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Topiramate in Stimulant Use Disorder: Is Topiramate All...
Transcript of 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
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%
MARIA P. BLAZE, PHARM.D. 2
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
MARIA P. BLAZE, PHARM.D. 3
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
MARIA P. BLAZE, PHARM.D. 4
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
MARIA P. BLAZE, PHARM.D. 5
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
MARIA P. BLAZE, PHARM.D. 6
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
MARIA P. BLAZE, PHARM.D. 7
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
MARIA P. BLAZE, PHARM.D. 8
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
MARIA P. BLAZE, PHARM.D. 9
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
MARIA P. BLAZE, PHARM.D. 10
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
MARIA P. BLAZE, PHARM.D. 11
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
MARIA P. BLAZE, PHARM.D. 12
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
Patients Inclusion criteria
≥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
MARIA P. BLAZE, PHARM.D. 13
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
Baseline characteristics
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
MARIA P. BLAZE, PHARM.D. 14
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
Table 17: Adverse events
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
Author’s 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
MARIA P. BLAZE, PHARM.D. 15
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
Patients Inclusion criteria
≥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
Baseline characteristics
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
MARIA P. BLAZE, PHARM.D. 16
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
Table 18: Adverse events
Event Topiramate (%) N=36
Paresthesia 29.5
GI complaints 16.8
Fatigue 12.6
Conclusions
Author’s 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
MARIA P. BLAZE, PHARM.D. 17
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
(Randomized, double-blind)
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
(Randomized, double-blind)
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
(Randomized, double-blind)
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
(Randomized, double-blind)
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
MARIA P. BLAZE, PHARM.D. 21
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