pharmacological treatment of cocaine

7/29/2019 Pharmacological Treatment of Cocaine

1/19

2002 Society for the Study of Addiction to Alcohol and Other Drugs Addiction, 97, 931949

Pharmacological treatment of cocaine dependence:

a systematic review

Maurcio Silva de Lima1,2, Bernardo Garcia de Oliveira Soares1,3, Anelise Alves Pereira Reisser1

& Michael Farrell4

Centro de Medicina Baseada em Evidncias, Universidade Federal de Pelotas, Brazil1, Mestrado em Sade e Comportamento, Universidade Catlica de

Pelotas, Brazil2, Departamento de Psiquiatria, Universidade Federal de So Paulo, Brazil3 and National Addiction Centre, Institute of Psychiatry, London, UK4

ABSTRACT

Aims Cocaine dependence is a common and serious condition, associated with

severe medical, psychological and social problems, including the spread of

infectious diseases. This systematic review assesses critically the efficacy of

pharmacotherapy for treating cocaine dependence.

Methods The literature search strategy included: electronic searches of

Cochrane Library holdings, EMBASE, MEDLINE, PsycLIT, Biological Abstracts

and LILACS; scans of reference lists of relevant articles, personal communica-

tions, conference abstracts, unpublished trials from the pharmaceutical indus-

try and book chapters on the treatment of cocaine dependence. Randomized

controlled trials (RCTs) focusing on the use of antidepressants (ADs), carba-

mazepine (CBZ), dopamine agonists (DAs) and other drugs used in the treat-

ment of cocaine dependence were included. The reviewers extracted data

independently, and relative risks (RR) with 95% confidence interval (CI) were

estimated. Qualitative assessments were carried out using a Cochrane validated

checklist. Where possible, analysis was carried out according to intention-to-

treat principles.

Findings The search strategy generated 45 different trials. Most studied drugs

were ADs (20 studies), DAs and CBZ. Data were very heterogeneous, with

dropout rates within the studies between 0 and 84%. A non-significant trend

favoring CBZ was found in terms of dropouts (RR 0.88; 95% CI 0.751.03) and

results from one trial suggest that fluoxetine patients are less likely to drop out.

The main efficacy outcome reported in the studies was the presence of cocaine

metabolites in the urine. No significant results were found, regardless the type

of drug or dose used for all relevant outcomes assessed.

Conclusions There is no current evidence supporting the clinical use of CBZ,

antidepressants, dopamine agonists, disulfiram, mazindol, phenytoin, nimo-

dipine, lithium and NeuRecover-SA in the treatment of cocaine dependence.

Larger randomized investigation must be considered, while taking into account

that these time-consuming efforts should be reserved for medications showing

more relevant and promising evidence. Given the high dropout rate among the

test population, clinicians may wish to consider adding psychotherapeutic sup-

portive measures aimed at keeping patients in treatment programs.

KEYWORDS Cocaine dependence, meta-analysis, pharmacotherapy,

systematic review.

REVIEW

Correspondence to:

Dr Maurcio Silva de Lima

Centro de Medicina Baseada em Evidncias

Departamento de Sade Mental

Faculdade de Medicina

UFPEL

Avenida Duque de Caxias

250 PelotasRS, Brazil

Submitted 17 July 2001;

initial review completed 30 October 2001;

final version accepted 6 March 2002

This review has been published partially in The Cochrane Library (Carbamazepine for Cocaine Dependence). It received the Kenneth

Warren Prize given for relevant systematic reviews from developing countries in the last annual Cochrane Meeting (Cape

Town, 2000).


2/19

932 Maurcio Silva de Lima et al.


INTRODUCTION

Cocaine consumption and related problems were epi-

demic in the 1920s in the United States, disappearing by

the end of that decade (Musto 1992). However, the use

of cocaine increased again between 1976 and 1979,

mainly in North America and some countries of South

America. Since the early 1980s, cocaine abuse in the

United States has again been at epidemic levels. Estimates

from a recent National Household Survey on Drug Abuse

based on a sample of 28 832 subjects indicate that there

are 1.3 million cocaine users in the United States, more

than five times the number of those addicted to heroin

(Gold 1997). Cocaine problems in Europe have become

more common since the early 1990s and now are part of

the European drug scene (EMCDDA 2000). It has become

a substantial public health problem, resulting in a signi-

ficant number of medical, psychological and social prob-

lems, including the spread of infectious diseases (e.g.AIDS, hepatitis and tuberculosis), crime, violence and

neonatal drug exposure. In consequence, there is an

urgent need to expand the treatment repertoire for this

condition.

Although there is no consensus regarding how to

treat cocaine dependence (Carroll et al. 1994), effective

pharmacotherapy can potentially play a major role

within a broader treatment setting. The past decade has

witnessed a sustained search for an effective pharma-

cotherapeutic agent for the treatment of cocaine depend-

ence. While the administration of cocaine increases

intercellular dopamine, serotonin and norepinephrinelevels acutely by blocking their presynaptic reuptake

(Gold 1997), chronic cocaine abuse leads to down-

regulation of monoamine systems. Post-cocaine use

depression and cocaine craving may be linked to this

downregulation.

These preclinical findings are the theoretical foun-

dations on which the use of antidepressants for the

treatment of cocaine dependence is based. Under

this assumption, antidepressant pharmacotherapy, by

increasing monoamine levels, may alleviate cocaine

abstinence symptomatology, as well as relieving dyspho-

ria and associated craving by general antidepressantaction (Margolin, Avants & Kosten 1995b).

There is a clear understanding that any discussion of

pharmacotherapy for cocaine dependence should be con-

textualized within a framework of broader psychosocial

interventions which could include therapeutic commu-

nity, day programme or out-patient drug free treatment.

A recent work (Simpson et al. 1999) looking at outcomes

from a range of psychosocial treatments indicates that

there is substantial positive impact from such treatments.

The question of combining and evaluating psychosocial

and pharmacotherapeutic interventions to improve

overall treatment outcomes will be a major challenge to

researchers and clinicians in the drug treatment field

over the coming decade.

Systematic reviews of scientific research allow for the

efficient integration of valid information and provide a

basis for rational decision-making. The use of explicit and

consistent methods in reviews limits bias (systematic

errors) and reduces random errors (simple mistakes),

thus providing more reliable results upon which to draw

conclusions and make decisions. In addition, meta-

analysis, or the use of statistical methods to summarize

the results of several independent studies, can provide a

more precise estimate of the effects of health care than

that which can be derived from the individual studies

included in a review. In this paper, we report the main

results of a series of Cochrane systematic reviews

about pharmacotherapy of cocaine dependence. The

various types of pharmacological interventions were

grouped as follows: antidepressant (ADs); carbamazepine(CBZ), dopamine agonists (DAs); and miscellaneous,

including other drugs such as naltrexone, mazindol and

lithium.

METHODS

In order to select all relevant randomized controlled trials

(RCTs) in the pharmacological treatment of cocaine use

disorders, a wide search strategy was performed.

Electronic searches of Cochrane Library (2001 issue 4),

EMBASE (from 1980 to October 2000), MEDLINE (from1966 to October 2000), PsycLIT (from 1974 to July

2000), Biological Abstracts and LILACS (from 1982 to

2000) were completed with scanning of the reference

lists of relevant articles and personal contacts with

authors and to the pharmaceutical industry.

RCTs focusing on the use of drugs for the treatment of

cocaine dependence were included, irrespective of the

diagnostic criteria. Trials where patients had an addi-

tional diagnosis such as opiate dependence were also eli-

gible. Outcomes of interest were retention in treatment

and the number of people reporting adverse events; effi-

cacy as measured by urine samples positive for cocainemetabolites; self-reported craving; severity of depend-

ence; amount of cocaine consumed; and quality of life

measures. If assessment was not possible and no other

outcomes were provided (such as continuous data,

without mean and standard deviation), authors were

contacted.

Quality of trials was assessed using a criterion based

on the evidence of a strong relationship between the

potential for bias in the results and the allocation con-

cealment (Schulz et al. 1995). Trials were considered

with a low risk of bias if they had adequate allocation


3/19

Pharmacological treatment of cocaine dependence 933


concealment, and with a high risk of bias if an inade-

quate allocation of concealment was performed.

Data were extracted independently by reviewers. For

dichotomous data a standard weighted estimate of the

typical treatment effect across studies, the relative risk

(RR)that is, the risk of an event occurring among

treatment-allocated individuals versus the correspond-

ing risk in the control groupwas calculated. If the

relative risk equals 1, this indicates no difference between

the groups compared. The relative risks and its 95%

confidence interval (CI) were calculated with Review

Manager 4.1 software, with the use of the DerSimonian

Laird random effects model (DerSimonian & Laird 1986).

The random effects model includes both within-study

sampling error and between-studies variation in the

assessment of the confidence interval of the results, but

the fixed effects model takes only within-study variation

to influence the confidence interval. Therefore, the

random effects model is a rather more conservativeapproach. Whenever possible, analyses were performed

according to intention-to-treat principles.

To avoid the pitfall of applying parametric tests to

non-parametric continuous outcome data, standard

deviations and means were required to be reported in the

paper or obtainable from the authors, and the standard

deviation, when multiplied by 2, had to be less than the

mean (otherwise, the mean is unlikely to be an appropri-

ate measure of the centre of distribution) (Altman &

Bland 1996). Data not satisfying these standards were

not included in the data analysis.

Heterogeneity in the results of the trials was assessedboth by graphical inspection and by calculating a test of

heterogeneity. Heterogeneity refers to the variation

observed between the results of the individual studies.

Statistically significant heterogeneity is said to be present

when more variation between the studies occurs than

can be explained by the play of chance alone. Possible

reasons for heterogeneity were prespecified. Responses

differ (Alim et al. 1995): according to the different drugs

(Alterman et al. 1992); when psychosocial therapies are

provided in conjunction with prescribed drugs (Altman

& Bland 1996); according to the characteristics of

patients participating in trials; and (Arndt et al. 1992)depending on length of treatment. Heterogeneity was

then assessed visually from graphs and by the c2 test of

heterogeneity. A significance level of less than 0.10 was

interpreted as evidence of heterogeneity.

RESULTS

The search

More than 1000 citations were found throughout the

search. Forty-nine different studies were identified from

these citations and were included in the review: 20 on

ADs, five on CBZ, 13 on DAs and 11 on miscellaneous

interventions. In four studies ADs were compared to both

placebo and DAs or another drug. Disulfiram (antabuse)

was compared to placebo in three RCTs, with participants

presenting co-morbidity, opioid dependence in two trials

(George et al. 2000; Petrakis et al. 2000) and alcohol

abuse or dependence in Carrol etal. (1998). Mazindol, an

amidazoline derivate that blocks reuptake of dopamine,

was evaluated in two trials (Margolin et al. 1995a; Stine

et al. 1995). Crosby et al. (1996) assessed the value of

phenytoin, an anticonvulsant agent, as an anticraving

medication. Rosse et al. (1994) compared nimodipine, a

calcium channel blocker, to placebo. Lithium carbonate,

a mood stabilizer used widely in the treatment of bipolar

disorders, was studied by Gawin et al. (1989). Cold

(1996) assessed the compound known as NeuRecover-

SA, which includes l-tyrosine and various vitamins

and minerals for which cocaine users present a defi-ciency. A double-blind placebo controlled trial compared

naltrexone with placebo (Somoza et al. 1998). In

Grabowsky et al. (2000), two doses of risperidone (2 and

4 mg/day), an atypical antipsychotic, were compared to

placebo.

Main features of included studies

The main characteristics of the trials included in this

review are displayed in Table 1.

Methodological quality

Different methods of randomization were employed in

clinical trials, but only nine author groups (Weddington

et al. 1991; Kranzler & Bauer 1992; Covi et al. 1993;

Moscovitz, Brookof & Nelson 1993; Kranzler et al. 1995;

Margolin et al. 1995b; Nunes et al. 1995; Cold 1996)

described adequate concealment of allocation (allocation

was performed by a person who was not involved in

recruitment of patients). These trials were rated as A:

adequate allocation concealment; all remaining studies

did not describe the concealment of allocation and were

classified as B.Most trials included (90%) used a double-blind design.

One study used diphenhydramine as an active placebo

(Covi et al. 1993). An external evaluator blind to the

interventions was used in Carrol et al. (1998), an open

study which evaluated three different psychosocial inter-

ventions in addition to the disulfiram or no medication.

Outcome reporting

Many outcomes could not be summarized because they

were presented in graphical form or only on statistical


4/19



Table

1

Pharmaco

therapyo

fcoca

ine

depe

ndence:c

haracter

isticso

fincludedrandom

ized

contro

lledtrials

.

Author/year

Methods

Participants

Interventions

Outcomesused

Car

bamazep

inestud

ies

Campbel

letal.1994

Ran

domalloca

tion

(compu

ter-

61coca

ine-

dependen

tout-p

atients

1.Des

ipram

ine

(n=2

1;dose

Durat

iono

ftrea

tmen

t

genera

tedlist)

,doub

le-b

lind,

(DSM

-III-R);meanage

32years;

unknown)

6mont

hsdu

ration,

threepara

llel

63%males;9

0%

blac

kCo-morb

idities:

2.Car

bamazep

ine

(n=

19;dose

groups,non-

ITT

alco

holdepen

dence

(n=

16),major

unknown)

depression

(11),an

tisocial

persona

lity

3.Placebo

(n=

25)

disorder

(16)

Corn

ishetal.1995

Ran

domalloca

tion;

doub

le-b

lind;

95coca

ine-

dependen

tout-p

atients

1.Car

bamazep

ine

(n=

37)

Nore

tent

ion

intrea

tment;urinesamples

10wee

ksdu

ration;

twopara

llel

(DSM

-III-R);agerange

215

1;

Dose

from

200mg/da

ytoreac

h

groups;non-

ITT;twostudysi

tes

98%males;9

8%

blac

k

serum

leve

ls412g

/ml

Hal

ikasetal.1997

Ran

domalloca

tion

(block

design

);

183coca

ine-

depen

dentout-p

atients

1.Car

bamazep

ine

400

mg

(n=

62)

Nore

tent

ion

intrea

tment;urinesamples

doub

le-b

lind;1

2wee

ksdurat

ion;

(DSM

-III-R);meanage

32.5

;

2.Car

bamazep

ine

800

mg

(n=

58)

threeparalle

lgroups;non-

ITT(33

71%males;6

6.1%

white

,withat

3.Placebo

(n=

63)

replacements)

leas

taneigh

thgra

deeducat

ion

Psyc

hosocial

intervent

ionswere

alsoo

ffere

dtoparticipants

Kranzleretal.1995

Ran

domalloca

tion

(under

taken

by

40coca

ine-

dependen

tout-p

atients

1.Car

bamazep

ine

600

mg

(n=

20)

Urinesamples;nore

tention

intrea

tmen

t;people

aresearchp

harmac

istno

tinvo

lved

(DSM

-III-R);agerange

184

5;

2.Placebo

(n=

20)

withat

leas

tonesideeffec

t;ASI

,BDI,SAS

inthecl

inicalcare);doub

le-b

lind;

100%males;3

2%

blac

k.Subjec

ts

12wee

ksdu

ration;

twopara

llel

usedat

leas

t4g

ofcoca

ine

during

groups;

ITT

thepreced

ingmont

h

Montoyaetal.1994

Ran

domalloca

tion;

doub

le-b

lind;

72coca

ine-

dependen

tout-p

atients

1.Car

bamazep

ine

800

mg/

day

Nore

tent

ion

intrea

tment

8wee

ksdur

ation;

twopara

llel

(DSM

-lll-R);meanage

33.2

;

(n=

28)

groups;non-

ITT

79%males;6

8%

blac

k.Atleas

t

2.Placebo

(n=

34)

14go

fse

lf-reportedcoca

ineuse

intheprev

ious3

mont

hs

Ant

idepressan

tstud

ies

Arn

dtetal.1992*

Ran

domalloca

tion

(2:1ra

tio);

79coca

ineabuse

rout-p

atients

1.Des

ipram

ine

250300mg/

day

Nore

tent

ion

intrea

tment;

doub

le-b

lind;1

2wee

ksdurat

ion;

(DSM

-III)inmet

hadone-m

aintaine

d

(n=

36)

nore

tent

ion

intrea

tment

forsi

deef

fect

twopara

llelgroups;non-

ITT

trea

tmen

tforhero

independence

2.Placebo

(n=

23)

Meanage

40.5;1

00%males,9

0%

blac

k;51%ofsub

jectsw

ithAPD

(DSM

-III)


5/19



Batkietal.1996

Ran

domalloca

tion;

doub

le-b

lind;

32coca

ine-

dependen

tout-p

atients

1.Fluoxe

tine

40mg/day

(20mg

Nore

tent

ion

intrea

tment;

12wee

ksdu

ration;

twopara

llel

(DSM

-III)

.Age~

34years;

66%

inthe

firstwee

k)(n=

16)

QCImo

difiedvers

ion

(daysused,

groups;non-

ITT

males,5

3%African-A

mer

ican

2.Placebo

(n=

16)

crav

ing,qual

ityo

fhigh

)

12part

icipan

tsw

ithmajor

depressive

disorder,s

ixwith

APD

,sixw

ith

alco

holabuse

dependence

(DSM

-III-R)

Campbel

letal.1994

Ran

domalloca

tion

(compu

ter-

65coca

ine-

dependen

tout-p

atients

1.Des

ipram

ine

(n=2

1;dose

Durat

iono

ftrea

tmen

t(no

SD)

genera

tedlist);doub

le-b

lind;

(DSM

-III-R);meanage

32;

unknown)

6mont

hsdu

ration,

threepara

llel

63%male;

90%b

lack

2.Car

bamazep

ine

(n=

19;dose

groups;non-

ITT

16su

bjec

tsw

ith

alco

holdepen

dence,

unknown)

11major

depression,

twogenera

lized

3.Placebo

(n=

25)

anxiety

disorderan

d16APD

Carro

lletal.1994

Ran

domalloca

tion;

doub

le-b

lind;

139coca

ine-

depen

dentout-p

atients

1.Des

ipram

ine

(mean

200mg/

day)

Nore

tent

ion

intrea

tment

12wee

ksdu

ration;

fourpara

llel

(DSM

-III-R)

+

RP(n=

29)

Cocaineuse

during

trea

tmen

t

groups;non-

ITT.Subjec

tsrece

ived

Age~

29years,7

3%males,4

6%

2.Des

ipram

ine

(mean

200mg/

day)

RPor

CM

Caucasians;4

9%

withAPD;6

5%

+

CM(n=

25)

anyo

therperson

alitydisorder,4

8%

3.Placebo+

RP(n=

29)

ASI

alco

holdepen

dence,

20%af

fect

ive

4.Placebo+

CM(n=

27)

disorder,1

3%anxiety

disorder

Cov

ietal.1993

Ran

domalloca

tion

(per

formed

bya

45coca

ine-

dependen

tout-p

atients

1.Fluoxe

tine

20mg(n

=

10)

Urineposi

tive

forcoca

inemetabo

lites

personw

ho

wasno

tinvo

lved

in

(DSM

-III-R).Meanage

30;8

0%

2.Fluoxe

tine

40mg(n

=

11)

recrui

tmento

fpa

tients);doub

le-b

lind;

males,5

6%w

hite

.67%w

ith

3.Fluoxe

tine

60mg(n

=

10)

12wee

ksdu

ration;

fourpara

llel

tobacco

dependence,2

2%alco

hol

4.Act

iveplacebo

(diphenhydram

ine)

groups;non-

ITT

dependence,18%

anxiety

disorders,

(n=

14)

7%APD

Ehrmanetal.1996

Ran

domalloca

tion;

doub

le-b

lind;

80coca

ine-

dependen

tout-p

atients

1.Ritanser

in10mg/da

y(n=

40)

Nore

tent

ion

intrea

tment

4wee

ksdur

ation

(med

ical

phase

);

(DSM

-III-R).Meanage

37;1

00%

2.Placebo

(n=

40)

twopara

llelgroups;non-

ITT

males,9

5.5%African-a

Aer

ican;

subjec

tshadregu

larcoca

ineuse

~6years

Gaw

inetal.1989

Ran

domalloca

tion;

doub

le-b

lind;

100coca

ine-

depen

dentout-p

atients

1.Des

ipram

ine

2,5mg/

kg(n=

31)

Urinesamples;durat

ionof

trea

tmen

t

6wee

ksdur

ation;

threepara

llel

(DSM

-III-R).Meanage

29;7

6%

2.Lithiumcarbona

te6

00mg

(n=

37)

groups;non-

ITT

males,7

1%Caucas

ians.M

ost

3.Placebo-a

trop

ine0.

1mg

(n=

32)

part

icipan

tshado

ther

diagnosis

suchas

ADD


6/19



Table

1

(Continued)

Author/year

Methods

Participants

Interventions

Outcomesused

Giann

inietal.1986

Ran

domalloca

tion

(using

Texas

40out-p

atients,

20chroniccoca

ine

1.Des

ipram

ine

150m

g/day

(n=

10)

Nore

tent

ion

intrea

tment

Instrumen

tP

rogrammab

le58

abusersan

d20c

hronicphencycl

idine

2.Placebo

(diphenhydram

ine)

randomselect

ionprogram

);

abusers;agerang

e20

34years,

(n=

10)

doub

le-b

lind;4

0days

durat

ion

100%male,

100%

Caucasians

fourpara

llelgroups;

ITT

Subjec

tsusedon

lythatpart

icular

drugat

leas

tthre

etimeswee

klyan

d

hada

historyofabuseo

fat

leas

t

1year

Giann

inietal.1987

Ran

domalloca

tion

(using

Texas

20pa

tientsonpriva

te-p

ract

ice

1.Des

ipram

ine

200m

g/day

(n=

10)

Non-abst

inen

t

Instrumen

tP

rogrammab

le68

psyc

hiatrygroup,w

ithspace-

base

2.Placebo

(n=

10)

Nore

tent

ion

intrea

tment

randomprogram

);doub

le-b

lind;

(com

bina

tionof

free-b

asecoca

ine

45days

durat

ion;

twopara

llel

andphencycl

idine)abusers.

Age

groups;

ITT

range

212

8years,1

00%male,

100%

Caucasians

Hal

letal.1994

Ran

domalloca

tion;

doub

le-b

lind;

94in

-pat

ientsat

beginn

ing

(~2

1.Des

ipram

ine

200m

g:cont

inui

ty

Urinesamples;-non-en

trance

in

12wee

ksdu

ration;

fourpara

llel

wee

ks),w

ithcocaine

dependence

(n=

23)

out-pa

tientprogram

(notleaving

groups;

ITT

(DSM

-III-R).Meanage

38years,

2.Des

ipram

ine

200m

g;stan

dard

the

hosp

ital)

100%males,8

5%

blac

k.Primary

(n=

22)

coca

ineabusers;pa

tientsw

hoabused

3.Placebo:con

tinui

ty(n=

28)

other

drugswerealso

included

4.Placebo:s

tandar

d(n

=

21)

Jenk

insetal.1992

Ran

domalloca

tion;

doub

le-b

lind;

60coca

ine-

dependen

tin

-pat

ients

1.Gep

irona:mean

dose

16.2

5mg/

day

Nore

tent

ion

intrea

tment;durat

iono

ftrea

tmen

t;

12wee

ksdu

ration;

twopara

llel

(DSM

-III-R)inthe

firstwee

ko

f

(n=

20)

urinesamples;noglo

balim

provemen

t(CGI)

groups;non-

ITT;mul

ti-center

trial,meanage3

0.8;95%males;

2.Placebo

(n=

21)

(fourcenters)

66%blac

k.Most

subjec

tswere

employed

livinginamo

dera

tely

stab

lesocial

situa

tion,w

ithno

APD

Kolaretal.1992*

Ran

domalloca

tion;

doub

le-b

lind;

24coca

ine-

dependen

tout-p

atients

1.Des

ipram

ine

200m

g(n=

8)

Nore

tent

ion

intrea

tment;urinesamples;

12wee

ksfor

desipram

inean

d

withmet

hadone-m

aintaine

d

2.Aman

tadine

200mg

followed

part

icipan

tspresen

tingatleastonesi

de-e

ffect

placebo;8wee

ksforaman

tadine

(DSM

-III-R).Meanage

34.8

;

byplacebo

(n=

5)

followed

by4wee

kso

fplacebo;

85%males,6

8%

blac

k.Average

3.Placebo

(n=

9)

threeparalle

lgroups;non-

ITT

useo

fcoca

ine:1

0years.

Co-

mor

bidities:at

ten

tion

deficit

disorder,a

ffective

andanxiety

disorders


7/19



Kostenetal.1992*

Ran

domalloca

tion;

doub

le-b

lind;

94out-p

atientsw

ithopio

idan

d

1.Des

ipram

ine

150m

g(n=

30)

Urinesamples;nore

tention

intrea

tmen

t;

12wee

ksdu

ration;

threepara

llel

coca

ine

depende

nce

(DSM

-III-R)

2.Aman

tadine

300mg

(n=

33)

nore

tent

ion

intrea

tment

forsi

deef

fect

groups;non-

ITT

Meanage

32yea

rs,5

2%males,

3.Placebo

(n=

31)

82%Caucasians.

Other

diagnosis:

APD(20%);major

depression

(5%),dyst

hym

ia(22%)

Margo

lin1995a*

Quasi-r

andom

ized

(strat

ifica

tion

149out-p

atients

withcoca

ine

1.Bupropion

300mg/

day

(n=

74)

Nore

tent

ion

intrea

tment;nore

tent

ion

in

bypresence

ofAPDan

dsequen-

dependence

(DS

M-II

I-R),met

hadone-

2.Placebo

(n=

75)

trea

tmen

tforsi

de-e

ffect;H

am-D

;ASI;craving

tiallyrandom

ized

);doub

le-b

lind;

maintaine

dforhero

independence.

12wee

ksdu

ration;

twopara

llel

Meanage

37.2y

ears,6

2%males,

groups;

ITT;mul

ticen

terstudy

45%Caucasians.

About

50%met

criteria

foran

tiso

cial

persona

lity

disorder

McE

lroyetal.1989

Ran

domalloca

tion;

doub

le-b

lind;

15in

-pat

ients,w

ithcoca

ine

1.Des

ipram

ine

200m

g(n=

9)

Urinesamples;nore

tention

intrea

tmen

t;

24wee

ksdu

ration;cross-o

ver

dependence

(DS

M-II

I-R)an

dalso

2.Placebo

(n=

6)

nore

tent

ion

intrea

tment

forsi

deef

fect

(at12weeks);non-

ITT

mee

tingcr

iteria

forcurren

torpast

abuseo

fo

therdrugs.M

eanage

29.5

;73%males.

Average

dura

tion

ofcoca

ineuse5

years

Nunesetal.1995

Ran

domstra

tifiedal

loca

tion,

113out-p

atients

withcoca

ineabuse

1.Imipram

ine

150300mg

(n=

59)

Nore

tent

ion

intrea

tment

adm

inistered

byanurseno

tinvo

lved

(DSM

-III-R).Meanage

32years,

2.Placebo

(n=

54)

Nore

tent

ion

intrea

tment

forsi

deef

fect

inrecrui

tment;doub

le-b

lind;12

73%males,5

2%

Caucasians

Noresponse

wee

ksdurat

ion;

twopara

llelgroups;

Depress

ive

disor

derpresen

tin61%

ITT

ofpart

icipan

ts

OBrienetal.1988*

Ran

domalloca

tion;

doub

le-b

lind,

47malesu

bjects

withcoca

ine

1.Des

ipram

ine

(n=2

4)

Nore

tent

ion

intrea

tment

assessedatfo

llow-u

p;12wee

ks

dependence

(DS

MIIIR)in

2.Placebo

(n=

14)

dura

tion;

two

para

llelgroups;

met

hadonemain

tenance,us

ing

non-

ITT

coca

ine

for

3or

moremont

hs

Agerange

2950

;thosew

ith

sedativeoralcoh

oldepen

dence

wereexcluded

Tennan

t&Tarver

1985

Ran

domalloca

tion;

doub

le-b

lind;

22su

bjec

tsw

ith

coca

ine

dependence.

1.Des

ipram

ine

(n=1

1)

Posi

tiveur

inesamples

forc

ocainemetabo

lites;no

12days

forpa

tientson

desipram

ine,

Age,s

ex,r

acean

dse

ttingun

known.

2.Placebo

(n=

11)

retent

ion

intrea

tmen

t

15forplace

bo;twopara

llelgroups;

Patientsw

ithoth

erdrug

dependence

analys

isuncle

ar

wereexcluded


8/19



Table

1

(Continued)

Author/year

Methods

Participants

Interventions

Outcomesused

Trifflemanetal.1992

Ran

domalloca

tion

(2

2);doub

le-

82male

in-p

atients

(for

the

first

2

1.Des

ipram

ine

200m

gqD

(n=

41)

Durat

iono

ftrea

tmen

t

blind;8wee

ksdurat

ion;

two

wee

ks)w

ithcrac

k-coca

ine

depen-

2.Placebo

(n=

41)

para

llelgroups;non-

ITT

dence.

Ageuncle

ar,8

5%blac

k,

76%unemployed

and32%

homeless

Wed

ding

ton

1991

Ran

domalloca

tion

(administere

d

83out-p

atientsw

ithcoca

ine

1.Des

ipram

ine

200m

g(n=

32)

Urinesamples;nore

tention

intrea

tmen

t;

byaperson

notinvo

lved

inrecrui

t-

dependence

(DS

M-II

I-R).Mean

2.Aman

tadine

400mg

followed

dura

tiono

ftrea

tmen

t;part

icipan

tspresen

tingat

men

t,us

ings

eriallynum

bere

d,

age

30years,

76%males,6

9%

placebo

(n=

23)

leas

tonesidee

ffect

opaque,e

nvelopes);s

ingle-

blind;

white

.Additional

diagnosis

3.Placebo

(n=

28)

12wee

ksdu

ration;

threepara

llel

includedat

tention

deficit

groups;non-

ITT

disorder,a

ffective

andanxiety

disorders

Dopam

ineagoniststud

ies

Altermanetal.1992

Ran

domalloca

tion

(completed

42day

hosp

italp

atientsw

ith

1.Aman

tadine

20040

0mg

(n=

21)

Nore

tent

ion

intrea

tment;urinesamples;B

DI

byaresearc

htechnicianus

inga

coca

ine

depende

nce

(DSM

-III-R);

2.Placebo

(n=

21)

cons

traine

dblock

);doub

le-b

lind;

meanage

35;10

0%males,9

0%

2wee

ksdur

ation;

TWOpara

llel

blac

k.Useo

fcoc

aine

15days

in

groups;

ITT

thepast

30days

andregu

larly

for

abou

t3years

Eileretal.1995

Ran

domalloca

tion;

doub

le-b

lind;

63male

in-p

atientsw

ithcoca

ine

1.Bromocr

iptine

2.510mg/

day

Nore

tent

ion

intrea

tment;nore

tent

ion

in

18days

durat

ion;

twopara

llel

dependence

(DS

M-II

I-R);mean

(n=

32)

trea

tmen

tforsi

deef

fect

groups;non-

ITT

age

35.6

;86%blac

k.Last

2.Placebo

(n=

31)

coca

ineusewith

in6days

before

studyen

trance

Giann

inietal1989

Ran

domalloca

tion

(Texas

Instrumen

t

30maleout-pati

ents

,coca

ine

1.Aman

tadine

400mg/

day

(n=

10)

Craving

Programmab

le68randomcompu

ter

abusers.

Agerange

243

2;

2.Bromocr

iptine

10m

g/day

(n=

10)

Sideef

fects

program

);do

uble

-blind;30days

100%Caucasians

.Intranasa

l

3.Placebo

(n=

10)

dura

tion;

threepara

llelgroups;

ITT

useona

dailyba

sis

forat

leas

t6

mon

ths

befores

tudy

.Foursu

bjec

ts

withAPD

Han

delsmanetal.1995*

Ran

domalloca

tion;placebowas

hout

67maleout-pati

entsw

ithcoca

ine

1.Aman

tadine

200mg/

day

(n=

19)

Nore

tent

ion

intrea

tment

(1wee

k);do

uble

-blind;8wee

ks

andhero

independence

(DSM

-III-R),

2.Aman

tadine

400mg/

day

(n=

23)

BDI

dura

tion;

threepara

llelgroups;

met

hadone-m

aintained;meanage

36

3.Placebo

(n=

25)

SCL-90

non-

ITT


9/19



Han

delsmanetal.1997*

Ran

domalloca

tion;

doub

le-b

lind;

60maleout-pati

entsw

ithcoca

ine

1.Bromocr

iptine

5mg

(n=

24)

Nore

tent

ion

intrea

tment

5wee

ksdur

ation;

twopara

llel

abuse/

dependence

(DSM

-III-R),

2.Placebo

(n=

26)

groups;non-

ITT

met

hadone-m

aintainedan

dus

ing

coca

ine

inthelast

30days.M

ean

age

39;2

4%black

Kampmanetal.1996

Ran

domalloca

tion

(strat

ified

61out-p

atientsw

ithcoca

ine

1.Aman

tadine

300mg

(n=

30)

Nore

tent

ion

intrea

tment;-non-abst

inen

t;

blockproced

ure);dou

ble-

blind;

dependence

(DS

M-II

I-R)

2.Placebo

(n=

31)

ASI;B

DI;BAI

4wee

ksdur

ation;

twopara

llel

Meanage

35yea

rs,8

0%males;

groups;

ITTforur

inesamples

70%blac

k.Coca

ineusew

ithin

10dayspr

iorto

study.

Alco

hol

andmar

ijuanade

pendencewere

included

Kolaretal.1992*

Ran

domalloca

tion;

doub

le-b

lind;

24out-p

atientsw

ithcoca

ine

1.Des

ipram

ine

200m

g(n=

8)

Posi

tiveur

inesample

forcoca

inemetabo

lites;

12wee

ksfor

desipram

inean

d

dependence

(DS

M-II

I-R),

2.Aman

tadine

200mg

followed

by

nore

tent

ion

intrea

tment

placebo;8wee

ksforaman

tadine

met

hadone-m

aintained.M

eanage

placebo

(n=

5)

followed

by4wee

kso

fplacebo;

34.8

;85%males,

68%blac

k

3.Placebo

(n=

9)

threeparalle

lgroups;non-

ITT

Averageuseofc

oca

ine:

10years

Co-m

orb

idities:A

DD

,affect

ive

andanxiety

disorders

Kostenetal.1992

Ran

domalloca

tion;

doub

le-b

lind;

94out-p

atientsw

ithopio

idan

d

1.Des

ipram

ine

150m

g(n=

30)

Urinesamples;nore

tention

intrea

tmen

t;

12wee

ksdu

ration;

threepara

llel

coca

ine

depende

nce

(DSM

-III-R)

2.Aman

tadine

300mg

(n=

33)

nore

tent

ion

intrea

tment

forsi

deef

fect

groups;

ITT

Meanage

32;52

%males,8

2%

3.Placebo

(n=

31)

white

.ADD(20%

);depression

(5%),dyst

hym

ia(22%)

Kranzler

&Bauer

1992

Ran

domalloca

tion

(capsu

les

20male

in-p

atientsw

ithcoca

ine

1.Bromocr

iptine

2.5m

g(n=

10)

Part

icipan

tspresen

tingatleastonesi

deef

fect

iden

tical

inappearanceadm

inis

-

dependence

(DS

M-II

I-R).Mean

2.Placebo

(n=

10)

Sideef

fects

tere

dbynursingstaf

f,blindto

age

27.7

years,8

5%w

hite

groupassignmen

t);doub

le-b

lind;

Subjec

tshaduse

danaverageo

f

21days

dura

tion;

twopara

llel

3go

fcoca

inedur

ing

themont

h

groups;non-

ITT

prior

totheadm

ission

Moscov

itzetal.1993

Ran

domalloca

tion

(per

formed

by

29maleout-pati

ents

,coca

ineusers

1.Bromocr

iptine

3.75

mg/

day

Urinesamples;nore

tention

intrea

tmen

t;

apharmacist

whohadnocontac

t

Meanage

37yea

rs.P

articipan

ts

(n=

14)

part

icipan

tspresen

tingatleastonesi

deef

fect

withsu

bjects

);doub

le-b

lind;2

usedcoca

ineat

leas

tfour

timesper

2.Placebo

(n=

15)

wee

ksdurat

ion;

twopara

llel

wee

kfor

thepre

viousmont

h

groups;non-

ITT


10/19



Table

1

(Continued)

Author/year

Methods

Participants

Interventions

Outcomesused

Tennan

t&Tarver

1987

Ran

domalloca

tion

(usingaco

in

14out-p

atientsw

ithcoca

ine

1.Aman

tadine

100mg/

day

(n=

7)

Urinesamples;nore

tention

intrea

tmen

t;

flip);doub

le-blind;10days

dependence.Age

range

163

8;

2.Bromocr

iptine

2.5m

g/day

(n=

7)

sideef

fects;si

deef

fects

dura

tion;

two

para

llelgroups;

ITT

Sex/raceunclear;useo

fcoca

ineat

leas

tfour

timesper

day

for

the

30

dayspr

ior

tothe

adm

ission

Wed

ding

tonetal.1991

Ran

domalloca

tion

(byaperson

83out-p

atientsw

ithcoca

ine

1.Des

ipram

ine

200m

g(n=

32)

Urinesamples;nore

tention

intrea

tmen

t;

notinvo

lved

withrecrui

tmen

to

f

dependence

(DS

M-II

I-R).Meanage

2.Aman

tadine

400mg

followed

dura

tiono

ftrea

tmen

t;part

icipan

tspresen

ting

patients,usingserial

lynum

bere

d,

30,7

6%males,6

9%w

hite

placebo

(n=

23)

atleas

tonesi

deef

fect

opaque,e

nvelopes);s

ingle-

blind;

Coca

ineuseof1

gormoreper

3.Placebo

(n=

28)

12wee

ksdu

ration;

threepara

llel

wee

kfor

12wee

ks.A

dditiona

l

groups;non-

ITT

diagnosis

include

d:ADD;a

ffect

ive

andanxiety

disorders

Miscel

laneous

drugsstud

ies

Co

ld1996

Ran

domalloca

tion

(byaperson

13in

-pat

ientswi

thcoca

ineabuseor

1.Neu

Recover-S

Asix

Abstinencesymptoms

(ASEmo

dified);

notresponsi

ble

forrecrui

ting

dependence

(DS

M-II

I-R).Agerange

capsules

daily(n=

8)

coca

inecrav

ing

(CCS)

patients);doub

le-b

lind;521

254

6years,

75%

male,raceunclear;

2.Placebo

(n=

4)

days

duration;

twopara

llelgroups;

10pa

tientsalso

trea

tedforalco

hol

non-

ITT

dependence

Crosbyetal.1996

Ran

domalloca

tion;

doub

le-b

lind;12

60out-p

atientsw

ithcoca

ineabuseor

1.Phenyto

in300mg/d

ay(n=

29)

Cocaineuse

(sel

f-report);n

ore

tent

ion

intrea

tmen

t;

wee

ksdurat

ion;

twopara

llelgroups;

dependence

(DS

M-II

I-R).Meanage

2.Placebo

(n=

31)

crav

ing;si

de-e

ffects

non-

ITT

34years,

80%male,

55%African-

Amer

ican

Gaw

inetal.1989

Ran

domalloca

tion;

doub

le-b

lind;6

100out-p

atients

withcoca

ine

1.Des

ipram

ine

2,5mg/

kg(n=

31)

Urinesamples;durat

ionof

trea

tmen

t

wee

ksdurat

ion,

threepara

llelgroups;

dependence

(DS

M-II

I-R)seek

ing

2.Lithiumcarbona

te6

00mg

(n=

37)

non-

ITT

trea

tmen

t.Mean

age

29years;

3.Placebo-a

tropine

0.1mg

(n=

32)

76%male;

71%C

aucasians.

Mos

t

part

icipan

tshado

ther

diagnosis

suchas

ADDr


11/19


12/19



tests and P-values. For most of the continuous variables,

standard deviation was not provided or data were

skewed. Variation was seen regarding trialists definition

of efficacy (positive urine samples for cocaine metabo-

lites, self-report of cocaine use, craving, abstinence

symptoms).

Efficacy findings

The main efficacy outcome reported in the studies was

the presence of cocaine metabolites in the urine. Usually,

the cut-off value considered to determine a positive test

sample was 300 mg/ml. Figure 1 shows these findings for

all drugs. No significant results were found, regardless

the type of drug or dose used.

Desipramine was evaluated in 14 trials. Some degree

of heterogeneity was found when all studies were con-

sidered, regardless of whether or not cocaine dependence

was a primary diagnosis. In a preliminary analysis, when

all desipramine trials with urinalysis data available were

included, significant heterogeneity was present (c2 =

12.7; d.f. = 6; P =0.048). This result favored desipramine,

but it was statistically non-significant (RR = 0.82; 95%CI 0.61.13). When trials were analysed separately

according to the presence of an additional diagnosis of

opioid dependence, the result on heterogeneity held for

the studies, including patients on methadone mainte-

nance treatment (Kolar et al. 1992; Kosten et al. 1992;

c2= 4.24; d.f. = 1; P = 0.04). A small RCT (n = 17) (Kolar

etal. 1992) showed an extremely non-significant positive

result favoring desipramine (RR = 0.16; 95% CI

0.021.04). The results for trials with primary cocaine

dependence patients were more homogeneous, with no

significant differences between desipramine and placebo.

Study

Active drug

n/N

Placebo

n/N

RR

(95%Cl Random)

Weight

%

RR

(95%Cl random)

01 Desipramine

Gawin et al. 1989

Hall et al. 1994

Kolar et al. 1992

Kosten et al. 1992

McElroy et al. 1989

Tennant & Tarver 1985

Weddington et al. 1991

Subtotal (95%Cl)

02 Fluoxetine

Covi et al. 1993

03 Gepirone

Jekins et al. 1992

04 Amantadine

Alterman et al. 1992

Kolar et al. 1992

Kosten et al. 1992


Subtotal (95%Cl)

05 Bromocriptine

06 CarbamazepineMoscovitz et al. 1993

Corinish et al. 1995

Halikas et al. 1997

Kranzler et al. 1995

Subtotal (95%Cl)

Subtotal (95%Cl)

Subtotal (95%Cl)

07 Disulfiram

08 Mazindol

George et al. 2000

Petrakis et al. 2000

Margolin et al. 1995a

Stine et al. 1995

09 Lithium carbonate

Gawin et al. 1989

10/24

13/22

1/8

22/30

2/9

4/11

24/32

76/136

13/31

6/12

1/15

4/5

28/33

18/23

51/76

10/14

13/37

44/58

14/20

71/115

6/11

31/36

37/47

10/18

17/22

27/40

18/24

20/24

11/21

7/9

27/31

3/6

3/11

19/28

90/130

5/14

5/14

6/15

7/9

27/31

19/28

59/83

13/15

11/45

53/62

16/20

80/127

5/9

29/31

34/40

13/19

15/21

28/40

20/24

18.1

17.1

2.6

27.8

4.1

5.4

25.0

100.0

100.0

100.0

1.5

15.3

51.5

31.7

100.0

100.0

7.4

69.2

23.4

100.0

3.9

96.1

100.0

32.0

68.0

100.0

100.0

0.50 [0.30,0.83]

1.13 [0.66,1,93]

0.16 [0.02,1.04]

0.84 [0.65,1.09]

0.44 [0.10,1.92]

1.33 [0.39,4.62]

1.11 [0.80,1.53]

0.82 [0.60,1.13]

1.17 [0.52,2.65]

1.40 [0.57,3.45]

0.17 [0.02,1.22]

1.03 [0.59,1.80]

0.97 [0.80,1.19]

1.15 [0.83,1.61]

1.01 [0.79,1.29]

0.82 [0.56,1.21]

1.44 [0.73,2.82]

0.89 [0.74,1.06]

0.88 [0.61,1.26]

0.92 [0.76,1.10]

0.98 [0.44,2.17]

0.92 [0.78,1.08]

0.92 [0.79,1.08]

0.81 [0.49,1.36]

1.08 [0.76,1.54]

0.99 [0.74,1.32]

0.90 [0.67,1.21]

0.1 0.2 1 5 10Favors active drug Favors placebo

Figure 1 Positive urine samples for cocaine metabolites


13/19



Regarding the pattern of cocaine use and craving, the

following outcomes were used: duration of treatment in

weeks; amount of grams used per day, days of cocaine

use per week; percentage of abstinent days; Addiction

Severity Index (ASI) drug scores at the end of the trial;

craving intensity and frequency. Most of these data,

however, were skewed and were not summarized. In

other words, there was such a high level of variation in

measures used across these studies that it was not pos-

sible to incorporate these data into the meta-analysis.

Other clinical ratings

A number of clinical ratings and scales were used in the

studies, including the Beck Depression Inventory (BDI),

the Spielberg State Anxiety Inventory (SSA), the

Symptom Check List 90Revised (SCL-90-R) and the

Patient Global Improvement (PGI), among others.

However, relevant data were provided for a limitednumber of scales. Many continuous outcomes were

described in terms of means without corresponding

standard deviations, or actual measure units for baseline

point and linear change per visit. Such data could not be

summarized or presented in graphical form.

Dropoutsno retention in treatment

In 10 studies, authors did not include descriptions of

those who dropped out before the end of the trial proto-

col (Gawin et al. 1989; Giannini et al. 1989; Kranzler &

Bauer 1992; Triffleman et al. 1992; Covi et al. 1993;Campbell et al. 1994; Hall et al. 1994; Rosse et al. 1994;

Cold 1996; Carrol et al. 1998).

A huge variation was seen in terms of dropout rates

in the following studies, ranging from 0% (Giannini &

Billet 1987patients from a private practice psychiatric

group) to 84% (Weddington et al. 1991), suggesting that

a very heterogeneous set of populations were compared.

However, for most of studies a high number of patients

who were not able to complete the protocol study was

found. In general, the rate of patients remaining in treat-

ment was similar for those taking medications or placebo.

A non-significant trend favoring CBZ was found interms of dropouts (RR 0.88 95%CI 0.751.03), with

four studies and 313 individuals included in the meta-

analysis.

No significant differences on retention in treatment

were obtained for desipramine, gepirone, ritanserin and

imipramine trials compared with placebo. Similar results

were found for dropout rates due to side effects. One sig-

nificant result was found by Batki et al. (1996): a higher

percentage of patients on fluoxetine completed the study,

in comparison with placebo (RR = 0.53; 95% CI

0.320.88, n = 32).

In a large RCT on pergolide (n = 464), a dopamine

agonist, with 40% of participants presenting co-morbid

alcohol and cocaine dependence (Malcolm et al. 2000),

dropout rates favored placebo, without reaching statisti-

cal significance. Figure 2 shows the dropout rates across

different types of drugs.

Side effects

In general, trials did not show significant results in terms

of specific side effects between medications and placebo,

which can be due to the small number of trials for some

drugs and different methods of collecting information on

this outcome.

In CBZ studies, several side effects were described,

including dermatological hypersensitivity reaction, dizzi-

ness, drowsiness, dry mouth, headache, nausea and

vomiting, but there were no statistically significant dif-

ferences between CBZ and placebo. Only two ADs trials

(McElroy 1989; Weddington et al. 1992) reported rele-

vant data on side effects. A trend was found suggesting

that patients on desipramine were more likely to present

at least one side effect during the trial than those on

placebo (RR = 1.65; 95% CI 0.982.79). Giannini et al.

(1989) did not find statistically significant differences

between amantadine and placebo in terms of side effects

(diarrhoea, headache, nausea and rash). No significant

results were found regarding bromocriptine in terms of

side effects and placebo.

Direct comparisons

Amantadine versus bromocriptine

Results from two trials (Tennant & Tarver 1987; Giannini

et al. 1989) did not find any significant difference

between these two dopamine agonists for all efficacy mea-

sures, including patients subjective reports. However, a

trend was observed favoring amantadine in terms of

retention in treatment and the occurrence of side effects.

When craving was assessed, a trend favoring bromocrip-

tine was found in Gianninis trial.

Amantadine versus desipramine

Three trials compared these products (Weddington et al.

1991; Kolar et al. 1992; Kosten et al. 1992). The first

two included methadone-maintained subjects while

Weddington evaluated cocaine dependence only. In

general, there were no differences when retention in

treatment and side effects were evaluated. A non-

statistically significant difference favoring desipramine

was found in methadone-maintained subjects, as

revealed by positive urine samples for cocaine metabolites

at the end of the trial.


14/19



Subgroup analysis

Given the heterogeneity of patients, diagnoses and set-

tings, subgroup analysis was performed separately for

two groups. Trials where patients had a primary diagno-

sis of cocaine dependence were compared to those where

patients had diagnoses for both cocaine and opioid

dependence or were in methadone maintenance treat-

Study

01 Bupropion

02 Desipramine

Margolin et al. 1995a

Arndt et al. 1992

Giannini et al. 1986

Kolar et al. 1992

Kosten et al. 1992

McElroy et al. 1989

O'Brien et al. 1988

Tennant & Tarver 1985


Subtotal (95%Cl)

Subtotal (95%Cl)

Subtotal (95%Cl)

Subtotal (95%Cl)

Subtotal (95%Cl)

Subtotal (95%Cl)

03 Fluoxetine

Batki et al. 1996

04 Gepirone

Jenkins et al. 1992

05 Imipramine

Nunes et al. 199506 Ritanserin

Ehrman et al. 1996

07 Amantadine

Alterman et al. 1992

Handelsman et al. 1995

Kampman et al. 1996

Kolar et al. 1992

Kosten et al. 1992


08 Bromocriptine

Eiler et al. 1995

Handelsman et al. 1995

Moscovitz et al. 1993

09 Pergolide

Malcolm et al. 2000

10 Carbamzaepine

Cornish et al. 1995

Halikas et al. 1997

Kranzler et al. 1995

Montoya et al. 1995

11 Disulfiram

George et al. 2000

Petrakis et al. 2000

12 Mazindol

Margolin et al. 1995b

Stine et al. 1995

13 Naltrexone

Somoza et al. 1998

14 PhenytoinCrosby et al. 1996

15 Risperidone 2mg/day

Grabowski et al. 2000

Active drug

n/N

Placebo

n/N

RR

(95%Cl Random)

Weight

%

RR

(95%Cl random)

11/74

17/53

2/10

0/8

8/30

5/9

8/32

5/11

27/32

72/185

9/20

24/59

11/40

5/21

2/23

24/30

2/5

8/33

27/32

68/144

17/32

6/24

9/14

32/70

8/16

111/156

29/46

35/58

9/20

19/28

92/152

3/11

11/36

14/47

3/18

7/22

10/40

18/24

23/29

23/30

13/75

3/26

0/10

5/9

4/31

5/6

1/15

5/11

16/28

39/136

15/16

11/21

27/54

13/40

5/21

3/25

19/31

5/9

4/31

19/23

55/140

17/31

4/26

10/15

31/72

89/153

34/45

42/62

7/20

27/34

110/161

2/9

4/31

6/40

4/19

8/21

12/40

15/22

25/31

42/45

100.0

11.8

2.5

2.8

12.5

20.5

5.0

15.4

29.5

100.0

100.0

100.0

100.0

100.0

2.9

1.2

31.1

2.3

2.9

59.7

100.0

52.6

8.5

39.0

100.0

100.0

33.4

35.1

4.3

27.2

100.0

30.8

69.2

100.0

26.9

73.1

100.0

100.0

100.0

100.0

0.86 [0.41,1.79]

2.78 [0.89,8.64]

5.00 [0.27,92.63]

0.10 [0.01,1.58]

2.07 [0.69, 6.15]

0.67 [0.34,1.32]

3.75 [0.51,27.33]

1.00 [0.40,2.50]

1.48 [1.04,2.10]

1.33 [0.82,2.15]

0.53 [0.32,0.88]

0.86 [0.46,1.62]

0.81 [0.54,1.22]

0.85 [0.43,1.66]

1.00 [0.34,2.95]

0.72 [0.13,3.96]

1.31 [0.94,1.82]

0.72 [0.21,2.44]

1.88 [0.63,5.62]

1.02 [0.80,1.30]

1.11 [0.92,1.33]

0.97 [0.61,1.53]

1.63 [0.52,5.07]

0.96 [0.57,1.64]

1.01 [0.73,1.41]

1.22 [1.03,1.45]

0.83 [0.63,1.10]

0.89 [0.68,1.17]

1.29 [0.60,2.77]

0.85 [0.63,1.16]

0.88 [0.75,1.03]

1.23 [0.26,5.82]

2.37 [0.84,6.69]

1.93 [0.82,4.59]

0.79 [0.21,3.06]

0.84 [0.37,1.90]

0.82 [0.41,1.66]

1.10 [0.76,1.59]

0.98 [0.76,1.27]

0.82 [0.66,1.02]

0.1 0.2 1 5 10

Favors active drug Favors placebo

Figure 2 Dropout rates


15/19



ment. Results were very similar to those obtained for the

main analysis, regardless type of drug, suggesting that

there is no current evidence to support distinctions

among patients with primary cocaine dependence or

in methadone maintenance as far the pharmacologi-

cal treatment of cocaine dependence is concerned. A

number of miscellaneous trials are summarized in the

figures. None of these trials were of substantial size and

none of the results suggested any significant differences.

Available data in the original reports did not allow

further subgroup analysis.

DISCUSSION

Although in this review a large number of RCTs on the

pharmacological treatment of cocaine dependence has

been identified, no evidence of efficacy was found,

regardless of the type of drug or dose used for all relevantoutcomes assessed.

A range of factors makes it difficult to draw con-

clusions from any synthesis of treatments for cocaine

dependence. These include differences in psychiatric

and substance use diagnoses, study quality and design,

definitions of outcome variables, varying amounts of

psychotherapy provided in conjunction with medications

and the limitations of meta-analysis per se. Meta-

analysis may be affected by biases of original studies and

it may often not be the best method for studying the diver-

sity of fields for which it has been used; this could be the

case as far the addiction field is concerned. Typical prob-lems related to the use of meta-analytical approaches

include: regressions are often non-linear; effects are often

multivariate rather than univariate; coverage can be

restricted; faulty studies may be included; the data sum-

marized may not be homogeneous; grouping different

causal factors may lead to meaningless effect sizes esti-

mates; and the failure to relate data to theories may

obscure discrepancies (Eysenck 1995).

In this review, every effort was made to reduce biases,

although the generally poor quality of reporting regard-

ing both trial performance and outcome may have

limited this aim. For example, the method of randomassignment to treatment was seldom described and so 37

of the 46 studies were classified as having a moderate risk

of selection bias, thus being more likely to favor the

experimental treatment (Schulz et al. 1995).

The key part of this discussion will focus on ADs

including desipramine, and CBZ because the largest

number of studies have been conducted on these medi-

cations. The other drugs reviewed included DAs and mis-

cellaneous drugs but, overall, size of studies was limited,

and there was little evidence to suggest benefit from these

medications.

Antidepressants

Methodological considerations

A meta-analysis of desipramine for the treatment of

cocaine addiction (Levin & Lehman 1991), including

seven randomized studies with a total of 200 patients,

found that desipramine is no better than placebo in

retaining patients in treatment. However, it was also sug-

gested that while patients were in treatment, desipramine

is helpful in promoting abstinence (data from six trials).

The authors state that the Fail-safe Nwhich provides

an estimate of the number of additional negative studies

that would be required to reverse a positive meta-

analytical findingin connection with desipramine

efficacy is 16. In other words, 16 studies finding no

advantage to desipramine compared with placebo

would be necessary to negate this finding.

These findings were discussed by Delucchi (1992),

who pointed out a number of limitations in the meta-analysis. The main problem was the use of an incorrect

method for combining the studies chosen by the authors.

Moreover, the main outcome measureabstinence

was defined in many different ways across the studies.

There are clear discrepancies between the results

and conclusions of Levin & Lehman (1991) review and

the present one. Different methods of combining

studies were used, but other differences also need to be

mentioned:

1 The first review was published 8 years ago, and further

randomized evidence has since become available: this

review includes 14 RCTs (eight studies with availabledata for efficacy);

2 Efficacy data used in this review were combined only

when authors defined efficacy in a similar and compa-

rable way. All eight studies used the number of patients

with positive samples for cocaine metabolites at the end

of the trial. Therefore, the estimates from the first meta-

analysis could be inflated by less restrictive definitions of

efficacy. Alternatively, our results can be considered con-

servative ones, given the selection of outcomes, criteria

for pooling analyses and the use of the random effects

model, which takes into account heterogeneity between

trials.

Efficacy findings

Data from 18 RCTs involving 1379 subjects suggest lack

of efficacy of ADs compared to placebo. Only three trials

(Giannini et al. 1986; Giannini, Loiselle & Giannini 1987;

Gawin et al. 1989) showed statistically significant differ-

ences favoring the intervention (desipramine) in efficacy

measures when compared to placebo. Most of the trials

showed a similar decrease in cocaine use and craving in

both the placebo and the active drug groups. When


16/19



relapse in cocaine-free patients was evaluated, the same

pattern of response was found (McElroy et al. 1989). It

was suggested that patients who had a history of opioid

use were more likely to relapse when treated with ADs

(Arndt et al. 1992), but current results were unable to

confirm any relevant differences for any of the efficacy

measures.

There is still a limited number of RCTs assessing other

agents such as fluoxetine, ritanserin, gepirone, bupropion

and imipramine. Previous experience with depression

suggests they may have similar effects regardless of the

proposed mechanism of action. When trials reported

results on urinalysis (Jenkins et al. 1992; Covi et al. 1993)

gepirone and fluoxetine performances were very similar

to those found for desipramine trials.


Although results from single trials suggest that patientson medications such as fluoxetine are less likely to drop

out, these results are from single trials and involve a

limited number of patients. SSRIs are thought to have

better acceptability, but this finding needs replication.

Giannini et al. (1986) found the lowest dropout rate

(10%). In this small study (n = 20), participants had a

history of cocaine abuse of at least 1 year, and received

supportive counselling at 5-day intervals. Batki et al.

(1996) found the highest dropout rate: 72%. Most of

the subjects in this trial (n = 32) had other psychiatric dis-

orders such as major depressive disorder (40%), antisocial

personality disorder (20%) and alcohol abuse and depen-dence (20%), and were paid to participate in the study:

$10 for the intake and each of the weekly assessments.

This finding is biased, possibly because of the very het-

erogeneous populations of clinical studies, and reinforces

the view that a specific set of conditions may be associ-

ated with higher percentages of dropouts, including

factors of co-morbidity, the absence of psychosocial

support and the method of recruitment. It is plausible

that the best results can be expected in highly motivated

populations or associated with highly structured psy-

chosocial interventions aimed at promoting and modu-

lating motivation.

Carbamazepine

Methodological considerations

The efficacy of CBZ for the treatment of cocaine-

dependent patients was first suggested by an open trial

with 35 participants (Halikas et al. 1989). These same

authors conducted a cross-over randomized controlled

study 2 years later confirming this finding (n = 32). Such

promising results, however, were based on limited

methods, the effects were modest, and the studies per-

formed by a single group. Despite this rationale and the

absence of a solid research base, the unfortunate conse-

quence of the early publicity was that carbamazepine

made its way into physicians practices (Johanson 1995).

Halikas et al. (1997) found significant results favoring

the use 400 mg of carbamazepine, although therapeutic

effects as assessed by clinicians showed that placebo per-

formed significantly better. In this same trial, a number

of continuous outcome variables were subjected to

sophisticated regression analysis. However, the most

consistent efficacy outcomepositive urine analysis

did not show any significant difference between groups,

even adopting the most positive results from Halikas et al.

(400 mg/day).


Pooled results from five RCTs involving 455 subjectssuggest a lack of evidence regarding the efficacy of car-

bamazepine. Type II error could be an explanation for

such findings but other factors such as illness behavior

must also be considered. However, the most prominent

finding for these studies concern the high dropout rates.

Although slightly favoring carbamazepine, these rates

were high for both those taking carbamazepine (61%)

and placebo (69%). These high dropout rates may be

inherent to the type of drug problem and to its severity.

The urgent demand by clinicians, patients, families

and the community as a whole for an adequate treatment

for cocaine dependence may lead to the adoption of ther-apeutic regimes even if the evidence of their efficiency is

weak. Alternatively, it is plausible that carbamazepine

illustrates a common problem of extrapolating results

from preclinical studies to clinical effects in adults, which

are not necessarily related to demonstrated and signifi-

cant clinical effects.

In the addiction field, there is a high correlation

between compliance with prescribed treatment and clini-

cal outcome (Meyer 1992). In open trials such as the one

conducted by Halikas et al. patients may be motivated and

are not representative of cocaine-dependent patients in

the general population. Cocaine-dependent subjects whoparticipated in clinical trials may manifest vastly differ-

ing degrees of motivation for change. Such motivation

may improve overall outcome significantly but to date

this has not been well demonstrated empirically. Ideally,

successful pharmacological intervention should act inde-

pendently of level of patient motivation for change.

Theoretically, motivation need not be a prerequisite for

the use of anticraving medication (Halikas et al. 1991).

Motivation may also be influenced significantly by the

overall quality of the program but this is equal for both

active drugs and placebo subjects.


17/19



Implications for practice

With the evidence currently available, there are no

data supporting the efficacy of antidepressants, carba-

mazepine, dopamine agonists, or other drugs such as

disulfiram, naltrexone and mazindol for the treatment of

cocaine dependence. In the absence of more reliable evi-

dence, clinicians may consider prescribing alternative

medications, where a higher number of studies and

patients evaluated are available (for instance, ADs).

Pharmacological treatments that affect the consumption

of other substances such as alcohol may also have a role

to play. Disulfiram as a treatment agent requires further

exploration; however, given the difficulty in determining

its role in alcohol dependence, further studies are

required before any conclusions can be drawn on its

impact in cocaine dependence.

It seems unlikely that, in the absence of motivation for

behavior change, pharmacological agents, with the

possible exception of cocaine-specific blocking or main-

tenance agents, are able to promote a significant

improvement in behavior.

The value of medications such as ADs, prescribed in

conjunction with a more potent psychosocial interven-

tion, remains unknown. However, until further efficacy

and effectiveness studies are available, clinicians may

consider adding psychosocial and psychotherapeutic

supportive measures aiming to keep patients in treat-

ment. Such advice does not rely on any direct evidence

from RCTs, but does consider the best available evidence,

the high dropout rates and illness behavior associated

with cocaine use. The use of ADs in the absence of

depression is not supported by current evidence of

impact. This does not preclude the use of ADs to treat

major depressive illness that is associated with cocaine

abuse and dependence but would clarify that the anti-

depressant does not have any specific anticraving effect.

Implications for research

There is a need for further exploration of other medica-

tions but there is also a need to clarify the current avail-

able evidence for psychosocial interventions and toensure that current psychosocial treatment programs

are organized to deliver the greatest possible treatment

impact (Carroll et al. 1994). Further studies need also to

take account of the organization of the treatment setting

when planning trials.

The unusually high dropout rates across studies and

drugs, rather than reflecting a simple methodological

flaw, may suggest that specific compliance promoting

approaches are needed to investigate clinical effects of

drugs for the treatment of cocaine dependence. If com-

pliance can be improved through psychosocial interven-

tions, what then would be the optimal duration of phar-

macological treatment? Is medication still useful after the

natural resolution of the withdrawal phase of abstinence

symptoms?

In reviewing RCTs on the treatment of cocaine de-

pendence, some outcome measures seem to be more reli-

able and useful than others. Trialists can choose to use

continuous data from one craving or psychiatric scale,

relying mainly on those that are widely used and vali-

dated. The ASI seems to be a useful instrument, given that

it is designed to assess the problem of severity in seven

areas affected commonly by addiction. Equivalent instru-

ments such as the Maudsley Addiction Profile (Marsden

1998) could be considered, but overall it is critical that val-

idated instruments are used in such studies.

Dichotomous variables are interpreted more easily by

clinicians, and provide estimations of effect size and

number needed to treat/number needed to harm, par-

ticularly in respect to:1 the number of subjects with positive urine samples for

cocaine metabolites at end-point;

2 self-reported use of cocainealthough less reliable,

these results can be compared to those from urinalysis;

3 retention in treatment (overall), and

4 retention in treatment for side-effects.

The absence of clinical effects based on a small

number of trials may lead to a general conclusion that

larger RCTs are needed. However, in light of the data

reviewed, it could be that this is not justified, due to the

lack of any clinically relevant results regardless of the

type of medication. More than trends and a smallnumber of significant results, on which the current evi-

dence relies, are needed. Larger randomized investiga-

tions are expensive and time-consuming and should

perhaps be reserved for medications showing more rele-

vant and promising evidence.

Given the relative lack of success of drugs assessed in

this review, it may be necessary to conduct a new set of

clinical studies, characterized by research designs that

verify expressly hypotheses concerning possible interac-

tions between treatment and relevant patient character-

istics. There is a need for a systematic review of

psychosocial interventions, as at present the prospects forhealth and social gain through psychosocial treatments

appears substantially more promising than currently

available pharmacotherapies.

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