Bupropion for the TreatmentBupropion for the Treatmentof Methamphetamineof Methamphetamine

DependenceDependence

Larissa Mooney, M.D.Larissa Mooney, M.D.

May 25, 2009May 25, 2009

OverviewOverview

Journal ArticleJournal Article: Elkashef A, Rawson A, Anderson E, Li S,: Elkashef A, Rawson A, Anderson E, Li S,Holmes T, Smith E, Holmes T, Smith E, et alet al., 2007. Bupropion for the Treatment., 2007. Bupropion for the Treatmentof Methamphetamine Dependence. of Methamphetamine Dependence. Neuropsychopharmacology Neuropsychopharmacology33(5): 1162-70.33(5): 1162-70.

Introduction/rationaleIntroduction/rationale Study designStudy design ParticipantsParticipants Data analysisData analysis ResultsResults DiscussionDiscussion

MethamphetamineMethamphetamine

Synthetic stimulant drugSynthetic stimulant drug Mechanism of action: increases dopamine/NEMechanism of action: increases dopamine/NE T ½: 12 hoursT ½: 12 hours Routes of administration: IV, smoking, intranasal, and oralRoutes of administration: IV, smoking, intranasal, and oral

EpidemiologyEpidemiology

Significant public health problem: serious medical,Significant public health problem: serious medical,social, and economic consequencessocial, and economic consequences

22ndnd most commonly abused drug worldwide most commonly abused drug worldwide High rates in Asia, Australia, Scandinavia, USHigh rates in Asia, Australia, Scandinavia, US

Medications considered forMedications considered forMethamphetamineMethamphetamine

Negative ResultsNegative Results +/+/Under ConsiderationUnder Consideration ImipramineImipramine BupropionBupropion DesipramineDesipramine ModafinilModafinil TyrosineTyrosine TopirimateTopirimate OndansetronOndansetron DisulfiramDisulfiram FluoxetineFluoxetine LobelineLobeline AripiprazoleAripiprazole GabapentinGabapentin SertralineSertraline

Rationale for BupropionRationale for Bupropion

No FDA-approved pharmacological treatmentNo FDA-approved pharmacological treatmentfor MA dependencefor MA dependence

Psychotherapeutic interventions remain thePsychotherapeutic interventions remain themainstay of treatmentmainstay of treatment

Bupropion (Wellbutrin SR/XL, Zyban) is FDA-Bupropion (Wellbutrin SR/XL, Zyban) is FDA-approved for treatment of depression andapproved for treatment of depression andnicotine dependence, also improves ADHD sxnicotine dependence, also improves ADHD sx’’ss

Mechanism of action: inhibits reuptake of NEMechanism of action: inhibits reuptake of NEand dopamineand dopamine

May help alleviate WD sxMay help alleviate WD sx’’s (mimic depression)s (mimic depression)

Rationale Rationale –– cont cont’’dd Chronic MA use results in low dopaminergic toneChronic MA use results in low dopaminergic tone Bupropion blocks DA transporterBupropion blocks DA transporter Bupropion pretreatment has been shown to protectBupropion pretreatment has been shown to protect

against acute MA-induced decreases in DA uptake inagainst acute MA-induced decreases in DA uptake inrats (Kim et al., 2000) and decrease neurotoxic effects inrats (Kim et al., 2000) and decrease neurotoxic effects inrats (Marek et al., 1990)rats (Marek et al., 1990)

Phase I study: bupropion was safe when co-administeredPhase I study: bupropion was safe when co-administeredwith MA (no increase in CV or behavioral effects), andwith MA (no increase in CV or behavioral effects), andattenuated some of subjective effects of MA (attenuated some of subjective effects of MA (““highhigh”” and andcraving) (Newton et al., 2006)craving) (Newton et al., 2006)

Some evidence in cocaine dependence (depressedSome evidence in cocaine dependence (depressedsubset)subset)

Study ObjectivesStudy Objectives

Objectives:Objectives: To assess the efficacy and safety ofTo assess the efficacy and safety ofbupropion in reducing methamphetamine use inbupropion in reducing methamphetamine use insubjects with methamphetamine dependence.subjects with methamphetamine dependence.

HypothesesHypotheses: Bupropion treatment, as compared to: Bupropion treatment, as compared toplacebo, will be associated with increased weeks ofplacebo, will be associated with increased weeks ofabstinence as measured by urine analysis.abstinence as measured by urine analysis. Bupropion will be efficacious in subgroup withBupropion will be efficacious in subgroup with

lower MA uselower MA use

Bupropion will be efficacious in reducing cravingBupropion will be efficacious in reducing craving Bupropion could help reduce MA dependence inBupropion could help reduce MA dependence in

subjects with MDD and ADHDsubjects with MDD and ADHD

Study DesignStudy Design

Double-blind, placebo-controlled study; 5 sitesDouble-blind, placebo-controlled study; 5 sites 151 adults with methamphetamine dependence151 adults with methamphetamine dependence

randomized to receive bupropion SR 150 bidrandomized to receive bupropion SR 150 bidvs. placebovs. placebo

Exclusion criteria: seizure disorder, seriousExclusion criteria: seizure disorder, seriousmedical illness, psychiatric disorder requiringmedical illness, psychiatric disorder requiringmedication, pregnancy, court mandatemedication, pregnancy, court mandate

12 week trial; 90-minute CBT and UDS 3x12 week trial; 90-minute CBT and UDS 3x’’s/wks/wk

Study SchemaStudy Schema

Randomization

Randomization Strata•use w/in the 30 days prior to study•gender•diagnosis/severity of depression

BupropionN = 75

PlaceboN = 75

Double-blindtreatment* &assessments(weeks 0 to 12)

Final follow-up at week 16

*Double blind treatment consists of daily bupropion (days 1 – 3: 150mg, days 4 – 81: 300 mg, days 82 – 84: 150 mg) or matching

placebo. Each arm also receives thrice-weekly cognitive behavioraltherapy.

ActivityStudyWeek

Screening/BaselineAssessments(weeks -4 to 0)

-4

16

12

0

Follow-up

AssessmentsAssessments SCID (baseline)SCID (baseline) Timeline follow-back SURTimeline follow-back SUR AEsAEs Concomitant medsConcomitant meds Med complianceMed compliance Urine Drug Screen (UDS)Urine Drug Screen (UDS) Brief Substance Craving Scale (BSCS) (weekly)Brief Substance Craving Scale (BSCS) (weekly) Vital signs (weekly)Vital signs (weekly) HAM-D (biweekly)HAM-D (biweekly) ASI-Lite (baseline and end of tx)ASI-Lite (baseline and end of tx) Physical exam, ECG, labs (baseline and end of tx)Physical exam, ECG, labs (baseline and end of tx)

Outcome MeasuresOutcome Measures

PrimaryPrimary % of participants who abstained from MA during each wk of% of participants who abstained from MA during each wk of

treatment (via UDS)treatment (via UDS)

SecondarySecondary Subgroup analyses for treatment effects on the primarySubgroup analyses for treatment effects on the primary

outcome: 1. gender, 2. low vs. high levels of MA use, 3. low vs.outcome: 1. gender, 2. low vs. high levels of MA use, 3. low vs.high levels of depression (HAM-D) 4. ADHD dxhigh levels of depression (HAM-D) 4. ADHD dx

Quantitative MA in urineQuantitative MA in urine Self-report of daily MA use (timeline follow-back)Self-report of daily MA use (timeline follow-back) Changes in addiction severity (ASI-Lite)Changes in addiction severity (ASI-Lite) Changes in craving (BSCS)Changes in craving (BSCS) Changes in depression (HAM-D)Changes in depression (HAM-D)

Data AnalysisData Analysis

Generalized estimating equations (GEE) toGeneralized estimating equations (GEE) tocompare weekly proportion of participants withcompare weekly proportion of participants withMA-free urine between treatment groupsMA-free urine between treatment groups

Primary outcome data fitted with nonlinearPrimary outcome data fitted with nonlinear(logistic) mixed effect model (NLMM) to further(logistic) mixed effect model (NLMM) to furthertest combined effect of balancing factors andtest combined effect of balancing factors andcorrect for multiple comparisonscorrect for multiple comparisons Adjusts for baseline differences while estimatingAdjusts for baseline differences while estimating

subject-specific effects of treatmentsubject-specific effects of treatment

Table 1. Baseline characteristics of randomized participants

Age 36.2 (9.2)* 35.7 (8.4)

Gender

Male 50 (63%) 51 (71%)

Female 29 (37%) 21 (29%)

Race

White, not Hispanic 59 (75%) 53 (74%)

Hispanic or Latino 5 (6%) 5 (7%)

African American or Black 2 (3%) 2 (3%)

Asian or Pacific Islander 11 (14%) 10 (14%)

Other 1 (1%) 0 (0%)

Years of education 12.6 (1.9)* 12.4 (1.7)

Days of methamphetamine use in last 30 days

< = 18 36 (46%) 35 (49%)

> 18 43 (54%) 37 (51%)

Life time years of methamphetamine use

10.42 (7.59)* 9.97 (6.10)

Route of lifetime methamphetamine use

Nasal 15 (19%) 10 (14%)

Smoking 49 (62%) 49 (68%)

Injection 15 (19%) 13 (18%)

Depression (HAM-D Total > 12)

No 64 (81%) 57 (79%)

Yes 15 (19%) 15 (21%)

*Standard Deviation

Bup Placebo

N =79 N = 72

Results: primary outcomeResults: primary outcomeFig 2 Percentage of Patients with Methamphetamine-Free Urine Week-Bupropion

Observed group means vs GEE fitted lines

Group means Bupropion Placebo

GEE fitted lines Bupropion Placebo

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Study Week Elapsed Since Randomization

-2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12

Results: low severity MA usersResults: low severity MA users

Fig 7 Percentage of Patients with Methamphetamine-Free Urine Week-Baseline Low Meth UseObserved group means vs GEE fitted lines

Group means Bupropion Placebo

GEE fitted lines Bupropion Placebo

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Study Week Elapsed Since Randomization

-2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12

Results: high level MA usersResults: high level MA usersFig 5 Percentage of Patients with Methamphetamine-Free Urine Week Baseline High Meth Use

Observed group means vs GEE fitted lines

Group means Bupropion Placebo

GEE fitted lines Bupropion Placebo

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Study Week Elapsed Since Randomization

-2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12

Results: secondary measuresResults: secondary measures

Comorbid ADHDComorbid ADHD Only 20 subjects w/ ADHD, not balancedOnly 20 subjects w/ ADHD, not balanced No change in primary outcome between groupsNo change in primary outcome between groups

ASIASI No significant differences between groupsNo significant differences between groups

BSCSBSCS No significant differences in slopes over timeNo significant differences in slopes over time

HAM-DHAM-D No significant differences between groupsNo significant differences between groups

Study LimitationsStudy Limitations

Imbalance between groups on presence ofImbalance between groups on presence ofADHDADHD

DSM-IV raters lacked training in inter-raterDSM-IV raters lacked training in inter-raterreliabilityreliability Only 15% prevalence ADHD foundOnly 15% prevalence ADHD found

ConclusionsConclusions Analysis of primary outcome showed trend towardAnalysis of primary outcome showed trend toward

statistical significance favoring bupropion for MA-freestatistical significance favoring bupropion for MA-freeweeks (GEE, p=0.09).weeks (GEE, p=0.09).

Secondary outcomes favored bupropionSecondary outcomes favored bupropion Bupropion showed a statistically significant effect forBupropion showed a statistically significant effect for

MA-free weeks in the low/moderate group (GEE,MA-free weeks in the low/moderate group (GEE,p=0.03).p=0.03).

Bupropion showed a statistically significant effect forBupropion showed a statistically significant effect forweekly methamphetamine-free weeks in males (GEE,weekly methamphetamine-free weeks in males (GEE,p=0.04).p=0.04). 2/3 female patients were in high-use subgroup2/3 female patients were in high-use subgroup

Results suggest that bupropion, in combination withResults suggest that bupropion, in combination withbehavioral group therapy, was effective for increaseingbehavioral group therapy, was effective for increaseingthe number of weeks of abstinence in participants withthe number of weeks of abstinence in participants withlow-to-moderate MA dependence.low-to-moderate MA dependence.

Phase 2 Trial of Bupriopion for MAPhase 2 Trial of Bupriopion for MADependenceDependence

12-week NIDA-funded multisite trial12-week NIDA-funded multisite trial

150 MA-dependent subjects to be randomized to150 MA-dependent subjects to be randomized tobupropion vs. placebo for 12 weeksbupropion vs. placebo for 12 weeks

Only subjects who report <=18 d MA use in past 30Only subjects who report <=18 d MA use in past 30 Strata: gender, depression, ADHD, clinical siteStrata: gender, depression, ADHD, clinical site Analysis of genetic variants involved in susceptibilityAnalysis of genetic variants involved in susceptibility

for MA dependence and response to bupropionfor MA dependence and response to bupropion Primary outcome: proportion of subjects who achievePrimary outcome: proportion of subjects who achieve

abstinence during last 2 weeks of med dosing periodabstinence during last 2 weeks of med dosing period