinations and delusions of abstinence (Berglund et al. 2003). Relapse to heavy persecution. In contrast to alcohol delirium, the drinking has also been shown in animal models even sensorium in these patients is clear. Alcohol psycho- after long periods of (forced) abstinence (Schumann sis occurs rarely, although more often than pre- et al. 2003). Consequently, abstinence is the primary viously believed (Tsuang et al. 1994). Although the goal recommended by most clinicians, though there prognosis is good, 1020% of patients with alcohol is growing interest in harm reduction strategies that psychosis will develop a chronic schizophrenia-like aim to reduce heavy drinking, even among patients syndrome (Glass 1989b). In these cases, differentiat- for whom the goal of treatment may not be ing alcohol psychosis from schizophrenia can be abstinence (Johnson et al. 2003, 2007; Kranzler difficult (Soyka 1990). The pathophysiology of et al. 2003a; Garbutt et al. 2005).
alcohol psychosis is not clear. There is no evidence Most clinicians and self-help organizations such as for a common genetic basis for alcohol psychosis and Alcoholics Anonymous consider alcohol dependence schizophrenia (Glass 1989a). Recent PET findings to be a chronic and disabling disorder for which they indicate a dysfunction of the thalamus in patients advocate long-term or lifelong abstinence. Although with alcohol psychosis (Soyka et al. 2005).
treatments that favour techniques aimed at regaining There are no studies of the pharmacotherapy of control over drinking (‘controlled drinking') in alcohol psychosis and no established therapy. Taking alcohol-dependent patients have been advocated, the often vivid psychotic symptomatology into ac- the available data call into question whether this is count, with the risk of aggressive or suicidal reac- an effective long-term strategy, at least for patients tions, antipsychotic treatment is warranted in most with moderate-to-severe alcohol dependence. Stu- patients, perhaps optimally in combination with dies of the long-term course of alcoholism indicatethat most individuals are unable to maintain con- benzodiazepines (Level D). There is no evidence trolled drinking (Vaillant 1996). Studies of effects of for an increased risk of seizures in patients with cognitive-behavioural therapy (CBT)-focused, self- alcohol psychosis treated with antipsychotics, espe- control training in patients with limited alcohol cially haloperidol (Soyka et al. 1992). Abstinent problems show some positive effects in comparison patients with full remission of symptoms have a good with no treatment (for a review, see Berglund et al.
prognosis, so there is no need for ongoing treatment 2003), but the effect in alcohol-dependent indivi- with antipsychotic medication.
duals remains controversial. Following a harm-reduction strategy for patients not motivated for abstinence-oriented interventions to promote a re-duction in drinking is acceptable in such situations The metabolism of glucose requires thiamine (vita- (Good Clinical Practice), but abstinence from min B1) as a co-factor. Therefore, supplementation alcohol remains the primary long-term goal for with thiamine is vital to prevent WernickeKorsakoff moderate-to-severe alcohol dependence.
Syndrome (Thomson et al. 2002) (Level A), espe-cially in malnourished patients with signs of hypovi-taminosis. Prophylactic parenteral thiamine should Psychosocial treatment be given before starting any carbohydrate-containing A variety of psychosocial interventions (including intravenous fluids to avoid precipitating acute Wer- psychotherapy) have been found to be effective in nicke's syndrome. Symptoms of morbus Wernicke alcohol treatment (for review, see Holder et al. 1991, (ophthalmoplegia, ataxia, loss of consciousness) 2000; Miller 1992; Miller et al. 1995; Berglund et al.
must not be overlooked. Intravenous treatment 2003). Long-term abstinence rates following alcohol with thiamine is vital in this setting and must be treatment rarely exceed 40%; many studies have initiated immediately after the diagnosis is made.
shown less favourable treatment results (Berglund Even with prompt treatment, mortality in this et al. 2003; Bottlender et al. 2006). It is difficult to disorder is still high. There is no established demonstrate the superiority of one active approach to pharmacological treatment of Korsakoff psychosis alcohol treatment over another (Project MATCH to improve the memory impairment.
Research Group 1997, 1998; Bottlender et al. 2006; Guidelines for Biological Treatment of Substance Use and Related Disorders Schmidt et al. 2007). Nonetheless, comprehensive reviews of treatment studies (see Holder et al. 1991, Community- and population-based epidemiological 2000; Miller 1992; Miller et al. 1995; Berglund et al.
studies consistently find a greater than 2-fold greater 2003) reveal that, generally speaking, alcohol treat- prevalence of depressive disorders in individuals with ment is more effective than no treatment.
alcohol dependence compared to the general popu- Interventions that have been found to be effective lation (Regier et al. 1990; Agosti and Levin 2006).
include strategies aimed at the enhancement of A review of 35 studies found that the median motivation for recovery, CBT, including broad prevalence of current or lifetime alcohol problems spectrum treatment with a CBT focus and other in individuals with depression was 16 and 30%, related forms, 12-step treatment, various forms of respectively, compared to 7 and 1624% in the family, social network, and marital therapy, and general population (Sullivan et al. 2004). Other social competence training. The data for psychody- studies show a modest association of unipolar namically oriented treatments and others are less depression and alcohol dependence (Schuckit et al.
convincing (Bottlelender et al. 2006).
1997). Alcoholism in depressive patients is of special Pharmacotherapy can be used in conjunction with importance for the course of depression, suicide/ psychosocial treatment to increase abstinence ratesor reduce relapse rates, treat other alcohol-related death risk, and social functioning (Hasin et al. 1996; disorders (see above), or treat comorbid psychiatric Agosti and Levin 2006).
disorders. In this context, psychotherapeutic or The differential diagnosis between depression and psychosocial interventions have been used to in- alcohol-induced disorders can be difficult to make.
crease motivation for abstinence, improve motiva- Depressive symptoms can sometimes be differen- tion for medication compliance, and to enhance tiated into primary (preceding the onset of alcoho- outcomes generally.
lism) and secondary (following alcoholism onset) Ledgerwood et al. (2005) provide a comprehensive based upon the chronological ordering of the dis- discussion of the use of combined medication and orders. Because many secondary depressive symp- psychotherapy for treatment of alcohol use disorders.
toms may take time to resolve in abstinent patients, They consider six different psychotherapeutic ap- reliable differential diagnosis can sometimes be proaches that have been used in studies of the made only after some weeks or even months of pharmacotherapy of alcohol dependence: brief inter- ventions, motivational enhancement therapy, CBT, There is consistent evidence for an excess rate of behavioural treatments (e.g., contingency manage- alcoholism in patients with bipolar disorder, with a ment, community reinforcement approaches), beha- prevalence that is up to 6-fold that seen in the vioural marital therapy, and 12-step facilitation.
general population (Regier et al. 1990; Kessler et al.
Although these approaches have been used widely together with pharmacotherapy, there are few con- In general, the same guidelines can be used for the trolled trials examining the interaction of psychothe- biological treatment of affective disorder in alcoholic rapy and pharmacotherapy in alcohol dependence, patients as for non-alcoholics (for WFSBP guide- and no standard psychotherapy has been established lines, see Bauer et al. 2002), although a few special in this respect. The COMBINE Study (Anton et al.
considerations are warranted. Apart from diagnostic 2006) represents a major effort to examine this problems, drug interactions with alcohol are of important area of research in alcohol treatment, but special relevance. Tricyclic antidepressants in com- it underscores the difficulty and high cost of such bination with alcohol may lead to toxic reactions, trials, since evaluation of interactive effects of medi- sedation, blackouts or seizures. This risk is substan- cation and psychosocial interventions requires large tially lower for newer antidepressants, especially samples to provide adequate statistical power.
selective serotonin reuptake inhibitors (SSRIs).
Compliance may be poorer among alcoholics thannon-alcoholics, an important issue to be addressed Treatment of comorbid psychiatric disorders by the clinician. For safety reasons, treatment with Few controlled treatment studies have been con- lithium requires excellent compliance.
ducted in patients with co-existing psychiatric dis- Treatment with antidepressants in alcoholics may orders, a topic that has received more attention in be most useful in combination with psychotherapeu- recent years. The limited research database indicates tic interventions such as cognitive behavioural that in these patients treatment of alcohol depen- therapy (Brown et al. 1997). A number of placebo- dence should be integrated with treatment of the controlled clinical trials have been conducted on the comorbid psychiatric disorder (Berglund et al.
efficacy of antidepressants (Ciraulo and Jaffe 1981; McGrath et al. 1996; Cornelius et al. 1997; Pettinati M. Soyka et al.
et al. 2001; Kranzler et al. 2006). In a recent review published studies showed a positive effect of buspir- and meta-analysis, Nunes and Levin (2004) identi- one on treatment retention and anxiety (Level B) fied 14 placebo-controlled studies with a total of 848 (Malec et al. 1996). The effect on alcohol consump- patients with comorbid depression and alcohol or tion was less clear.
other drug dependence: five studies of tricyclicantidepressants, seven of SSRIs, and two of antide-pressants from other classes. Data indicated that antidepressant medication exerts a modest beneficial Up to 34% of schizophrenic patients have an alcohol effect for patients with both disorders (Level B).
use disorder and 47% have a drug use disorder SSRIs performed less well overall than tricyclics or (Regier et al. 1990; Soyka 1996). Dual-diagnosis other classes of antidepressants (Level B). This patients have a higher risk of psychotic relapse and finding was in part due to a high placebo response rehospitalisation, poor medication adherence, and rate in some of the SSRI studies, and must be are at risk of suicide and aggressive behaviour balanced against the risk of interactions, as addressed (Green et al. 2002).
above. When medication was effective in treating Case series and chart reviews suggest that second- depression, there was also some effect on alcohol use, generation antipsychotics, especially clozapine, are but few patients achieved abstinence. These findings more effective than first-generation drugs in redu- indicate that the treatment of depression alone is not cing substance use by patients with schizophrenia sufficient in these dual-diagnosis patients, but must (Drake et al. 2000; Green et al. 2002; Green 2005; be combined with alcohol-specific interventions.
Noordsy et al. 2001). In the absence of controlled Although there is some limited evidence for SSRIs clinical trials, it is difficult to recommend any to reduce alcohol consumption, the overall evidence specific medication for these types of patients (Level for non-depressive patients to benefit from this D). Patients with schizophrenia and comorbid sub- treatment is limited (LeFauvre et al. 2004; Nunes stance use have a higher risk for adverse effects of and Levin 2004). A recent meta-analysis by Torrens antipsychotic treatment, especially tardive dyskinesia et al. (2005) concluded that in alcohol dependence (Miller et al. 2005) and extrapyramidal symptoms without comorbid depression, the use of any anti- (Potvin et al. 2006), suggesting an advantage for depressant is not justified.
second-generation antipsychotics (Level C). They In a recent placebo-controlled trial among alco- may also adversely affect the reward system less than hol-dependent individuals with comorbid bipolar first-generation antipsychotics (Chambers et al.
disorder, valproate treatment was associated withimproved drinking outcomes (Salloum et al. 2005).
2001). For patients with prominent depressive There are no other published studies on this subject symptoms, antidepressants can be given concomi- tantly (Siris 1990).
With respect to anti-craving compounds, based on limited evidence, the use of naltrexone and disul- Anxiety disorders firam has been recommended in patients withpsychotic Community-based epidemiological studies show a 2006a). Since disulfiram also blocks dopamine-b- 2.2-fold increased risk for anxiety disorders among hydroxylase, the risk of a psychotic relapse resulting individuals with alcohol dependence compared tothe general population (Agosti and Levin 2006).
from reduced metabolism of dopamine must be There is a lifetime prevalence of 620% for anxiety disorders among alcoholics. Social and specificphobias have the highest risk (Kessler et al. 1997; Pharmacological relapse prevention Grant et al. 2005; Conway et al. 2006). Differentialdiagnosis can be difficult due to overlapping symp- Disulfiram was the first medication approved speci- toms. Self-medication of anxiety symptoms with fically for the treatment of alcoholism. In the last alcohol may partially explain the high comorbidity decade or so, a number of additional agents for the rate. Cognitive-behavioural interventions have been treatment of alcohol dependence have been intro- found to be effective in these patients (Randall et al.
duced into clinical practice, including acamprosate and naltrexone (American Psychiatric Association Few pharmacotherapeutic trials have been con- 2007). A number of reviews and meta-analyses have ducted in patients with alcohol dependence and been published addressing this topic (Hughes and anxiety disorder. One study found paroxetine to Cook 1997; Garbutt et al. 1999; Kenna et al.
reduce anxiety symptoms in patients with comorbi- 2004a,b; Mann et al. 2004; Kranzler 2006; Soyka dity (Randall et al. 2001) (Level D). A review of five and Roesner 2006, Roesner et al. 2008).
Guidelines for Biological Treatment of Substance Use and Related Disorders Disulfiram. Disulfiram, an irreversible inhibitor of Efforts have been made to develop long-lasting, acetaldehyde dehydrogenase (ALDH), has was ap- implantable formulations of disulfiram to improve proved for alcohol dependence treatment by the US adherence. There are few studies of this approach. A Food and Drug Administration in 1949. Drinking while taking disulfiram results in an elevated con- 1991) failed to show efficacy of the disulfiram centration of acetaldehyde and precipitation of the implant. At present, this treatment cannot be disulfiram-alcohol reaction (DAR). The DAR is unpleasant and occasionally dangerous, with avariety of symptoms including nausea, flushing, Acamprosate. The exact mechanism, including the vomiting, sweating, and hypotension, among others.
molecular targets, by which acamprosate diminishes The rationale for using the medication is to deter the alcohol consumption and the likelihood of relapse is patient from drinking alcohol again. Disulfiram is not entirely clear. The effects of alcohol on the usually given at a dosage of 200500 mg/day.
glutamatergic system are complex. Acutely, alco- Data on the efficacy of disulfiram are mixed (Level hol reduces glutamatergic neurotransmission via C) (Chick et al. 1992, Hughes and Cook 1997; NMDA receptor blockade, though it also promotes Garbutt et al. 1999). The largest placebo-controlled glutamate release in several important pathways in study of the drug compared disulfiram 250 mg with the brain. In addition to its effects on NMDA disulfiram 1 mg and placebo (Fuller et al. 1986).
receptors, alcohol's effects on the glutamatergic The study failed to show an effect of disulfiram on system are also mediated by AMPA and kainate the likelihood of abstinence over the 1-year treat- receptors (Moghaddam and Bolino 1994; Costeret al. 2000; Crowder et al. 2002; Krystal and ment period. However, among individuals who Tabakoff 2002). Acamprosate modulates glutama- relapsed to drinking, treatment with disulfiram 250 tergic neurotransmission, counteracting hyper-glu- mg was associated with a significantly lower number tamatergic states (Littleton 1995; Spanagel and of drinking days compared with the other two Zieglgansberger 1997). Recent work indicates that treatment conditions. Most of the other studies of acamprosate reduces brain glutamate levels and disulfiram that have been conducted have not used a alcohol consumption in mice that are mutated for rigorous clinical trial methodology, and compelling the Per2 gene (Spanagel et al. 2005). Per2 is a clock evidence that disulfiram increases abstinence rates is gene that influences the glutamatergic system and lacking (for review, see Hughes and Cook 1997).
modulates alcohol intake. In addition, acamprosate Garbutt et al. (1999) concluded that the efficacy may act as an antagonist of the mGluR5 subtype of evidence for disulfiram is inconsistent and that there metabotropic glutamate receptor, thereby blocking is more often negative evidence on other outcome the excitotoxicity produced by ethanol (Harris et al.
measures such as relapse (Level C). Recent open- 2003). There is also evidence that, following stimu- label studies showed a better outcome for patients lation of glutamate receptors, acamprosate blocks treated with disulfiram compared to acamprosate or enhanced extracellular dopamine levels in the nu- naltrexone (de Sousa and de Sousa 2004, 2005). A cleus accumbens, a key neurobiological structure in recent, randomized trial in patients with comorbid the development of addiction (Cano-Cebrian et al.
psychiatric disorders showed that treatment with 2003). Therefore, in addition to effects on glutamate disulfiram (open-label administration with no pla- systems, acamprosate may also exert therapeutic cebo control) and naltrexone (double-blind, pla- effects through changes in dopamine-mediated alco- hol reinforcement (Spanagel and Weiss 1999).
efficacy (Petrakis et al. 2005, 2006b).
Acamprosate has poor oral bioavailabilty; there- Poor adherence is a major problem with disulfiram fore, the dosage used clinically is comparatively high: treatment; most patients discontinue treatment 1998 mg (two 333-mg tablets three times daily in within a few months (Azrin et al. 1982). Therefore, patients with a body weight greater than 60 kg; two the use of supervised disulfiram treatment has been 333-mg tablets twice daily in lighter patients). The advocated. A comprehensive review of 13 controlled drug is not known to have any psychotropic (e.g., and five uncontrolled studies of the drug concluded sedative, antidepressant) effects or to interact with that supervised disulfiram reduced drinking and other psychotropic agents, either pharmacodynami- improved the rate of retention in treatment com- cally or pharmacokinetically. Acamprosate is usually pared with unsupervised disulfiram or a no-disul- well tolerated but should not be given to patients firam control group (Brewer et al. 2000). Disulfiram with hypercalcemia. The most frequent adverse is best considered a second-line medication in effect is diarrhoea.
relapse prevention, which can be combined with Acamprosate significantly reduced relapse rates either acamprosate or naltrexone.
in alcohol-dependent patients in a number of M. Soyka et al.
placebo-controlled, double blind trials (Level A).
ton and Whelan 2001; Bouza et al. 2004; Srisur- Acamprosate has been studied in more than 5,000 apanont and Jarusuraisin 2005; Roesner et al. 2008).
alcohol-dependent patients in 19 double-blind, pla- The meta-analysis by Bouza et al. (2004) included cebo-controlled clinical trials conducted in 14 dif- 19 studies of naltrexone involving 3,205 participants ferent countries (Bouza et al. 2004; Mann et al.
with alcohol dependence. The large majority of these 2004). Meta-analyses provide clear evidence of the studies were of short duration (i.e., 512 weeks).
efficacy of acamprosate for the maintenance of Using relapse to heavy drinking as an outcome, these abstinence (Kranzler and Van Kirk 2001; Bouza studies yielded an OR 0.62 [95% CI 0.52, 0.75, et al. 2004; Mann et al. 2004; Roesner et al. 2008).
P B0.00001], reflecting a 38% lower likelihood of For example, in a meta-analysis of data from 11 relapse with naltrexone treatment. The likelihood of European clinical trials that included more than total abstinence, while also favouring naltrexone, 3,000 patients, acamprosate nearly doubled the failed to reach statistical significance (OR 1.26; likelihood of preventing relapse to drinking [odds 95% CI 0.97, 1.64, P 0.08). Secondary out- ratio (OR) 1.88, 95% confidence interval (CI)  comes in this meta-analysis were also significantly 1.57, 2.25, P B0.001] and increased the likelihood better in the naltrexone-treated group, including that patients would remain in treatment by nearly time to relapse, percentage of drinking days, number one-third (OR 1.29, 95% CI 1.13, 1.47, P B of drinks per drinking day, days of abstinence, total 0.001). Perhaps the most robust effect of acampro- alcohol consumption during treatment, and levels of sate was seen in a German multi-centre study, where g-glutamyl transpeptidase and aspartate aminotrans- the abstinence rate after 1 year was 41%, compared to 22% in the placebo group, an effect that persisted Two long-acting (up to 1 month), injectable during a 1-year period following the discontinuation (intramuscular) formulations of naltrexone have of study medication (Sass et al. 1996). However, a also been evaluated in clinical trials to improve multi-centre trial conducted in the US (Mason et al.
adherence to the medication and to increase bioa- 2006) did not show an intent-to-treat effect of vailability by avoiding first-pass metabolism. One acamprosate (though secondary analyses did provide formulation (Drug Abuse Sciences, Inc.) was admi- support for the drug over placebo), while the recent nistered at a dosage of 300 mg in the first month and COMBINE Trial failed to show an effect of acam- then 150 mg monthly for 2 months, in conjunction prosate on relapse prevention, either alone, or in with motivational enhancement therapy. Although it combination with naltrexone (Anton et al. 2006).
did not reduce the risk of heavy drinking, the activeformulation delayed the onset of any drinking, Opioid receptor antagonists. Based on evidence that increased the total number of days of abstinence endogenous opioid peptides, such as b-endorphin, and doubled the likelihood of subjects remaining are involved both in the rewarding effects of ethanol abstinent throughout the 12-week study period and risk for alcoholism (Gianoulakis et al. 1989, (Kranzler et al. 2004). A second formulation 1996), naltrexone and nalmefene, opioid receptor (Alkermes, Inc.) was evaluated in two dosage antagonists with no intrinsic agonist properties, have strengths (Garbutt et al. 2005) and in combination been studied for the treatment of alcohol depen- with a low-intensity psychosocial intervention. Com- pared with placebo treatment, the 380-mg formula-tion resulted in a 25% reduction in the event rate of Naltrexone. Early studies with naltrexone found that heavy drinking (P 0.02). There was a significant it reduced craving for alcohol, alcohol's reinforcing effect in men (48% reduction), but not in women.
The 190-mg formulation produced a non-significant chances of continued drinking following a slip or (P 0.07) 17% reduction in heavy drinking.
lapse, suggesting that naltrexone blocked the en-dogenous opioid system's contribution to the ‘pri- Comparative studies of acamprosate and naltrexone.
ming effect' of alcohol (Volpicelli et al. 1995; Three published studies have directly compared O'Malley et al. 1996a). However, the beneficial acamprosate, naltrexone, and their combination. In effects of naltrexone were found to diminish gradu- one study, naltrexone, acamprosate, and the two ally after the 12-week medication treatment period medications combined were significantly more effi- (O'Malley et al. 1996b; Anton et al. 2000).
cacious than placebo (Kiefer et al. 2003). The Many, but not all, subsequent studies of naltrex- combined medication group had a significantly one showed it to be efficacious in the treatment of lower relapse rate than either placebo or acampro- alcohol dependence (Level A). The efficacy of sate, but it did not differ statistically from naltrex- naltrexone has been confirmed in several published one. In addition, there was a non-significant trend meta-analyses (Kranzler and Van Kirk 2001; Stree- for naltrexone to produce a better outcome than Guidelines for Biological Treatment of Substance Use and Related Disorders acamprosate on the time to the first drink and time trial, the drug diminished drinking and increased to relapse. The US COMBINE Study (COMBINE abstinence among patients with an early onset of Study Research Group 2003a,b) compared naltrex- alcohol dependence (i.e., before age 25) (Johnson one, acamprosate, and their combination, together et al. 2000). In an open-label study in 40 patients, with either medical management or an intensive ondansetron 4 mg twice daily decreased drinks per psychotherapy. It found naltrexone to be efficacious, day in early-onset, but not in late-onset alcoholics while neither acamprosate alone nor acamprosate in (Kranzler at al. 2003b). Taken together, these data combination with naltrexone was superior to pla- suggest that ondansetron is a promising agent for use cebo (Anton et al. 2006). A single-site, open-label, among early-onset alcoholics.
non-randomized study from Australia showed thatthe combination of acamprosate and naltrexone was superior to either medication alone (Feeney et al.
Carbamazepine, valproate, and topiramate havebeen studied for the treatment of alcohol depen- Nalmefene. Three clinical trials of the efficacy of dence (for a review, see Ait-Daoud et al. 2006).
nalmefene have been published (Level C). One study Carbamazepine reduced drinks per drinking day and found no efficacy at 20 or 80 mg/day, although when time to first drink in abstinent alcoholics (Mueller combined, the nalmefene-treated groups had signi- et al. 1997; Malcolm et al. 2002) (Level C). Small ficantly lower rates of heavy drinking compared to studies of valproate in alcohol-dependent individuals the placebo group (Mason et al. 1999). A second suggest that it might reduce relapse to heavy drink- study found no efficacy for nalmefene at 5, 20 or ing and promote abstinence (Brady et al. 2002; 40 mg/day on any measure of treatment outcome Longo et al. 2002) (Level D). Topiramate has been (Anton et al. 2004). Recently, Karhuvaara et al.
studied in more detail, although few animal studies (2007), reported the results of a multi-centre, have been published to date (Gabriel et al. 2005; randomized trial of targeted nalmefene combined Farook et al. 2007; Hargreaves and McGregor 2007; with a minimal psychosocial intervention, in which Nguyen et al. 2007). A single-site clinical trial of alcohol dependent subjects were encouraged to use topiramate in alcohol-dependent individuals who 1040 mg of the medication when they believed were actively drinking showed that it reduced drinks drinking to be imminent. Nalmefene was signifi- per day, drinks per drinking day, and percentage of cantly better than placebo in reducing heavy drink- heavy drinking days, and increased the percentage of ing days, very heavy drinking days, and drinks per days abstinent, compared with placebo (Johnson drinking day and in increasing abstinent days. After 2003). Recently, the results of a 14-week, multi- 28 weeks, when a subgroup of nalmefene-treated centre trial of topiramate, combined with coun- subjects was randomized to a withdrawal extension, selling to enhance medication compliance, were subjects randomized to receive placebo were more published (Johnson et al. 2007) (Level B). That likely to return to heavier drinking.
study showed the medication to be superior to In conclusion, there is abundant evidence sup- placebo in reducing the percentage of heavy drinking porting the use of naltrexone for treatment of days, as well as a variety of other drinking outcomes.
alcohol dependence (Level A). However, the optimal However, the medication was associated with more dosage and duration of treatment are two important adverse events and a higher rate of premature study clinical questions that remain to be adequately discontinuation than placebo. The greater tolerabi- addressed, along with the patient population and lity of topiramate in the single-site study may have treatment goal (i.e., harm reduction versus absti- resulted from a slower rate at which the dosage of the nence) that are most likely to yield beneficial effects.
medication was increased (i.e., titration to the 300- New approaches to the use of naltrexone, including mg target dosage in the single-site study occurred long-acting injectable formulations, promise to en- over 8 weeks, compared to 6 weeks in the multi- hance the clinical utility of the medication. Although centre study).
it has shown some promise, additional research isrequired to evaluate more fully the utility of nalme-fene in the treatment of alcohol dependence.
Other medications A number of other drugs are currently being testedfor the treatment of alcohol dependence, including the GABAB agonist baclofen (Heilig and Egli 2006).
The selective 5-HT3 receptor antagonist ondanse- Other drugs modulating glutamatergic neurotrans- tron has shown promise in a subset of patients with mission and receptors for stress-related neuropep- alcohol dependence (Ait-Daoud et al. 2001). In one tides (i.e., neuropeptide Y, corticotrophin releasing M. Soyka et al.
factor) are also being studied. Drugs blocking the Berglund, Prof. Gorelick and Prof. Hesselbrock cannabinoid CB1 receptor may represent a novel have no financial conflicts of interest to declare.
mechanism of action for the treatment of addictivedisorders (Gelfand and Cannon 2006). The CB1 Conflict of interest antagonist SR141716A (rimonabant) is the firstclinically available, potent, selective, and orally Supported by BMBF (Ministry of Science and active antagonist of the CB1 receptor. Rimonabant Education, Germany) and Schweifer alkohol stiftung reduces voluntary alcohol intake in an animal model of alcoholism (Basavarajappa and Hungund 2005).
No clinical studies of rimonabant for alcohol depen- dence treatment have yet been published.
The final draft of the guidelines was sent to allPresidents of the various national societies of biolo- Disclosure statement gical psychiatry that belong to the WFSBP; ourthanks go to those Presidents who sent us their These treatment guidelines have been developed by comments on the guidelines.
psychiatrists who are in active clinical practice and/or primarily involved in research or other academicendeavours. It is possible that through such activities some task force members have received income Addolorato G, Balducci G, Capristo E, et al. 1999. Gamma- related to treatments discussed in this guideline.
hydroxybutyric acid (GHB) in the treatment of alcohol with- Task force members are asked to disclose any drawal syndrome: a randomized comparative study versusbenzodiazepine. Alcohol Clin Exp Res 23:15961604.
potential conflict of interest that may bias (or appear Agosti V, Levin FR. 2006. The effects of alcohol and drug to bias) their contribution, whether as an author or dependence on the course of depression. Am J Addict 15:71 reviewer of the guidelines. Guideline drafts are reviewed not only by task force members but also Ait-Daoud N, Johnson BA, Prohoda TJ, Hargita ID. 2001.
Combining ondansetron and naltrexone reduces craving among by the Chairman of the WFSBP Committee on biologically predisposed alcoholics: preliminary clinical evi- Scientific Publications, the Presidents of those na- dence. Psychopharmacology 154:2327.
tional societies of biological psychiatry that belong to Ait-Daoud N, Malcolm RJ, Johnson BA. 2006. An overview of the WFSBP, and the WFSBP Executive Committee medications for the treatment of alcohol withdrawal and members. Revised versions of the guidelines address alcohol dependence with an emphasis on the use of older andnewer anticonvulsants. Addictive Behav 31:16281649.
or integrate the comments of these multiple re- American Psychiatric Association. 2000. Diagnostic and statistical viewers. The development of the WFSBP treatment manual of mental disorders. 4th ed. Text revision.
guidelines is not financially supported by any com- American Psychiatric Association. 2007. Practice guideline for the treatment of patients with substance use disorders, secondedition. Am J Psychiatry 164: Supplement.
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CLINICAL CROSSROADS CONFERENCES WITH PATIENTS AND DOCTORS An 83-Year-Old Woman With ChronicIllness and Strong Religious BeliefsHarold G. Koenig, MD, Discussant strength was decreased, sensation to pinprick was de-creased in the digits bilaterally, and motor strength of the DR BURNS: MRS A IS AN 83-YEAR-OLD WOMAN WHO HAS MUL- lower extremities was 2/5 proximally and 3/5 distally. Her

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High Resistance of Plasmodium falciparum toSulphadoxine/Pyrimethamine in Northern Tanzania andthe Emergence of dhps Resistance Mutation at Codon581 Samwel Gesase1, Roly D. Gosling2*, Ramadhan Hashim1, Rosalynn Ord2, Inbarani Naidoo2,3, Rashid Madebe1, Jacklin F. Mosha4, Angel Joho1,4, Victor Mandia1, Hedwiga Mrema1, Ephraim Mapunda1, Zacharia Savael1, Martha Lemnge1, Frank W. Mosha4, Brian Greenwood2, Cally Roper2, Daniel