Ogni antibiotico è efficace in relazione a un determinato gruppo di microrganismi acquista antibiotici onlinein caso di infezioni oculari vengono scelte gocce ed unguenti.

Cns drugs 10: 43-59, jul 1998

CNS Drugs 1998 Jul; 10 (1): 43-59 Adis International Limited. All rights reserved.
Cocaine Abuse and Dependence
Approaches to Management

Kalpana I. Nathan, William H. Bresnick and Steven L. Batki Department of Psychiatry, University of California at San Francisco, School of Medicine,Division of Substance Abuse and Addiction Medicine, San Francisco General Hospital,San Francisco, California, USA 5. Pharmacological Treatment of Cocaine Dependence . . . . . . . . . . . . 50 Cocaine abuse and dependence constitute major health and social problems in the US and elsewhere. They are associated with a wide range of psychiatric andmedical morbidity, including an increased risk of transmission of HIV.
The 2 major approaches to the treatment of cocaine abuse and dependence are psychosocial interventions and pharmacotherapy to reduce withdrawal and crav-ing, and to ensure abstinence initiation and relapse prevention. These approachesare often combined to optimise outcome. Numerous medications have been testedin the treatment of cocaine dependence. To date, however, there is no conclusiveevidence in support of any generally effective pharmacotherapy for cocaine crav-ing, withdrawal or abstinence initiation. Therefore, the mainstay of treatment isthe use of psychosocial interventions.
Nathan et al. 1. Overview of Cocaine
Crack cocaine can be readily smoked due to its as a Drug of Abuse
lower melting point.
Thousands of years ago, South American na- 1.2 Pharmacological Effects tives began chewing the leaves from the coca shrub Cocaine possesses local anaesthetic effects as a in order to experience its stimulating effects. In the result of blockade of sodium channels, thus inhib- 1880s and 1920s, cocaine abuse reached epidemic iting the initiation or conduction of nerve impulses.
proportions in the US. Another epidemic occurred In higher concentrations, cocaine can slow cardiac during the 1970s and 1980s, which primarily in- conduction and impair contractility, possibly con- volved the intranasal use of cocaine hydrochloride.
tributing to arrhythmias and sudden death. Cocaine The epidemic has continued throughout the 1990s, is also a sympathomimetic and exerts its clinical but with the use of cocaine in the smoked free base actions by blocking the reuptake of noradrenaline form. This latest epidemic has taken its greatest toll (norepinephrine), serotonin (5-hydroxytryptamine; in the US among ethnic minorities and lower in- 5-HT) and dopamine. Blockade of dopamine re- come groups.
uptake acutely increases dopamine levels in the Cocaine is a centrally acting stimulant that af- synapse and it is this effect, particularly in the fects the reward system in the brain and produces mesolimbic and mesocortical pathways, that is activation and euphoria. The stimulation of the linked to the rewarding effects of cocaine, although brain reward system appears to be linked to both other neurotransmitters such as serotonin are also animal and human self-administration of cocaine and reinforces continued use, often to the point ofabuse or dependence. DSM-IV[1] defines the diag- 1.3 Routes of Administration nostic criteria for cocaine abuse and dependence and Patterns of Use (tables I and II).
The route by which cocaine is administered determines the amount absorbed and rapidity of absorption (see table III). Bioavailability of bothorally and intranasally administered cocaine is Cocaine is an alkaloid derived from the leaves about 30 to 40% when compared with the intrave- of Erythroxylon coca, which is indigenous to South nous route, while the initial effects after smoking America.[2] Cocaine is prepared by processing the are even more intense and more rapid in onset than dried coca leaves to make coca paste, which can be comparable intravenous doses.[4] further processed into 2 forms: cocaine hydrochlo- Cocaine intake produces an initial ‘rush' or ride powder or ‘crack' (i.e. free base cocaine).
‘high' that is similar to the euphoric effects pro-duced by other drugs of abuse. However, cocaine Table I. DSM-IV[1] criteria for substance abuse
has a unique role in stimulating the brain reward Maladaptive pattern of substance use leading to a clinically pathway and in producing intense craving trig- significant impairment or distress, with 1 or more of the following gered by cues, with drug intake being more related occurring within a 12-month period: to brain reward rather than induced by withdrawal Recurrent substance use resulting in a failure to fulfil major role obligations at work, home or school states.[5] The pleasurable effects fade dramatically Recurrent substance use in situations in which it is physically even before the blood concentrations fall signifi- cantly, leading to the use of high doses in binges or Recurrent substance-related legal problems ‘runs', in an attempt to prolong the high. A binge Continued substance use despite having persistent or recurrent can last 24 hours or more, with several ‘hits' per social or interpersonal problems caused by the effects of the substance hour, followed by a ‘crash' marked by depression Symptoms do not meet criteria for dependence and exhaustion that may last for several days. This  Adis International Limited. All rights reserved.
CNS Drugs 1998 Jul; 10 (1) Cocaine Abuse and Dependence Table II. DSM-IV[1] criteria for substance dependence
somnia, increased appetite, psychomotor retarda- Maladaptive pattern of substance use leading to clinically tion or agitation.[1] The acute withdrawal syndrome significant impairment or distress, with 3 or more of the following emerges a few hours to a few days following ces- occurring within a 12-month period: sation of cocaine use. It can be followed by a pro- tracted dysphoric syndrome – often including de- Substance is taken in larger amounts or over a longer period creased activation, anxiety, boredom and lack of than was intended motivation, with markedly diminished intensity of Persistent desire or unsuccessful efforts to cut down pleasurable experiences (anhedonia). This dyspho- A great deal of time is spent in activities necessary to obtain the ria, when contrasted with memories of cocaine- induced euphoria, induces severe cocaine cravings, Important social, occupational or recreational activities are given up to obtain/use the substance resumption of use and cycles of recurrent binges.[8] Substance use is continued despite knowledge of having a persistent physical or psychological problem that is exacerbated by the substance is often followed by intense craving which can lastfor weeks.[6] Serial annual surveys have documented trends associated with cocaine use in the US over the past 1.4 Clinical Symptomatology few years. About 25 million Americans have triedcocaine at least once in their lifetime and, when questioned, almost 1.5 million admitted to having Cocaine intoxication is characterised by height- used cocaine in the previous month.[9] ened alertness, euphoria and behavioural changes The 1995 US National Household Survey on Drug such as gregariousness and hyperactivity, pro- Abuse (NHSDA) estimated that there were about gressing to restlessness, hypervigilance, anxiety, 500 000 ‘frequent' cocaine users (defined as 51 or stereotypy, impaired judgement and impaired more days of use within the past year) and 2.5 million functioning. Intoxication is usually accompanied ‘occasional' users (less than 12 days of use within the by tachycardia, pupillary dilation, elevated blood past year) in 1995.[9] While the number of frequent pressure, diaphoresis, anorexia, hyperactivity and cocaine users in 1985, 1994 and 1995 were not sig- agitation. Extreme intoxication can lead to more nificantly different (estimates of 781 000, 734 000 pronounced agitation, respiratory depression, chest and 582 000, respectively), the number of occa- pain or cardiac arrhythmias, confusion, seizures, sional users had sharply declined (from about 7 dystonias or coma.[1] million in 1985 to 2.5 million in 1995).[9] 1.4.2 Withdrawal Syndrome
The NHSDA estimate of new users in 1994 was While controversy and ambiguity exist in the about 500 000 persons, which was down from 1 to scientific literature,[7] clinical observations appear 1.5 million initiates per year during the early to indicate that stimulant withdrawal may produce 1980s.[9] While the number of occasional cocaine dysphoric mood and the following signs: fatigue, users in the US has decreased since the mid-1980s, vivid and unpleasant dreams, insomnia or hyper- the amount of cocaine consumed has not. In the Table III. Pharmacokinetic/pharmacodynamic effects of various routes of administration of cocaine
Duration of effect Blood concentrations Free base (‘crack')  Adis International Limited. All rights reserved.
CNS Drugs 1998 Jul; 10 (1) Nathan et al. US, street prices for cocaine, especially the increas- Cocaine use can lead to increased HIV risk ingly popular crack cocaine form, have decreased through injection of the drug and through high risk since the mid-1980s. Not surprising, increased sexual behaviour.[11] Promiscuous sexual behavi- cocaine-related morbidity and mortality has been our is associated with the use of cocaine, often in- noted in many large American cities, with increased volving the exchange of sex for drugs. Goldstein numbers of cocaine-related emergency room visits.
and colleagues[12] reported findings from 3 studies The 1996 Drug Abuse Warning Network (DAWN) that showed that women who exchange sex for report of US emergency room visits shows a con- drugs tend to be the heaviest users of drugs, partic- tinued high incidence of cocaine-related episodes ularly of cocaine.
in 1995 (about 143 000, or about 27% of all drug- Those who smoke cocaine are susceptible to related hospital emergency room episodes).[10] acute respiratory symptoms (e.g. cough, chest pain,haemoptysis) and numerous pulmonary complica- tions such as exacerbation of asthma, pneumotho-rax, pulmonary haemorrhage and pulmonary in- Caucasian men still represent the greatest abso- farction.[13] Intranasal intake of cocaine damages lute number of cocaine users. However, recent the nasal mucosa and can lead to bleeding and to a studies and surveys have shown that, in the 1990s, perforated septum.
there has been a greater prevalence of cocaine use Cocaine is also associated with bodyweight loss among ethnic minority groups. The NHSDA re- and malnutrition due to its appetite-suppressing ported that, in 1995, cocaine was used by 1.1% of effects. Chest pain is a common symptom and co- African-Americans, 0.7% of Hispanics and 0.6% caine use may cause acute cardiac complications of Caucasians evaluated.[9] DAWN data indicate such as dilated cardiac myopathy, sudden aortic dis- that 54% of cocaine-related episodes involved Af- section and myocarditis, as well as systemic hyper- rican-Americans, while 29% involved Caucasians tension, tachycardia, supraventricular and ventric- and 8% involved Hispanic/Mexican-Americans.[10] ular arrhythmias, myocardial infarction and even The rate of current cocaine use in 1995 was sudden death.[14] highest among Americans aged 18 to 34 years (rate Cocaine use can also produce neurological com- of approximately 1.3%), in those with less educa- plications such as headache, syncope, blurred vision, tion and among the unemployed.[9] The NHSDA transient ischaemic attacks, seizures, confusional also found a lower rate of current cocaine use in states, cerebral haemorrhage, cerebral infarction women compared with men (about 0.4 and 1%, re- and toxic encephalopathy.[14] Cocaine use during pregnancy is associated with pre-term labour, intrauterine growth retardation, ab- ruptio placentae, low birth-weight infants (<2500g), Cocaine abuse is associated with significant med- neonatal death and sudden infant death syndrome ical and psychiatric morbidity. In addition to the potentially life-threatening effects of acute intoxi-cation, there are numerous medical and psychiatric 3.2 Psychiatric Morbidity problems that arise as a consequence of cocaineuse.
Cocaine abuse is associated with several major types of psychiatric morbidity such as mood and 3.1 Medical Morbidity anxiety disorders and psychosis.[16-18] Cocaine-induced psychosis is relatively less common than Among the medical problems associated with co- cocaine-induced depression and anxiety. Cocaine- caine abuse are HIV infection, hepatitis and tuber- induced psychotic disorder usually commences at the time of cocaine intoxication and may persist  Adis International Limited. All rights reserved.
CNS Drugs 1998 Jul; 10 (1) Cocaine Abuse and Dependence for weeks; the most prominent symptoms are per- • a history of prior treatments for substance abuse secutory delusions and hallucinosis. Individuals and psychiatric disorders who are cocaine-dependent often have temporary • a family and social history.
depressive symptoms that meet symptomatic and Laboratory screening for abused substances duration criteria for major depressive disorder. In and other laboratory tests to help confirm the pre- addition, they may experience a variety of anxiety sence or absence of comorbid conditions associ- symptoms with panic attacks and symptoms re- ated with substance use disorders (such as HIV in- sembling generalised anxiety.
fection, hepatitis and tuberculosis) should also be Cocaine use may also exacerbate pre-existing psychiatric problems. Comorbid primary and sec-ondary psychiatric disorders are common in co- caine abusers.[16-18] Two recent studies by Halikasand colleagues[16] and Ziedonis and co-workers[17] Treatment of cocaine dependence may be of- demonstrated that about 60% of patients seeking fered in a number of treatment settings. In general, treatment for cocaine abuse had current psychiatric the choice of setting depends on a variety of factors disorders that were not associated with the abuse such as treatment needs, preferences of the patient, of a substance, while about 70% had had at least etc.[20] In a nonrandomised study[21] that compared one such psychiatric disorder at some time in their 149 inpatients and 149 outpatients who were co- life (antisocial personality, affective and anxiety caine abusers, those requiring inpatient treatment disorders were most common).
had more severe psychopathology and social im-pairment, and heavier drug use. However, at 1-year follow-up, those who received inpatient treatmenthad less severe problems in terms of psychopathol- The management of cocaine dependence in- ogy and drug use. A randomised study that com- cludes assessment, treatment of intoxication and pared the effectiveness and costs of day hospital withdrawal when necessary, and the development with inpatient rehabilitation for cocaine depend- and implementation of a comprehensive treatment ence, found that both were effective, but that day plan. Cocaine dependence affects many domains hospital treatment was associated with costs that of functioning and frequently requires multimodal were 40 to 50% less than the inpatient treatment treatment using a biopsychosocial model. The goals of treatment include achieving abstinence or atleast reducing the amount of cocaine used and its harmful effects by applying the ‘harm reduction'[19] Several psychological, social and alternative approach. Treatment is also aimed at reducing the interventions and treatment options are available.
severity and frequency of relapse, decreasing the Psychosocial Treatments morbidity and sequelae of cocaine use, and im- The goal of psychosocial treatment should be proving psychological and social functioning.
to provide support for behaviour change and toameliorate the problems caused by cocaine use.
Prolonged drug abstinence and recovery are often The assessment of cocaine dependence involves difficult to achieve. The most frequent and consis- tently effective treatments involve both psycholog- • a detailed history of the patient's substance use ical and social interventions.[23,24] As reviewed and its effect on cognitive, psychological, later in this section, about 50% of patients involved behavioural and physiological functioning in psychosocial treatments can achieve at least sev- • a general medical and psychiatric history and eral weeks of cocaine abstinence; however, pro- longed abstinence rates vary greatly and are deter-  Adis International Limited. All rights reserved.
CNS Drugs 1998 Jul; 10 (1) Nathan et al. mined by several factors such as the duration of uations (see later in this section for more informa- treatment and study designs (e.g. self-report vs urine toxicology for monitoring the extent of use).
Relapse Prevention Therapy (RPT) involves the Psychosocial treatment may offer individual, identification, understanding, avoidance and man- group and family therapies, either alone or, more agement of the numerous physical and psychoso- often, in combination. Individual treatment begins cial cues, triggers and high-risk situations that are with education and psychosocial support. Treat- often associated with cocaine use and relapse.[25-28] ment usually begins once acute drug intoxication Carroll and colleagues[25] proposed that treatment is over and the patient is medically stable and able success requires that patient ambivalence be ad- to actively participate in his or her care. While less dressed, cocaine availability reduced, high-risk sit- commonly utilised today, such individual support- uations eliminated, coping strategies to deal with ive, insight-oriented, cognitive-behavioural or dy- conditioned cues and craving be improved, and life- namic psychotherapies still play important roles in style modified. In 1991, Carroll et al.[26] reported the treatment of substance use disorders. Key is- on 42 patients who were randomly assigned to a sues that can be addressed by these therapies in- 12-week RPT or general interpersonal psychother- clude motivation for change, reasons for cocaine apy protocol. RPT patients were approximately use, evaluation of life issues and goals, coping twice as likely to attain 3 or more continuous weeksof abstinence (57 vs 33%), be classified as recov- strategies and stress management.
ered at the point of treatment termination (43 vs Group-based approaches are commonly used in 19%) and complete treatment (67 vs 38%). In a the treatment of cocaine abuse. Group treatment more recent study, these authors found that RPT led can include psychoeducational approaches, con- to increased treatment retention and longer absti- frontation and psychosocial support for behaviour nence periods in depressed and more severe co- change. Didactic lectures, media presentations and caine users than did basic case management, or the discussions serve as important components of drug use of desipramine or placebo.[27] education. Patients can benefit from the experi- Contingency Management is a behavioural model ences of other group members who are in various of drug treatment involving the patient, his or her phases of recovery. Peer support and confrontation community support and the use of reinforcement can be especially helpful for patients who minimise according to conditioning principles. Abstinence or deny problems associated with their drug use.
from cocaine can be achieved through providing One of the most widely known and used forms contingent rewards and offering patient and family of support is the 12-step approach, a self-help sys- education and counselling. This method encour- tem based on the premise that the user can achieve ages increased participation in healthy and reward- a drug-free life by seeking empowerment from a ing activities (i.e. hobbies, recreation and volunteer ‘higher power', such as God. Members can seek a or paid work). Cocaine abstinence (confirmed by sponsor who can serve as a mentor and source of drug-free urine tests) leads to an immediate reward support during the recovery period. Examples of such as a voucher that can be redeemed for a de- 12-step groups that specifically address the prob- sired commodity, with immediate loss of reward lems of cocaine users are Cocaine Anonymous (CA) for recurrent cocaine use.[29] and Narcotics Anonymous (NA). These meetings Higgins et al.[30] reported on 38 cocaine-depend- are conducted by members who are in various ent patients enrolled in a randomised trial and stages of recovery, and are open to all users seeking found that, compared with standard drug abuse support. While 12-step meetings are widespread, counselling, 12-week outpatient behavioural treat- little conclusive information about their effective- ment led to greater treatment acceptance, longer ness is available from scientific, well-controlled eval- continuous cocaine abstinence and better retention  Adis International Limited. All rights reserved.
CNS Drugs 1998 Jul; 10 (1) Cocaine Abuse and Dependence within the treatment programme. The addition of dependent on cocaine, almost all of whom were the voucher reward system to behavioural therapy African-American men who smoked crack. The improved continuous cocaine abstinence (about 50% individuals were randomly assigned to 4-month for individuals receiving voucher rewards vs about standard (90 minutes twice per week) or intensive 10% for those not receiving vouchers) and treat- (120 minutes 5 times per week) group therapy and ment retention (93% receiving vouchers retained within these 2 groups, either received no additional vs 67% not receiving vouchers retained) in the services, individual therapy, or individual plus randomised study.
family therapy. Results showed an average treat- More recent randomised studies of the effect ment completion rate of 38%. There were no dif- of reinforcement contingencies (vouchers) on co- ferences in retention or 12-month follow-up co- caine dependence by Higgins and colleagues[31] caine use outcome for the different treatment (40 adults, mostly Caucasian men using intranasal modalities or intensities.[35] Overall, individuals and intravenous cocaine) and Silverman et al.[32] exhibited significant decreases in regular cocaine (37 individuals in concurrent methadone mainte- use (84% on admission vs 23% at 12 months post- nance treatment) have demonstrated similar higher rates of treatment retention and continuous cocaine abstinence associated with community reinforce- Some success has been reported with other types ment–contingency management techniques.
of therapies, including chemical aversion ther- Matrix Neurobehavioural Model Treatment was apy[36] and acupuncture.[37-39] developed by Rawson and colleagues.[33] It is a Frawley and Smith[36] reported on 20 Caucasian comprehensive and highly structured programme intranasal cocaine abusers who were studied at a that requires patients to attend individual therapy, private drug treatment programme. Conditioned family education, relapse prevention groups and aversion to the sight, smell and taste of a cocaine 12-step meetings, with mandatory urine drug test- substitute was associated with a 6-month total absti- ing. The authors reported on an open Matrix trial nence rate of 56%.
involving 486 cocaine abusers, mostly Caucasian Several reports have been published in recent men, of whom 51% smoked cocaine. They found years which suggest that acupuncture can decrease that 39% of these individuals completed their 6- cocaine use or relapse rates in abusers;[37-39] how- month programme and 43% were drug-free at com- ever, randomised and well-controlled trials are pletion.[33] Shoptaw et al.[34] have more recently needed to confirm these reports.
reported results from about 130 cocaine abusers,mostly male and Caucasian of whom 72% smoked cocaine, who were randomly assigned to either Ma- While pharmacological treatments may be use- trix model treatment only, Matrix plus desipramine ful in treating cocaine intoxication, the role of treatment, or Matrix plus placebo. There was no medication in the treatment of withdrawal and de- significant medication effect, but 36% of partici- pendence is limited. Numerous medications have pants in the Matrix treatment alone group remained been tested in the treatment of cocaine dependence.
continuously abstinent for at least 8 treatment Many of the studies have methodological prob- weeks. Findings from studies of Matrix treatment lems, such as small sample sizes, lack of adequate illustrate that the concurrent utilisation of multiple controls, unclear diagnostic criteria, inconsistent intensive psychosocial treatment approaches may outcome measures (self-reports as opposed to be helpful in the treatment of cocaine dependence.
urine tests), failure to standardise the type and Combined Psychotherapies have been studied ‘dose' of the accompanying psychosocial interven- by Hoffman et al.[35] They recently published find- tions, and lack of clarity about the term ‘craving' ings involving 184 individuals who abused or were and its role in cocaine dependence.
 Adis International Limited. All rights reserved.
CNS Drugs 1998 Jul; 10 (1) Nathan et al. agitation. As with the treatment of acute intoxica- Treatment for cocaine intoxication is symp- tion, lorazepam may be used in doses of 1 to 2mg tomatic and supportive. During acute intoxication, orally every 2 to 4 hours as needed, with the total patients may become anxious and agitated, and may dosage not exceeding 8 mg/24 hours.
experience paranoid delusions, but these symptomsoften resolve spontaneously. In clinical practice, DependenceJohnson and Vocci[40] defined 3 possible indica- benzodiazepines appear to be helpful for pa- tions for pharmacological treatment of cocaine tients whose symptoms do not resolve. For exam- dependence: (i) initiation and facilitation of absti- ple, lorazepam may be used in doses of 1 to 2mg nence; (ii) treatment of cocaine withdrawal syn- orally every 2 to 4 hours as needed for agitation, drome; and (iii) prevention of relapse. A variety of with the total dosage not exceeding 8 mg/24 hours.
medications have been used to treat the cocaine- There is no evidence that anticonvulsants prevent induced biochemical changes that may play a role cocaine-induced seizures, hence their routine use in relapse to compulsive cocaine use. These are is not indicated.
outlined in detail in section 5. The National Insti- tute of Drug Abuse (NIDA) Medications Develop- Occasionally, individuals who abuse cocaine de- ment Division (MDD) has considered some 20 med- velop a stimulant-induced psychotic disorder that ications.[22] Of these, 15 have undergone human persists for several days or longer, and for which trials [amantadine, bromocriptine, buprenorphine, antipsychotic medication is indicated. In clinical amfebutamone (bupropion), carbamazepine, desip- practice, a high potency antipsychotic drug such as ramine, fluoxetine, flupenthixol, imipramine, levo- haloperidol is used in low doses and on an as- dopa, tryptophan, mazindol, methylphenidate, needed basis for the treatment of these psychotic nifedipine and sertraline] and 5 are in the animal symptoms. However, antipsychotics should be used testing phase (diltiazem, monoclonal antibodies, cautiously since they have the potential to lower SCH-23390, sulpiride and verapamil). Antidepres- the seizure threshold, which may increase the risk sant medications have been used most frequently of cocaine-induced seizures.
since they block reuptake of biogenic amines and The adjunctive use of benzodiazepines such as are thought to have the potential to relieve symp- lorazepam is strongly recommended because they toms secondary to cocaine withdrawal.
can reduce the amount of antipsychotic medicationrequired. Benzodiazepines are relatively less toxic 5. Pharmacological Treatment
than antipsychotics, and so may be tried first for of Cocaine Dependence
targeting the symptoms of agitation and anxiety.
Several pharmacological strategies have been pro- Benzodiazepines can also reduce the muscle rigid- posed for initiating abstinence: (i) replacement ity that can accompany cocaine intoxication and treatment with an agonist such as a delayed-release can also reduce rigidity related to antipsychotic CNS stimulant (e.g. methylphenidate); (ii) treat- ment with a medication that ameliorates cocaine- induced alterations in the CNS and hence reduces The treatment of cocaine withdrawal is aimed at cocaine intake (e.g. bromocriptine, a dopaminergic the presenting symptoms. Withdrawal symptoms agent, which could be expected to reverse the do- generally resolve spontaneously in the first 72 hours pamine deficit associated with chronic cocaine following cessation of cocaine use and typically no use); (iii) treatment with a cocaine antagonist that pharmacotherapy is needed. Those who experience would block the reinforcing actions of cocaine; and increased fatigue in the ‘crash' phase may do well (iv) treatment with catalytic antibodies (which de- with rest and nutrition. Benzodiazepines such as grade cocaine to inactive products, provided that lorazepam may be helpful in treating anxiety or this reaction can be achieved rapidly enough to  Adis International Limited. All rights reserved.
CNS Drugs 1998 Jul; 10 (1) Cocaine Abuse and Dependence deprive the user of the rewarding effect of the treatment. Although this open trial appeared prom- drug[41]). A summary of published controlled med- ising, controlled trials have not replicated the ef- ication trials in the treatment of cocaine depend- fectiveness of imipramine (table IV).[62,63] ence is shown in table IV.
5.1 Antidepressants Despite an early promising open-label study of fluoxetine in cocaine abuse,[78] double-blind trials have been disappointing. Fluoxetine was associ- Early open trials[74] and double-blind studies[54] ated with reduced cocaine use in only 1 trial, which showed favourable results with desipramine, which involved methadone-treated patients,[79] although suggested that it was a promising medication for retention was improved in another trial primarily the treatment of cocaine abuse. In a double-blind, involving crack abusers (table IV).[59] Additionally, randomised study comparing desipramine and lith- a human laboratory trial showed that fluoxetine ium with placebo, Gawin et al.[54] found that indi- was effective in reducing the effects of cocaine.[80] viduals treated with desipramine had a higher ab- However, other controlled trials, including larger stinence rate for 3 weeks compared with those studies of primarily crack cocaine abusers, have receiving lithium or placebo (table IV).
been entirely negative (table IV).[60,61] Although an early meta-analysis appeared to support the efficacy of desipramine for abstinence 5.1.4 Amfebutamone (Bupropion)
(but not with retention in treatment),[55] a number Open-label studies[81,82] with amfebutamone have of more recent controlled trials have shown, at best, shown mixed results, but a recently completed mixed results, and even positive findings have not large multicentre controlled trial in methadone- been robust. Arndt et al.[56] found that desipramine maintained patients showed no significant differ- had no effect in a methadone-maintained popula- ences between amfebutamone and placebo.[46] tion (n = 59). Similarly, Carroll et al.[57] found littleeffect whether or not the drug was combined with 5.2 Dopaminergic Agonists psychotherapy and whether or not patients weredepressed (n = 110); however, they did find some efficacy in lower severity users in the first 6 weeks Bromocriptine is a dopamine receptor agonist.
of desipramine treatment. Finally, Hall et al.[58] Of 5 controlled trials of bromocriptine,[47-50] only also showed desipramine to have no additive ben- 1 small trial showed efficacy,[47] while the others efit over psychotherapy.
were inconclusive or showed no effect (table IV).
Fischman et al.[75] showed that desipramine had In the positive study, Giannini et al.[47] reported no effect on cocaine self-administration and that that bromocriptine was helpful in reducing craving there was potential for cardiovascular toxicity with and dysphoria in the early abstinence phase.
the combination of desipramine and cocaine. Fur- thermore, Foltin et al.[76] found that desipramine Amantadine is an indirect dopamine agonist.
was associated with increased heart rate and dias- Controlled studies[42-44] have failed to demonstrate tolic pressure when combined with cocaine, but not efficacy. For example, Kosten et al.,[42] in their when combined with placebo.
double-blind placebo-controlled study of metha- done-maintained patients, found that abstinence Nunes et al.[77] found that 9 (53%) of 17 consec- rates at the end of 12 weeks of treatment with de- utive cocaine-abusing patients receiving metha- sipramine, amantadine or placebo were not signif- done maintenance treatment and who had primary icantly different (table IV). Higher dosages of or chronic depression experienced an improve- amantadine do not appear to be effective, as there ment in both mood and drug use after imipramine was no significant difference in terms of cocaine  Adis International Limited. All rights reserved.
CNS Drugs 1998 Jul; 10 (1) Table IV. Controlled trials of pharmacological agents for the treatment of cocaine dependence
Patient characteristics Treatment outcomes Kosten et al.[42] DSM-III-R[73] cocaine and opioid Double-blind, placebo- No significant differences between controlled, randomised treatments: abstinence from cocaine 27% for desipramine, 15% for amantadine and 13% for placebo at d.
All right Cocaine dependence Amantadine 200 mg/day Randomised, double- No difference between the groups in Amantadine 400 mg/day terms of cocaine use or craving Kampman et al.[44] Cocaine dependence Double-blind, placebo- No significant difference between groups in treatment retention ornumber of cocaine-positive urinesamples Alterman et al.[45] Cocaine-dependent men in day hospital Amantadine 200 mg/day Double-blind, placebo- At the end of the drug trial and at a 1-month follow-up, individualsreceiving amantadine were more likelyto have cocaine-negative urine tests Margolin et al.[46] DSM-III-R cocaine and opioid dependence, No significant differences in cocaine randomised, placebo- use between treatments Giannini et al.[47] Cocaine use at least 3 times/wk for 6mo Randomised, placebo- Bromocriptine effective in reducing craving and dysphoria in earlyabstinence phase Preston et al.[48] Cocaine use for 1-16y 12 drug conditions with Double-blind randomised Pretreatment with bromocriptine cocaine (0, 12.5, 25, did not modify physiological and subjective effects of cocaine bromocriptine (0, 1.2,2.5mg 2h before cocaine) Moscovitz et al.[49] Cocaine use >3 times/wk for the last month 3/14 patients treated with bromocriptine tested negative for cocaine; inconclusive findings DSM-III-R cocaine dependence Randomised, double- No difference between groups in cocaine use or craving Moscovitz et al.[49] Cocaine use in emergency room setting Bromocriptine can be used safely; CNS Drugs 1998 Jul; 10 (1) randomised, placebo- inconclusive for effect on cocaine use Oliveto et al.[51] DSM-III-R opioid dependence and cocaine Buprenorphine 2 or 6mg Randomised, double- No difference in cocaine use between Nathan et al. Methadone 35 or 65mg Cocaine Abuse and D Hatsukami et al.[52] Cocaine use at least twice/wk for 6 Double-blind, placebo- No effect on subjective responses to controlled, crossover; after 5 days, cocaine 40mg administered Cornish et al.[53] DSM-III-R cocaine dependence Double-blind, placebo- No difference between groups in retention time, cocaine use and urine- positive samples, or craving DSM-III-R cocaine dependence Double-blind, randomised 6 Abstinent for 3 wks within the 6 week treatment: 59% for desipramine; 17% for placebo, 25% for lithium Desipramine is helpful with randomised placebo- abstinence, but not with retention in controlled trials of DSM-III-R cocaine and opioid dependence, Randomised, double- No significant differences in cocaine use between treatments Outpatient primary cocaine abusers Double-blind, placebo- Desipramine was significantly more effective than placebo in reducingcocaine use over 6, but not 12, wks oftreatment; desipramine was alsoassociated with improved abstinenceinitiation among patients with lowerseverity of cocaine use at baseline Primarily cocaine-abusing men Randomised, double- No difference in cocaine use between desipramine and placebo; desipramineblood concentrations above 123 µg/Lat wk 2 predicted longer stays inoutpatient treatment DSM-III-R cocaine dependence No differences between groups in cocaine use or craving; retention much longer for fluoxetine group Grabowski et al.[60] DSM-III-R cocaine dependence Randomised, placebo- Fluoxetine ineffective in reducing Cocaine and opioid dependence cocaine use or craving Cocaine dependence Fluoxetine 20 mg/day Randomised, double- Those with detectable Fluoxetine 40 mg/day blind, with counselling Fluoxetine 60 mg/day concentrations had less cravings; fluoxetine 60 mg/day was least CNS Drugs 1998 Jul; 10 (1) diphenhydramine 12.5mg Galloway et al.[62] DSM-III-R cocaine dependence Randomised, double- Retention in treatment longer for the DSM-III-R amphetamine dependence blind, controlled imipramine group; no difference instimulant use or craving Continued over page Table IV. Contd
Patient characteristics Treatment outcomes Imipramine group had greater reduction in cocaine craving. cocaineeuphoria and depression. Rate ofcocaine-free wks greater in imipramine(19%) than placebo (7%) group Cocaine dependence No difference in abstinence after 2 doses of levodopa/carbidopa Tryptophan and tyrosine
Chadwick et al.[65] Cocaine dependence Tryptophan 1g + tyrosine Double-blind, crossover, No significant difference between groups in cocaine craving or withdrawal Kosten et al.[66] DSM-III-R cocaine dependence, Self-reported use of cocaine decreased and decrease in cocaine-induced euphoria in mazindol group Preston et al.[67] Cocaine use for 4 to 18y 12 conditions with cocaine Double-blind Mazindol did not alter subjective (0, 12.5, 25, 50mg IV) and effects of cocaine or craving; may mazindol (0, 1, 2mg PO increase cardiovascular risks of 2h before cocaine) Margolin et al.[68] Cocaine abuse, methadone-maintained No difference between the groups. All patients were in ‘action' stage of change, with 17% positive forcocaine Cocaine dependence Double-blind, placebo- No differences between treatment DSM-III-R cocaine abuse or dependence Crossover, double-blind Craving for cigarettes and cocaine, as and nicotine dependence days with patch measured on day 3, was decreased in group receiving nicotine patch Muntaner et al.[71] Nifedipine 10mg or Repeated measures, Nifedipine attenuated subjective effects of cocaine; also directly administration of placebo reduced blood pressure but did not CNS Drugs 1998 Jul; 10 (1) or cocaine 20 or 40mg antagonise effects of cocaine on bloodpressure Nathan et al. Crosby et al.[72] Double-blind, placebo- Cocaine use and craving reduced in phenytoin group Duration of each crossover period.
IV = intravenously; NS = not stated; PO = orally.
Cocaine Abuse and Dependence use or craving between patients receiving aman- serve as replacement therapy in cocaine-dependent tadine 200 or 400 mg/day or placebo (table IV).[43] patients. An early report of 3 patients appeared prom- While Kampman et al.[44] found that amant- ising;[85] however, there have not yet been any pub- adine had no significant effect on the number of lished reports of controlled trials.
cocaine-positive urine samples, an earlier double-blind, placebo-controlled trial reported that urine 5.5 Buprenorphine toxicology data at 1-month follow-up indicated Open trials by Kosten and colleagues[86,87] that more patients receiving amantadine (83%) were compared the effects of methadone and buprenor- cocaine-free, compared with those receiving pla- phine in cocaine-abusing patients. They reported significantly less cocaine use in those individualsreceiving buprenorphine. A controlled study,[51] 5.3 Anticonvulsants and Mood Stabilisers however, did not replicate this finding, with no dif- ferences found in cocaine use in patients who had The effect of the potent anticonvulsant carbam- opioid dependence and cocaine use and who were azepine appeared to be promising in early open randomised to receive buprenorphine or metha- clinical trials,[83] but could not be replicated in dou- done for a period of 24 weeks (table IV).
ble-blind controlled work (table IV).[52,53] 5.3.2 Phenytoin
Recent work with phenytoin has found a sig-
5.6.1 Controlled Trials
nificantly lower level of cocaine use in patients Wolfsohn and Angrist[64] reported an improve- treated with the drug, as measured by self-report ment in withdrawal symptoms by patient self- and urinalysis (table IV).[72] No other studies in- report in an open trial of levodopa; however, the volving phenytoin have yet been reported, so no drug was not effective in promoting abstinence confirmation of this finding exists to date.
in a controlled trial (table IV).[88] Tryptophan[65] has been reported to be ineffec- tive in the treatment of cocaine craving or with- In a 6-week controlled study of 72 patients, lith- drawal (table IV).
ium (25%) was found to be less effective than des- Wiseman and McMillan[70] found that nicotine ipramine (59%), compared with placebo (17%), in patches decreased craving for both cocaine and achieving abstinence over a 3-week period.[54] cigarettes in patients with nicotine dependence andcocaine abuse or dependence (table IV). However, 5.4 Cocaine-Like Agonists this finding has not been replicated. Nifidepine was reported to attenuate the subjective effects of In an early open trial,[84] mazindol appeared to cocaine in a controlled human laboratory trial (ta- be effective in reducing cocaine use, but subse- ble IV),[71] but no outpatient clinical trials have yet quent controlled trials have failed to demonstrate been reported.
the effectiveness of the drug in the treatment of 5.6.2 Open Trials
cocaine dependence.[66-69] However, in a placebo- There are data from open trials of the effects controlled crossover study in methadone-maintained of disulfiram on cocaine dependence,[89,90] but no patients, some decrease in cocaine-induced eupho- controlled trials have yet been reported. Higgins et ria and self-reported cocaine use was reported al.[89] showed that disulfiram reduced cocaine use in an open study of 16 patients who received disul- firam on and off for 2 weeks. Similarly, flupen- Like cocaine, methylphenidate is a potent dopa- thixol has been shown to rapidly decrease cocaine mine reuptake inhibitor and would be expected to use and craving in an open trial involving 10 pa-  Adis International Limited. All rights reserved.
CNS Drugs 1998 Jul; 10 (1) Nathan et al. tients,[91] although another study reported that a ment approaches. In addition to the multiple, on- mean dose of flupenthixol 12mg was associated going clinical studies investigating the efficacy of with extreme akathisia after the use of crack.[92] different agents for cocaine addiction, a better Khouzam et al.[93] reported on 3 individuals who understanding is needed of the heterogeneity of were treated with trazodone, in whom there were no cocaine users and their differential responses to relapses to cocaine use during a 3-month follow- treatment. For example, patients with depression or up. Another antidepressant, sertraline, was reported other primary psychiatric illness, those who are in- to decrease cocaine craving in an open trial of 11 fected with HIV and those on methadone mainte- patients, with 5 patients abstaining for 3 weeks.[94] nance programmes may respond differently to po- No controlled trials of either of these drugs have yet been reported.
In summary, the most effective treatment inter- Goldwyn[95] reported that the monoamine oxi- ventions for cocaine abuse at present are psycho- dase inhibitor phenelzine was effective in an open social treatment modalities. Although a variety of trial in 26 patients, all of whom provided cocaine- different pharmacological agents have been used in negative urine samples for 6 months. However, the the treatment of cocaine addiction, none has been use of phenelzine must be regarded as potentially approved by an international regulatory authority, hazardous, as no human laboratory studies have yet such as the US Food and Drug Administration, and been done demonstrating the effects of phenelzine- none has achieved consensus support for its effi- cocaine interactions. In contrast, Margolin et al.[96] cacy. Ongoing research may make effective biolog- reported that the selective monoamine oxidase-B ical treatment for cocaine dependence a possibility inhibitor selegiline (deprenyl) was not effective in in the future. However effective these pharmaco- reducing cocaine use in an open trial in 5 patients.
logical treatment approaches may become, they Pemoline has also been shown to be ineffective should always be used in conjunction with psy- in a small open trial involving 10 patients,[97] with 50% of the study participants discontinuing treat-ment due to adverse effects. Those who did com- plete the study had a 79% rate of positive urinescreens for cocaine.
Supported by NIDA Grants R01 DA08526, P50 DA 01696 (Drug Dependence Clinical Research Program) andP50 DA 09253 (San Francisco Treatment Research Center).
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in patients abusing cocaine and alcohol. Am J Psychiatry Am J Drug Alcohol Abuse 1995; 21 (4): 469-81 1993; 150 (4): 675-6 69. Stine SM, Krystal JH, Kosten TR, et al. Mazindol treatment 90. Carroll KM, Ziedonis D, O'Malley SS, et al. Pharmacological for cocaine dependence. Drug Alcohol Depend 1995; 39 (3): interventions for abusers of alcohol and cocaine: disulfiram versus naltrexone. Am J Addict 1993; 2: 77-9  Adis International Limited. All rights reserved.
CNS Drugs 1998 Jul; 10 (1) Cocaine Abuse and Dependence 91. Gawin FH, Khalsa-Denison EM, Jatlow P. Flupenthixol-induced 96. Margolin A, Avants SK, Falcioni J, et al. Preliminary investiga- aversion to crack cocaine. N Engl J Med 1996; 334 (20): tion of selegiline for the treatment of cocaine dependence. Am J Addict 1996; 15 (3): 275-6 92. Gawin FH, Allen D, Humblestone B. Outpatient treatment of 97. Margolin A, Avants SK, Kosten TR. Pemoline for the treatment ‘crack' cocaine smoking with flupenthixol decanoate. Arch of cocaine dependence in methadone-maintained patients. JPsychoactive Drugs 1996; 28 (3): 301-4 Gen Psychiatry 1989; 46: 322-5 93. Khouzam HR, Mayo-Smith MF, Bernard DR, et al. Treatment of crack-cocaine-induced compulsive behavior with trazo-done. J Subst Abuse Treat 1995; 12 (2): 85-8 94. Kosten TA, Kosten TR, Gawin FH. An open trial of sertraline Correspondence and reprints: Dr Steven Batki, University of for cocaine abuse. Am J Addict 1992; 1 (4): 349-53 California, San Francisco 7M12, San Francisco General Hos- 95. Goldwyn DH. Cocaine abuse treated with phenelzine. Int J pital, 1001 Potrero Ave, San Francisco, CA 94110, USA.
Addict 1988; 23 (9): 897-905 Vol. 9, No. 4, page 318: Section 2.3 Drug Interactions should read: ‘In vitro studies have shown that modafinil inhibits isoenzyme
cytochrome P450 (CYP) 2C19 activity with Ki of ≈39 µmol/L (data on file, Cephalon Inc). In addition, the drug slightlyinduces CYP1A and CYP3A.[41] Modafinil may therefore decrease the exposure of patients to drugs which are metabo-lised via these isoenzymes,[41] but the clinical significance of this has yet to be established'.
[McClellan KJ, Spencer CM. Modafinil: a review of its pharmacology and clinical efficacy in the management of narcolepsy. CNS Drugs 1998 Apr; 9 (4): 311-324]  Adis International Limited. All rights reserved.
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JOURNAL OF BONE AND MINERAL RESEARCHVolume 12, Number 10, 1997Blackwell Science, Inc.© 1997 American Society for Bone and Mineral Research Long-Term Effects of Intravenous Pamidronate in Fibrous Dysplasia of Bone ROLAND D. CHAPURLAT,1 PIERRE D. DELMAS,1,2 DANIEL LIENS,1 and PIERRE J. MEUNIER1 Fibrous dysplasia of bone (FD) is a rare disorder characterized by proliferation of fibrous tissue in bone marrowleading to osteolytic lesions. It causes bone pain and fractures. To date the only treatment is orthopedic.Histological and biochemical similarities between FD and Paget's bone disease related to increased osteoclasticresorption led us to propose treatment with the bisphosphonate pamidronate. The aim of the study was to assessthe long-term effects of intravenous pamidronate in FD. In this open label phase III study, 20 patients with FD (11males and 9 females; mean age 31 years) received courses of 180 mg of intravenous pamidronate every 6 months(60 mg/day during 3 days by infusion). The mean duration of follow-up was 39 months (range 18 – 64). Severity ofbone pain, number of painful skeletal sites per patient, X-rays of all involved areas, serum alkaline phosphatase,fasting urinary hydroxyproline, and urinary type I collagen C-telopeptide were assessed every 6 months. Theseverity of bone pain and the number of painful sites appeared to be significantly reduced. All biochemical markersof bone remodeling were substantially lowered. We observed a radiographic response in nine patients with refillingof osteolytic lesions. A mineralization defect proven by bone biopsy was observed in one case. Four patientssustained bone stress lines, but no fracture occurred. We suggest that intravenous pamidronate alleviates bonepain, reduces the rate of bone turnover assessed by biochemical markers, and improves radiological lesions of FD.Few side effects were observed. (J Bone Miner Res 1997;12:1746–1752)