topiramate in stimulant use disorder: is topiramate all...

Topiramate in Stimulant Use Disorder: Is Topiramate All it’s

Cracked Up to Be?

Maria P. Blaze, PharmD

PGY1 Pharmacy Practice Resident

South Texas Veterans Health Care System, San Antonio, Texas

Division of Pharmacotherapy, The University of Texas at Austin College of Pharmacy

Pharmacotherapy Education and Research Center

The University of Texas Health Science Center at San Antonio

April 10, 2015

Learning Objectives

1. Discuss the history, pharmacology, clinical use, and abuse of cocaine

2. Describe the etiology, clinical presentation, and consequences of cocaine use disorder

3. Evaluate the literature regarding the role of topiramate in the treatment of cocaine use disorder

4. Formulate a clinical recommendation regarding the use of topiramate in cocaine use disorder

http://www.atticpaper.com/proddetail.php?prod=1967-coca-cola-coke-ad-large-can&cat=67

MARIA P. BLAZE, PHARM.D. 1

Background

I. Cocaine

A. History1-3

i. Originates from a plant indigenous to South America called the Erythroxylum

coca

ii. The ancient Incas chewed coca leaves as a stimulant and they may have been

aware of its local anesthetic properties

iii. Albert Niemann a German chemist, first synthesized the active alkaloid of the

coca leaf in 1860 noting the numbing properties

B. Mechanism of action (MOA)1, 3-6

i. Local anesthetic

a) Mediated through inhibition of the initiation and conduction of nerve

impulses

b) Blocks fast sodium channels in the cell membrane which decrease

depolarization

ii. A powerful central nervous system (CNS) stimulant, mediated through the

activation of the sympathetic nervous system (SNS)

iii. Blocks presynaptic reuptake of norepinephrine (NE), dopamine (DA), and

serotonin (5-HT)

iv. Enhances the effects of excitatory amino acids such as glutamate

v. Decreases the transmission of inhibitory neurotransmitters such as γ-

Aminobutyric acid (GABA)

C. Pharmacokinetics1, 3, 4, 6

i. Cocaine can be absorbed across all mucosal surfaces

Table 1: Absorption1, 3, 4, 6

Route of Exposure Onset of Action Peak Action Duration of Action

IV <1 min 3–5 min 30–60 min

Nasal insufflation (snorting) 1–5 min 20–30 min 60–120 min

Inhalation (smoking) <1 min 3–5 min 30–60 min

GI 30–60 min 60–90 min Unknown

ii. Metabolism1, 3, 4

a) Primarily metabolized by plasma cholinesterase to metabolites of

unknown activity

1. Ecgonine methyl ester

2. Benzoylecgonine

b) Half-life ~75 minutes

iii. Elimination1, 2

a) Primarily renal as metabolites

b) Unchanged drug is <10%


D. Illegal usage 1, 3-7

i. Most common routes of cocaine abuse

a) Inhaled

b) Smoked

c) Injected

1. Intravenous

2. Intramuscular

ii. Street names include blow, C, coke, crack, flake, and snow6

Figure 1: Cocaine Hydrochloride (salt)6

iii. Four formulations of cocaine

a) Paste

b) Powder (salt)

c) Free base

d) Crack rocks

E. Cost8

i. Varies by state, an eight ball of cocaine (3.5 grams) costs ~$50-$200

ii. Crack rocks are usually sold in 1/10 gram and costs ~$20

Figure 2: Free Base3 Figure 3: Crack Rocks6


F. Drug Enforcement Administration (DEA) schedule1, 2, 9

i. Classified as a Schedule II agent

a) Drugs with a high potential for abuse

b) Less abuse potential than Schedule I drugs

c) Use can potentially lead to severe psychological or physical dependence

d) There is a medically accepted use1, 2

1. First documented use of cocaine was in 1884

2. Used in a local ophthalmic procedure as a local anesthetic

e) Other examples of Schedule II drugs are methadone, hydromorphone,

meperidine, oxycodone, fentanyl, amphetamine/dextroamphetamine,

and methylphenidate

Cocaine Use Disorder

II. Epidemiology

A. Incidence/prevalence1, 6, 7

i. Crack cocaine is the 2nd most abused illegal drug in the United States, cocaine

HCl (powder) is the 4th

ii. Average age of first use is ~23 years10

iii. Around 33.7 million (13.8%) Americans reported lifetime use of cocaine

iv. Around 7.9 million Americans ≥12 years reported lifetime use of crack cocaine

v. It is estimated that 600,000 Americans are frequent users (≥51 days during the

preceding year)7

vi. It is estimated that 2.4 million Americans are occasional users (use ≤12 days

during the preceding year)7

B. Risk factors for cocaine use disorder4, 6, 10

Table 2: Risk factors4, 6, 10

Family history/genetics Unemployment Psychiatric disorders

Cigarette smokers Heavy alcohol drinkers Multiple previous arrest

Female gender Substance abusing parents Other substance abuse

III. Etiology

A. DA, glutamate, and GABA systems play key roles in mediating drug-induced

neuroadaptation16

B. DA is responsible for the psychological and reinforcing effects

C. Blockade of the DA reuptake transporter (DAT)5, 6, 12,14, 15


https://www.cnsforum.com/educationalresources/imagebank/substance_abuse/mao_cocaine

Figure 4: DA re-uptake by cocaine

D. Reward center dysregulation

i. Dopaminergic, glutamatergic, and GABAnergic pathways project from the

ventral tegmental area (VTA) to CNS reward centers3, 6, 11-15

a) Nucleus accumbus (NAcc)

b) Amygdala

c) Hippocampus

d) Prefrontal cortex

e) These structures mediate the important reinforcing effects of cocaine12

ii. Increased DA concentration at critical brain sites such as ventral tegmental area

(VTA) 5, 6 ,14-16

iii. Up-regulation of glutamate receptors and increased glutamate release11, 12

iv. Increased in cellular expression of α-Amino-3-hydroxy-5-methyl-4-

isoxazolepropionic acid (AMPA) receptors on both glutamate and DA

receptors16

v. Diminished (GABA) transmission in the VTA16

IV. Presentation1, 3-7, 10

A. Acute intoxication with cocaine leads to a variety of physical and mental status changes

Table 3: Acute cocaine intoxication1, 3-7, 10

Physical

Decreased need for food Increased energy Hypersexuality

Hypervigilance Mydriasis Diaphoresis

Tachycardia Tachypnea Hyperactivity

Hyperthermia Hypertension Increased alertness

Mental status

Agitation Psychosis Panic

Paranoia Anxiety Disorientation

Euphoria Confusion Fear

https://www.cnsforum.com/educationalresources/imagebank/substance_abuse/mao_cocaine


B. Chronic cocaine use can lead to a variety of physiological consequences

Table 4: Chronic cocaine use consequences1, 3, 6, 10

Chronic use

Weight loss Insomnia Retinal hemorrhages

Nasal septum perforation Skin tracks Loss of sense of smell

C. Withdrawal symptoms occur after prolonged or heavy usage of cocaine

Table 5: Withdrawal symptoms1, 3-6, 10

Withdrawal symptoms

Cocaine craving Irritability Paranoid ideation

Depression Fatigue Vivid dreams

D. Urine drug screen (UDS)1, 4, 6, 10

i. Immunoassays

a) Most tests are highly specific for the metabolite benzoylecgonine

b) Sensitive up to 300 nanograms/mL

ii. Use within the past 24-72 hours are typically detected

iii. In chronic users benzoylecgonine may be detected for up to 22 days

iv. More sensitive techniques can detect cocaine for up to 2 weeks from last use

a) Radioimmunoassay

b) Gas chromatography

V. Diagnostic criteria

A. Dependence develops in 5-6% of users within the first year of use6

B. Only 1/3 of users will become and remain abstinent6

C. Around 42% of patients enrolled in cocaine addiction programs do not complete4

D. Diagnostic and Statistical Manual of Mental Disorders 5 classification (DSM-5)10


Table 6: Criteria for stimulant use disorder10

A pattern of amphetamine-type substance, cocaine, or other stimulant use leading to clinically significant impairment or distress, as manifested by at least two of the following, occurring within a 12-month period:

1. The stimulant is often taken in larger amounts or over a longer period than was intended

2. There is a persistent desire or unsuccessful efforts to cut down or control stimulant use

3. A great deal of time is spent in activities necessary to obtain the stimulant, use the stimulant, or recover from its effects

4. Craving, or a strong desire or urge to use the stimulant

5. Recurrent stimulant use resulting in a failure to fulfill major role obligations at work, school, or home

6. Continued stimulant use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of the stimulant

7. Important social, occupational, or recreational activities are given up or reduced because of stimulant use

8. Recurrent stimulant use in situations in which it is physically hazardous

9. Stimulant use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the stimulant

10. Tolerance

11. Withdrawal

Severity: Mild 2-3 symptoms, Moderate 4-5 symptoms, Severe ≥6 symptoms

VI. DSM-5 updates for substance related disorder10

A. No specific cocaine use disorder changes from DSM-IV to DSM-5

B. DSM-5 does not separate the diagnoses of substance abuse and dependence as in DSM-

IV

C. Threshold for substance use disorder diagnosis

i. DSM-5 is set at two or more criteria

ii. DSM-IV was three or more

D. Additions

i. Withdrawal is new for DSM-5

ii. Craving or a strong desire or urge to use a substance


VII. Health consequences1, 3-7

Table 7: Organ systems1, 3-7

Cardiac

Vasoconstriction in coronary arteries Cardiomyopathy QRS interval prolongation

CNS Seizures Stroke Coma

Pulmonary

Pulmonary edema and hemorrhage Pneumonitis Asthma

Gastrointestinal (GI) Mesenteric vasospasm Ulceration Perforation

Reproductive

Men

Impotence, gynecomastia Women

Galactorrhea, amenorrhea, infertility Renal

Rhabdomyolysis

Creatine kinase levels >2000 units/L Acute renal failure

VIII. Economic costs

A. Total cost of illicit drug abuse is $193 billion (2007)17

B. These costs take into consideration crime, health, and productivity costs

Table 8: Economic costs17

Health Care Overall

Tobacco $96 billion $193 billion

Alcohol $30 billion $235 billion

Illicit Drugs $11 billion $195 billion

C. Estimated 2.5 million drug misuse or abuse emergency department (ED) visits occur

yearly (2011)18

D. Equivalent to 402 ED visits for each 100,000 persons in the U.S. population18

i. The highest rates were found with cocaine and marijuana

ii. Cocaine accounts for ~40% of ED visits

Treatment of Cocaine Use Disorder

IX. Treatment

A. Goals of therapy12

i. Achieve abstinence or reduction in the use and effects of cocaine

ii. Reduce the frequency and severity of relapse


iii. Improve psychological and social functioning

B. Treatment5

i. No specific cocaine use disorder treatment guidelines

ii. Treatment principles are based on detoxification, initial recovery, and relapse

prevention

iii. Management of acute intoxication and withdrawal

a) Supportive care depending on presentation

b) Symptom specific pharmacotherapy

C. Non-pharmacologic3-6, 12

i. Cognitive-behavioral therapy (CBT) has shown to be effective

ii. Contingency management (CM)/Motivational incentives (MI)

a) Rewards patients who remain abstinent

b) Voucher or prize based system

iii. 12 step programs-Cocaine Anonymous

D. Pharmacotherapy3-6, 12, 19

i. No FDA approved pharmacotherapy options

ii. Summary of pharmacotherapy agents that have been researched for use in the

treatment (Appendix A)4, 6, 12, 19, 20

X. Topiramate

A. Classification/Indication21, 22

i. Neurological agent

ii. Anticonvulsant

Table 9: Topiramate indications21,22

Labeled Off-label

Lennox-Gastaut syndrome; Adjunct

Migraine; Prophylaxis

Partial seizure, Initial monotherapy and adjunct

Tonic-clonic seizure, Primary generalized; Adjunct and monotherapy

Alcohol use disorder

Eating disorders

o Binge eating disorder

o Bulimia nervosa

Essential tremor

Obesity

B. MOA21, 22

i. Blockage of voltage-sensitive sodium channels

a) Reduces the duration of abnormal discharges

b) Reduces the number of action potentials

ii. Enhances the activity of the inhibitory neurotransmitter GABA at the GABA-A

receptors by increasing the frequency at which GABA activates GABA-A

iii. Inhibits excitatory transmission by antagonizing glutamate receptor AMPA

iv. A weak carbonic anhydrase inhibitor


C. Dosing21, 22

i. 200mg-400 mg/day-Lennox-Gastaut syndrome; Adjunct

ii. 50mg-100 mg/day-Migraine; Prophylaxis

iii. 100mg-400 mg/day-Partial seizure, Initial monotherapy and adjunct

iv. 100mg-400 mg/day-Tonic-clonic seizure, Primary generalized; Adjunct and

monotherapy

D. Pharmacokinetics

Table 10: Pharmacokinetics21, 22

Absorption Distribution Metabolism Elimination

80% bioavailable Low plasma protein binding

Hepatic: not extensive Inducer (mild): CYP3A4

Inhibitor (mild): CYP2C19

70% unchanged

Half-life: 21 hours

E. Adverse effects

Table 11: Topiramate adverse effects21, 22

Common Serious

Weight loss

Increased bicarbonate level

Memory impairment/Reduced concentration span

Sedation

Paresthesia

Steven Johnson Syndrome

Liver failure

Hyperammonemia

Hypohidrosis

Increased body temperature

Nephrolithiasis

XI. Landmark trial of topiramate efficacy in cocaine use disorder23

Table 12: Landmark topiramate trial23

Author Patient characteristics Intervention Results

Kampman et al., 2004

(Randomized, double-blind)

13 week

N=40

DSM-IV cocaine-dependent

Topiramate 200 mg/day

Placebo

After week 8, topiramate-treated subjects were more likely to be abstinent from cocaine vs. placebo (p=0.01)

Topiramate-treated subjects were also more likely to attain 3 weeks of continuous abstinence from cocaine (59% vs. 26%, p=0.05)

Take home points

The trial suggest that topiramate may be a promising medication for the treatment of cocaine dependence


XII. Rating scales used in cocaine use disorder (Appendix B)

A. Visual analog scale of cocaine effects (VAS-C)24

B. Multiple choice questionnaire (MCQ)24

C. Profile of mood states (POMS)24

D. Clinical Global Impression-Observer (CGI) scale25

E. Obsessive compulsive drinking scale (OCDS)

Clinical Evidence

Johnson BA, et al. Topiramate's effects on cocaine-induced subjective mood, craving and preference for money over drug taking. Addict Biol. 2013;18(3):405-16.24

Overview

Objective To determine whether topiramate can reduce significantly low dose vs. high-dose cocaine-induced subjective mood changes and preference for money over drug taking

Trial design Double-blind, crossover, 25 week trial

Patients Inclusion criteria

DSM-IV cocaine dependent

Aged 18-55 years

Experienced injected cocaine or psychoactive substances

Exclusion criteria

Axis I psychiatric disorders

Outcomes Primary

VAS-C

MCQ

Secondary

POMS

Adverse events

Interventions Two separate 9 day blocks with a 1 week washout period

Days 1-5, patients were pre-treated with either topiramate 100 mg BID or placebo BID

Experimental days 6-8, patients received a single IV infusion of each of the three dose levels

o No drug IV injection o Low dose cocaine 0.325 mg/kg IV o High dose cocaine 0.65 mg/kg IV

VAS-C completed 60 minutes before morning dose of medications, before infusions and at 2-10 min (every 2 hours), 20-60 min (every 20 min), and 120 minutes post infusions

MCQ completed after doses of cocaine and on day 9

POMS completed 60 minutes before morning dose of medications, then 20, 60, and 120 minutes after infusions

Results

Baseline characteristics

N=24

Mean age 34 years

Gender 79% male

Ethnicity 63% African American

Self-reported days of cocaine use in past 30 days, ~13 days


Primary outcomes

Mixed effects ANCOVA model analyzed effects of treatment and cocaine dose to assess group differences

Figure 5: VAS-C and MCQ results

Topiramate vs. placebo was not significant for overall measures of the VAS-C and MCQ (p>0.1)

Topiramate vs. placebo on high dose cocaine, significance was found on a individual component of the VAS-C rating scale (VAS-craving, p=0.0026) and MCQ-price (p<0.0001)

Topiramate’s effects on low-dose cocaine showed an enhanced effect for VAS-euphoria, VAS-stimulated, and MCQ-price

Secondary outcomes

Mixed effects ANCOVA model analyzed effects of treatment and cocaine dose to assess group differences

POMS o No significant effect between topiramate vs. placebo on cocaine

dose

Adverse events

Table 13: Adverse events

Event Topiramate (%) Placebo (%)

Headache 26 26

Fatigue 26 18

Paresthesia 24 12

Dizziness 20 12

Taste alteration 14 10

No events were statistically significant, p>0.05


Conclusions

Author’s conclusions

Topiramate decreased craving for cocaine and the amount of money that subjects were willing to pay to receive additional high doses of cocaine

Certain cocaine effects can be enhanced by topiramate with low doses of cocaine

Strengths Validated rating scales

Reported adverse events Limitations Small sample size

Cross over study design

Mostly males

Mostly African Americans

Take home points

Focus of the study was on topiramate’s efficacy with the symptoms associated with cocaine use

Max dose of topiramate was 200 mg/day

The specific injected cocaine doses may not be generalizable to real world cocaine users

Johnson BA, et al. Topiramate for the Treatment of Cocaine Addiction. JAMA Psychiatry 2013; 70 (12):1338-46.26

Overview

Objective To determine the efficacy of topiramate vs. placebo as a treatment for cocaine dependence

Trial design Randomized, double-blind, placebo-controlled, 12 week trial


≥18 years

DSM-IV cocaine dependent

≥1 cocaine-positive urine specimens (>300 ng/mL) during screening AND

≥4 positive urine specimens during the 2-week baseline screening period

Exclusion criteria

Alcohol dependence with significant withdrawal symptoms

Psychiatric illness with ongoing treatment

Seizure disorder

Bulimia/anorexia

Outcomes Primary

Weekly difference from baseline in the proportion of cocaine nonuse days during weeks 6 to 12

Secondary

Urinary cocaine-free weeks during weeks 6 to 12

Exploratory

CGI-Observer scale

Adverse events

Interventions

Phase I: Screening

2 weeks

≥4 cocaine positive urine specimens (>300 ng/mL) Phase II: Randomization 1:1

Topiramate (N=71) or placebo (N=71)

Three times/week: Self report cocaine use, UDS, adverse events, and CGI

Both with weekly CBT


Interventions Table 14: Topiramate Dosing schedule

Week Morning dose (mg) Night dose (mg) Total (mg)

0-1 1 x 25 1 x 25 50

1-2 1 x 25 2 x 25 100

2-3 1 x 25 plus 1 x 50 1 x 25 plus 1 x 50 150

3-4 1 x 100 1 x 100 200

4-5 1 x 100 plus 1 x 25 1 x 100 plus 1 x 25 250

5-6 1 x 100 plus 2 x 25 1 x 100 plus 2 x 25 300

6-12 1 x 100 plus 2 x 25 1 x 100 plus 2 x 25 300

Results


N=142

Mean age 44 years

Gender 75% male

Ethnicity 70% African American

Self-reported days of cocaine use in past 30 days, ~13 days

Lifetime use of cocaine 16 years

Route of cocaine use o Intranasal N=21 o Smoked N=123

Primary outcomes

A mixed effects linear regression model was used to assess group differences between treatment and time

Figure 6: Weekly Mean Proportion of Cocaine Nonuse Days From Baseline Through Study Week 12

There was a significant effect of topiramate vs. placebo on cocaine non-use days from baseline to week 12

8.9% vs. 3.7%; 95% CI: (0.2%-10.1%) p=0.04


Secondary outcomes

Table 15: Generalized linear mixed-effects model (repeated measures)

Odds Ratio 95% CI P value

Urinary cocaine-free weeks

topiramate vs. placebo

3.21 (1.24-8.32) p=0.02

(16.6% vs. 5.8%)

Patients who received topiramate vs. placebo had a significantly greater likelihood of achieving urinary cocaine-free weeks

Table 16: Generalized linear mixed-effects model (repeated measures)

Mean 95% CI P value

CGI-Observer total score

-1.74 [(-3.12)-(-0.35)] p=0.02

Topiramate vs. placebo was associated with a significant reduction in total scores


Event Topiramate (%) N=60 Placebo (%) N=57

Decreased weight 63.5 49.3

Fatigue 45.1 35.2

Headache 38 38

Paresthesia 50.7 21.1

Taste perversion 42.3 2.9

Statistically significant adverse events: o Paresthesia, p<0.001; Taste perversion, p=0.03

Conclusions


Topiramate was significantly more efficacious than placebo at achieving the primary outcome during the efficacy period of increasing the mean weekly proportion of cocaine non-use days

Topiramate was significantly more efficacious than placebo at achieving the secondary outcome during the efficacy period of increasing the likelihood of urinary cocaine-free weeks

Topiramate compared with placebo was significantly associated with improvements in CGI-Observer scale

Strengths Double-blind

Stratified randomization

Required CBT

Treatment seeking population

Limitations Small sample size

Majority African American

Majority crack smokers

Duration of study

Take home points

Focus of the trial was on topiramate’s efficacy in promoting abstinence from cocaine

Max topiramate dose is up to 300 mg/day

Results may only be beneficial in a subset of patients with cocaine use disorder


Nuijten M, et al. Treatment of crack-cocaine dependence with topiramate: a randomized controlled feasibility trial in The Netherlands. Drug Alcohol Depend. 2014;138:177-84.27

Overview

Objective To evaluate the acceptance and effectiveness of topiramate as an add-on therapy to CBT compared to CBT alone in crack-cocaine dependent patients

Trial design Randomized, open-label, 12 week trial


≥18 years

DSM-IV Cocaine dependent

Regularly use cocaine ≥8 days in the previous month

Administer cocaine primarily by means of basing

Exclusion criteria

Severe medical or psychiatric problems

Pharmacotherapy with a potentially effective medication for cocaine dependence

Outcomes Primary

Treatment retention defined as number of CBT-sessions attended

Secondary

Medication adherence

Crack-cocaine use days

Cocaine craving

Adverse events

Interventions Randomization

Outpatient CBT plus topiramate

Outpatient CBT Topiramate dosing schedule

Topiramate was prescribed for 12 weeks

Initiated at 25 mg/day and was titrated within 3 weeks to a maximum oral dose of 200 mg/day

Other parameters

Adverse events assessed at each study visit

Urine samples analyzing benzoylecgonine levels were collected at baseline, then once weekly for the last 4 weeks of the study

Results


N=74

Mean age 42 years

Ethnicity 64% European

Gender 81% male

Lifetime regular cocaine use, ~13 years

Cocaine use in the last 30 days,~ 20 days

29.7% Heroin users

54% Cannabis users

36% receiving methadone maintenance treatment

Primary outcomes

Cox regression survival analysis analyzed treatment retention baseline to 12 weeks

o Unadjusted for covariates, not significant HR=0.67; 95% CI (0.4-1.2); p=0.15


Primary outcomes

o Adjusted for covariates, significant HR=0.53; 95% CI (0.3-1.0); p=0.03

Secondary outcomes

Medication adherence: 13.9% of patients completed at least 11 weeks of topiramate at a mean dose of 189 mg/day

Repeated measures ANCOVA analyzed o Crack-cocaine use days (mean)

Not significant 9.1 vs. 11.1; p=0.23 o Cocaine craving (mean)

Not significant 5.2 vs. 6.3; p=0.83

Adverse events reported with topiramate use


Event Topiramate (%) N=36

Paresthesia 29.5

GI complaints 16.8

Fatigue 12.6

Conclusions


Topiramate’s acceptance was generally low

Topiramate was generally well-tolerated

No indications of efficacy of topiramate in CBT retention, crack-cocaine use, and craving

Strengths CBT

Specific crack cocaine population

Stratified randomization

Treatment seeking population

Limitations Short duration

Small sample size

Majority Europeans

Open-label

Low adherence to study medication

Allowed other substance abuse disorders

Measured cocaine craving with a modified OCDS scale

Take home points

Focus of the trial was on topiramate’s efficacy in promoting treatment retention as an add-on therapy with CBT

Medication adherence to topiramate was very low

Topiramate plus CBT o Adjusted for covariates was shown superior to CBT alone for

treatment retention o Not shown superior to CBT alone for cocaine craving or a decrease

in cocaine use days


Conclusion

Topiramate may be effective for treatment in cocaine use disorder patients

o Outcomes in limited trials suggest, topiramate may be effective in maintaining cocaine

non-use days and urinary free-weeks

Topiramate in addition to CBT can potentially have a synergistic effect in treatment retention

Topiramate appears relatively safe for use in patients, longer study durations may be needed

Recommendations

There is a need for more robust studies with longer duration, larger sample sizes, and more

diverse cocaine dependent subjects to further assess topiramate’s role in the treatment of

cocaine use disorder

Based on the limited clinical studies with topiramate in the treatment of cocaine use disorder

and the mixed results of the current clinical evidence, topiramate should not be used first line as

treatment in cocaine use disorder

o CBT should continue to be first line

Currently, there are no approved pharmacotherapy options for the treatment in cocaine use

disorder, but based off the clinical evidence, topiramate may be a useful treatment option in

certain situations/populations:

o Combination with CBT for maintaining treatment retention

o Severe cocaine use disorder patients in decreasing cocaine euphoria, craving, and

stimulatory symptoms

o African Americans

o Crack-cocaine dependent patients

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Appendix A19, 20, 28-33

Table 19: Summary of pharmacotherapy agents used for cocaine dependence use disorder

Author Patient characteristics

Intervention Results

Dackis et al., 2012

N=210

DSM-IV cocainedependence

Modafinil 200mg/day

Modafinil 400mg/day

Placebo

All patient receivedCBT

No significant differencesbetween modafinil and placeboon cocaine abstinence, craving,withdrawal, or retention

Significant gender differencesshowed male patients treatedwith 400 mg/day were moreabstinent than their placebo-treated counterparts

LaRowe et al., 2013


8 weeks

N=111

DSM-IV cocainedependence

N-acetylcysteine(NAC) 1200 mg/day

(NAC) 2400 mg/say

Placebo

All patient receivedCBT

Failed to demonstrate that NACreduces cocaine use in cocaine-dependent individuals

Some evidence it preventedreturn to cocaine use in thosewho had already achievedabstinence from cocaine

Somoza et al., 2013


24 weeks

N=186

DSM-IV cocaine

dependence

Vigabatrin 3grams/day

Placebo

CBT

Biweekly counseling

CM

No significant differences wereobserved between the vigabatrinvs. placebo

Winhusen et al., 2007


12 weeks

N=141

DSM-IV cocaine

dependence

Tiagabine 20mg/day

Placebo

CBT

Participants in both groupsimproved significantly on cocainecraving and global functioning

Mancino et al., 2014

(Randomized, double-blind)1

12 weeks

N=99

DSM-IV cocaine

dependence

Hamilton

Depression Scale

(HAM-D) score

>15

Sertraline 200mg/day

Sertraline 200mg/day plusgabapentin 1200mg/day

Placebo

Sertraline alone showed asignificantly lower overallpercentage of cocaine-positiveurine samples vs. placebo

Retention in treatment did notsignificantly differ betweentreatment groups

Kosten et al., 2014


16 weeks

N=300

DSM-IV cocaine

dependence

Received five IMvaccinations of 400µg (0.5ml)

Placebo

For trial duration cocaine positiveurine rates showed no significantdifference between the groups


Appendix B24, 25, 39

Table 20: Rating Scales

Rating Scale Description/Use Interpretation

Visual analog scale of cocaine effects (VAS-C)

Assess current feelingsassociated with cocaine use

Rated in clusterso Euphoriao Stimulant effectso Craving

Self-administered

14 item scale

Scale from “not to at all” to“extremely”

Multiple chose questionnaire (MCQ)

Measured preference for drugover monetary reward

Self-administered

72 items

Validated

Patients indicate theirpreference between “today’scocaine dose” and a designatedamount of money

Money sequentially increased$0.25-$25

Profile of mood states (POMS)

Assessment of drug-relatedmood changes

Self-administered

65 items

Validated

Composed of adjectivesdescribing different moods orfeelings states

Clinical Global Impression-Observer (CGI) scale

Change from the initiation oftreatment on the severity ofsymptoms

Clinician administered

7 point scale

Validated

1= very much improved,2=much improved, 3=minimallyimproved, 4=no change frombaseline, 5=minimally worse,6=much worse, 7=very muchworse

Obsessive compulsive drinking scale (OCDS)39

Characterizes and quantifyingthe obsessive and compulsivecognitive aspects of craving andheavy drinking

Self-administered

14 item

Composed of adjectivesdescribing drinking-relatedthought, urges to drink, and theability to resist those thoughtand urges

topiramate in stimulant use disorder: is topiramate all...

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