The use of Topiramate in Alcohol withdrawal

and dependence A

presentation by Edward

Gomm

Reasons and Methods Personal interest

Substance abuse clinic Drinking in media

Methods Textbooks Medline/Cochrane Library searches Drug Clinic/personal correspondence

Alcohol dependence syndrome - Key

elements Desire or compulsion to drink Salience of drinking/ Neglect Increased tolerance Withdrawal symptoms - relieved by further drinking

Difficulty controlling drinking Narrowing of repertoire Reinstatement after abstinence

The withdrawal state Severity related to size of dependence and quantity habitually consumed.

Mild symptoms include: mood disturbances (anxiety, depression), sweating, tremor, nausea, vomiting, raised pulse, hyperaucusis and raised BP.

Severe symptoms: “Delerium tremens”, hallucinations, seizures (grand mal).

Alcohol Detoxification

May be managed in out-patient. Acute detox - Benzodiazapine indicated.

Day Diazepam Chlordiazepoxide1 15mg, qd 30mg,qd2 10mg,qd 30mg,td3 10mg,td 20mg,bd4 5mg,qd 10mg,bd5 5mg,td 10mg,bd6 5mg,bd 10mg,nocte7 5mg,nocte

Dependence Syndrome - Relapse Prevention

Psychological therapy e.g Motivational interviewing.

Pharmacological: Disulfiram (Antabuse) Acamprosate (Campral) Others - not licensed for alcohol dependence (Naltrexone, SSRIs, Buspirone, Ondansetron)

Both should be incorporated into comprehensive treatment program.

Problems with current medications

Benzodiazepine Potential for abuse Potential for respiratory depression

Disulfiram: Inappropriate for: CV or respiratory disease, hepatic or renal impairment, diabetes, epilepsy, and pregnant or breastfeeding women.

Requires commitment and/or supervision. Drug interactions.

Acamprosate Relatively safe, but should not be prescribed to hepatic/renal impairment or pregnant/breastfeeding women.

UK trial showed little benefit over Placebo (Chick et al,2000).

Naltrexone: Potential liver toxicity Problem with opioid analgesia

Topiramate (Topamax)

From naturally occurring sulfamate fructopyranose.

Anticonvulsant used to prevent epileptic seizures

Multiple actions: Blocks VgNa+ and VgCa2+ channels Inhibits carbonic anhydrase Inhibits activity of AMPA and kainate subtypes of glutamate receptors

Facillitates GABAergic neurotransmission

Reproduced from www.drugs.com

Mechanism in preventing alcohol dependence

Reproduced from Ait-Daoud et al, 2006

Mechanism in withdrawal

May reduce the over-activity of the sympathetic NS and neuronal hyperactivity seen in withdrawal.

As effective as Lorazepam in treating withdrawal (Choi et al, 2005).

Evidence Only one RCT- Johnson et al, Lancet 2003. Method:

12 wk, double blind, placebo controlled trial Recruited 150 alcohol dependants (DSM-IV criteria). Received daily 300mg oral topiramate or placebo, with weekly compliance therapy

Results - compared to placebo. 2.88 fewer drinks per day 3.10 fewer drinks per drinking day 27.6% fewer heavy drinking days 26.2 more days abstinent Reduction in plasma gama-glutamyl transferase

Benefits Good pharmacological profile.

Quick absorption (within 2hrs) Not affected by food consumption Poor plasma protein binding

Could be used in withdrawal AND dependence syndrome.

Seizure protection Not addictive. No adverse reaction if alcohol consumed.

Conclusion Current medication is limited.

Can be abused Can interact with other medication Do not treat withdrawal and dependence syndrome together.

Topiramate may be used in withdrawal and relapse prevention.

Initial trials indicate it is effective at preventing relapse.

Further investigation is required.

Reflection - Strengths and Weaknesses.

Limitations: Only focused on one drug Psychological therapy also crucial

Learning: Details of alcohol dependence Refined literature searching/presentation skills

The importance of exploration of possible new roles for current medications

References Ait-Daoud N, Malcolm R.J, andJohnson B.A (2006) An overview of medications for the treatment of alcohol withdrawal and alcohol dependence with an emphasis on the use of older and newer anticonvulsants. Addictive Behaviors. 31:1628-49

Chick J, Howlett H, Morgan M Y, and Ritson B (2000) United Kingdom Multicentre Acamprosate Study (UKMAS): a 6-month prospective study of acamprosate versus placebo in preventing relapse after withdrawal from alcohol. Alcohol 35:587-593.

Choi E. A, Ki S. W, Kim S. E, Kim J. W, and Park, J. K. (2005). The efficacy and safety of topiramate in the treatment of alcohol withdrawal. Journal of the Korean Neuropsychiatry Association, 44, 328-333.

Garbutt J C, West S L, Carey T S, Lohr K N, and Crews F T(1999). Pharmacological treatment of alcohol dependence: a review of the evidence. JAMA: 281: 1318-25.

Griffith Edwards, E.Jane Marshall, and Christoher C.H. Cook (2003). The treatment of drinking problems.4th Edition. Cambirdge university press.

Hamid Ghodse (2002). Drugs and addictive behaviour; a guide to treatment. 3rd Edition. Cambridge university press.

Johnson B.A, Ait-Daoud N, Bowden CL et al( 2003). Oral topiramate for treatment of alcohol dependence: a randomized controlled trial. Lancet.361: 1677–85.

Ma J.Z, Ait-Daoud N, and Johnson B.A (2006) Topiramate reduces the harm of excessive drinking: implications for public health and primary care. Addiction.101:1561-1568.