CSAM Addiction Medicine Review Course Newport Beach, October 30, 2010

Stimulants:Cocaine and Methamphetamine

(and Caffeine)(and Caffeine)

Steven L. Batki, M.D.UCSF Department of Psychiatry

San Francisco VA Medical CenterAddiction Research Program

steven.batki@ucsf.edu

Stimulants Overview: I. Background & HistoryII. EpidemiologyIII. GeneticsIV. Diagnostic factorsgV. Pharmacology VI Clinical EffectsVI. Clinical EffectsVII. Pathophysiology/Adverse effectsVIII TreatmentVIII. Treatment

Caffeine: briefly covered2

Caffeine: briefly coveredNot covered: prescription stimulant abuse, MDMA

IA Cocaine :IA. Cocaine :Background & History

• Traditional use of cocaineTraditional use of cocaine– Cultural origins

• Modern use• Modern use

3

Coca

• Erythroxylon coca• shrub grows in Andes• used by indigenous

people in South fAmerica for millenia

• contains 0.5% cocaine(G ld & Mill 1997)(Gold & Miller 1997)

4

Traditional use of coca• Leaves are harvested• Chewed with cud inside cheek• Lime used to change mucosal pH toLime used to change mucosal pH to

help absorption• Effects mild compared to pure cocaine

5

Modern History of Cocaine

• Cocaine isolated 1860• Local anesthetic 1884Local anesthetic 1884• Freud: Uber Coca 1884

H i A t 1914• Harrison Act: 1914• Epidemics in 1920s, 1970s• Crack in 1980s-now

Gorelick D, 2002 6

IB. Amphetamines: History• Amphetamine first synthesized in 1887; methamphetamine

in 1918

• first available in the U.S. as benzedrine inhaler (OTC) 1932

• Other forms of amphetamines available by Rx in 1939;

• widespread availability for nonmedical uses continued through the 1960s

• tighter regulation of manufacture and prescription in 1972

7

IIA. Cocaine: EpidemiologyP l f C i U (i >12 )Prevalence of Cocaine Use (in >12 y.o.)

• 11.2% of U.S. population report ever using cocaine (NHSDA 2000)

• 1.5% report use within the past year (NHSDA 2000)

• 1.9 million (0.7%) report use within the past month (NSDUH 2008)

• Most common in 18-25 age group (NHSDA 2000)

• 663,000 received treatment for cocaine in past year (NSDUH 2008)

8

IIA. Epidemiology: Methamphetamine

• Recent increase, after steady decline until 1991 (DAWN data)

• Spread of MA particularly extensive in Western US

• Ethnic differences from cocaine users: fewer African Americans

• Gay men in US metropolitan areas particularly affected

(NIDA 1992; USDHHS/SAMHSA 1995)

9

Prevalence of Methamphetamine Use2000 National Household Survey on Drug Abuse2000 National Household Survey on Drug Abuse

• 4.0% of U.S. population >12 yo report ever using MA

• 0.5% report using MA within the past year

• 0.2% report using within the past month

• Most common in 18-25 yo age group

• 245,000 received treatment for stimulants in past year

NHSDA 2000 10

Past Year Methamphetamine Use among Persons Aged 12+ by Region:among Persons Aged 12+, by Region:

2002 and 2006Percent Using in Past Year

1.6 1.6

1 5

2.0

20022006

1.0

1.5 2006

0.6 0.6

0 3

0.5

0.7

0.5

1.0

0.1

0.3

0.0

11

Northeast Midwest South West

Past Month Use of Illicit Drugs in Persons Aged 12 or Older: 2008

(NSDUH 2008; SAMHSA, 9/2/10)

Substances for Which Most Recent Treatment Was Received in the Past Year 12 or Older:

2008 (NSDUH 2008, accessed 9/2/10)

Dependence or Abuse - Past Year 12 or Older: 2008 (NSDUH 2008, SAMHSA accessed 9/20/10)

DAWN 2007 Cocaine & Stimulant ED Visits(DAWN 2007 SAMHSA accessed 9/2/10)( ) (DAWN 2007, SAMHSA, accessed 9/2/10)

Rates per 100,000 population

12SOURCE: Office of Applied Studies, SAMHSA, Drug Abuse Warning Network, 2007 (08/2008 update).

IIIA.Genetics of Cocaine DependenceG ti id i l i t di t hi h d f h it bl• Genetic epidemiologic studies support a high degree of heritable vulnerability for cocaine dependence.

• Polymorphisms in genes coding for DA receptors and transporter, opioidPolymorphisms in genes coding for DA receptors and transporter, opioid receptors, endogenous opioid peptides, cannabinoid receptors, and 5-HT receptors and transporter are all associated with vulnerability.

CONCLUSION Despite progress identification of specific genes and• CONCLUSION: Despite progress, identification of specific genes and quantification of risk remain to be elucidated.

– Saxon et al (2005) Genetic determinants of addiction to opioids and cocaine. Harv Rev Psychiatry. 2005 Jul-Aug;13(4):218-32.

• Similar conclusions in:– Yeforov et al. 2010 Ann NY Acad Sci 1187:184-207– Phillips et al 2008 Neurosci Biobehav Rev 32: 7-7-59Phillips et al. 2008 Neurosci Biobehav Rev 32: 7 7 59– Khokhar et al 2010 Annu Rev 50:39-61

• Pharmacogenetics will be increasingly important in txg g y p– Haile et al 2008 Am J Drug Alc Abuse 34:355-81– Khokhar et al 2010 Annu Rev 50:39-61

IIIB. Genetics of MA Use DisordersDisorders

• Genetic Association Studies of MA UseGenetic Association Studies of MA Use Disorders: A Systematic Review [Bousman et al, 2009]

• 38 studies• 39 genes examined: 18 were found to have a

i ifi t t i ll li d/ h l t isignificant genotypic, allelic, and/or haplotypic association with MA use disorder

– “the genetic epidemiology of MA use disordersthe genetic epidemiology of MA use disorders is complex and likely polygenic”.

IV. Diagnostic Categories DSM-IV-TRCocaine and AmphetaminesCocaine and Amphetamines

• dependence• abuse• abuse • cocaine- or amphetamine-induced disorders:

i t i ti– intoxication– withdrawal– intoxication delirium– intoxication delirium– psychotic disorders– mood disorder– anxiety disorder– sexual dysfunction

15– sleep disorder

V.A. Cocaine Pharmacology

• Pharmacological action of cocaine• PharmacokineticsPharmacokinetics• Clinical effects

16

Major Acute Actions of CocaineMajor Acute Actions of Cocaine• Local anesthetic

– Blocks membrane sodium channels• Stimulates CNS

– Blocks presynaptic neurotransmitter reuptake pumps (transporters): dopamine, norepinephrine serotoninnorepinephrine, serotonin

• Stimulates sympathetic nervous system• Chronic effects unclear• Chronic effects unclear

(neurotransmitter depletion? receptor upregulation?)

D. Gorelick, NIDA IRP 17

upregulation?)

Cocaine vs Methamphetamine: Effects at Sthe Synapse

AA A

A VMAT

AA AA

A

C

VMAT

DAT DAT

ACCC

AmphetamineIncreases release

CocaineBlocks reuptake

DAT DAT

D. Gorelick, NIDA IRP, 2002 18

Mechanism of Cocaine’s P h ti Eff tPsychoactive Effects

• Binding to dopamine transporter correlates best withBinding to dopamine transporter correlates best with behavioral potency in animals → ↑ dopamine levels in nucleus accumbens

• Lesions of mesolimbic dopamine circuit (“reward”• Lesions of mesolimbic dopamine circuit ( reward circuit) abolish cocaine self-administration

• However, “knockout” mice without dopamine t t d t h t ti l ti l

D G li k NIDA IRP 2002

transporter do not show motor stimulation or sleep suppression, but still get reinforcement from cocaine

D. Gorelick, NIDA IRP 2002

• Important roles for nicotinic, cannabinoid, GABAergic, glutamatergic and opioidergic systems

19

glutamatergic, and opioidergic systems

Cocaine Pharmacokinetics, 1: MetabolismMetabolism

• MetabolismMetabolism– primarily (95%) by esterases

principal metabolite is benzoylecgonine– principal metabolite is benzoylecgonine (BE)

• Half life of cocaine (plasma)• Half-life of cocaine (plasma)– generally ranges from 40-90 min

t 40 60 i h i 1 5 h l– acute ~40-60 min; chronic ~ 1.5 h or longer

20

Cocaine Pharmacokinetics 2:Cocaine Pharmacokinetics, 2: Excretion

• Excretion– largely eliminated in urinelargely eliminated in urine– BE is metabolite in highest concentration

• Detection by urine drug tests• Detection by urine drug tests– BE persists 24-72 hrs, may be as long as

96 hrs96 hrs

21

Cocaine Pharmacokinetics, 3: Cocaine and Alcohol forms Cocaethyleneand Alcohol forms Cocaethylene– alcohol-cocaine forms cocaethylene– metabolite formed in presence of heavy

alcohol intake together with cocaine– formed by transesterification– similar effects to cocaine, longer half-life,

more severe toxicity when present along with cocaine

– greater than additive effects on heart rate and violence potential (Pennings et al. 2002 Addiction)

22

2002 Addiction)

V.B. Pharmacology: Methamphetaminegy p

• Mostly release of monoamines; lesser• Mostly release of monoamines; lesser reuptake inhibition of DA, NE & 5-HT

• lesser MAOI effects

• Overall, tolerance develops rapidly, but sensitization can also occur (e g tosensitization can also occur (e.g. to psychosis)

23

Mechanisms of methamphetamine acute actions: enhanced monoaminergic neurotransmissionenhanced monoaminergic neurotransmission

• Methamphetamine (MA) is an indirect• Methamphetamine (MA) is an indirect catecholamine and 5-HT agonist

• MA releases newly synthesized (versusMA releases newly synthesized (versus stored) DA, NE, & 5-HT (King & Ellinwood 1997))– MA enters neuronal membranes through

membrane transporters and storage vesicles via vesicle transporters

• May deplete catecholamines and 5-HT

24

MA Chronic NeurochemicalMA Chronic Neurochemical Effects in Animals

• Decreased DA storesD d DA t k it d d• Decreased DA uptake sites, decreased DA transporters

• Decreased tyrosine hydroxylase & tryptophan hydroxylase activity

25

Sensitization to Cocaine andSensitization to Cocaine and other Stimulants

• Sensitization (reverse tolerance) = enhanced response to drug because of prior exposure

May especially apply to:– May especially apply to:• craving in response to cues• dysphoria, anxiety/panic, psychosis

ibl i• possibly seizures

• Kindling = low intensity, intermittent brain stimulation

D. Gorelick, NIDA IRP 2002

g y(electrical, pharmacological) leads to enhanced response to later stimulation

26

MA Pharmacokinetics• Absorption rapid after oral and other routes• MA ½ life= 11-12 hrs IV or smoked (Karch

1996)• metabolism: MA→amphetamine by CYP450

2D6 lti l th t2D6; multiple other routes• drug interactions: CYP450 2D6 blockers such

fl ti ld t ti ll l MAas fluoxetine could potentially prolong MA presence in blood, but no evidence yet

• acidification of urine hastens excretion• acidification of urine hastens excretion• duration of effects: 10-12 hrs (vs 30-50

minutes for cocaine)27

minutes for cocaine)

Routes of Administration and F f C i & MAForms of Cocaine & MA

• Intranasal (nasal insufflation,snorting)– powder cocaine HCl, or MA water soluble

• Injectionj– powder cocaine HCl or MA– quickest effects, in secondsquickest effects, in seconds

• Pulmonary (smoked)Rapidity of effect rivals IV in 6 8 seconds– Rapidity of effect rivals IV, in 6-8 seconds

– crack = free base cocaine, alkaloidal cocaine, has lower melting point and can be smoked

28

has lower melting point and can be smoked– “ice” = pure crystal meth – not free base

Forms of Cocaine UsePowdered Cocaine HCl

for Intranasal or Injection useMaking freebase cocaine

29

Crack cocaine

Kinetics of Smoked Cocaine

R.T. Jones, 1983 30

VI Cocaine & MA ClinicalVI. Cocaine & MA Clinical Effects

Medical Use of Stim lantsMedical Use of Stimulants• COCAINE:• COCAINE:

– Topical, local anesthetic

• OTHER STIMULANTS:– Attention deficit (hyperactivity) disorder( yp y)– Narcolepsy– Appetite suppression for weight loss

D ti– Decongestion– Bronchodilation (ephedrine)– Depression (esp. geriatric, medically ill)

32

p ( p g , y )– Reduce fatigue, drowsiness

Federal Schedule of Controlled S b t S h d l II Sti l tSubstances, Schedule II Stimulants

• Examples: – cocaine, amphetamine, methamphetamine,

methylphenidate, phenmetrazine• Schedule II Criteria:

– High potential for abuseg p– Accepted medical use with severe

restrictions– Abuse may lead to severe psychological or

physical dependence

D. Gorelick, NIDA IRP, 2002 33

Cocaine & MA: Subjective and Behavioral Effects

• Onset– Intranasal effects within minutes (5-15)– Smoked effects within seconds

• Acute EffectsE h i h ti it ( t i & b l) h lit– Euphoria, hyperactivity (motoric & verbal), hypersexuality initially

– Insomnia, anorexia.– Persecutory delusions (paranoia) and hallucinosis (aud visPersecutory delusions (paranoia) and hallucinosis (aud, vis,

& tactile), agitation– Confusion rare except in very high doses when delirium can

occurSt t d t (t th i di ki– Stereotyped movements may occur (teeth grinding, skin picking)

• Chronic use produces tolerance to euphoria positive

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Chronic use produces tolerance to euphoria, positive effects decrease, agitation & anxiety increase()

Cocaine & MA Effects: PhysiologicalPhysiological

• Sympathomimetic effectsSympathomimetic effects– Elevated

• BPBP• HR• Tempp

• At high doses:– Hyperthermiaype e a– Rigidity– Seizures

35

Stimulants: Withdrawal

• “Crash” after discontinuation of prolonged high dose use –first described for cocaine (Gawin & Ellinwood 1988)

– depression, fatigue, may have suicidal ideation– improves over several days -weeks– withdrawal symptoms not uniformly reported – Intense craving and anhedonia are common

• DSM-IV-TR for both Cocaine & Amphetamine WD: dysphoric mood consisting of:dysphoric mood consisting of:1. Fatigue2. Vivid, unpleasant dreams3. Insomnia or hypersomnia4. Increased appetite5. Psychomotor retardation or agitation

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5. Psychomotor retardation or agitation

Changes in Mood with Cocaine AbstinenceWeddington et al, Arch Gen Psych 1990

37

MA Clinical presentation• Patterns of use

– frequency: often weekend binge pattern -- binges 12 24 h t 2 3 d i d b id12-24 hrs to 2-3 days; accompanied by rapid tolerance

– amount varies enormously from 10 mg to 1 gramamount varies enormously from 10 mg to 1 gram or more/day

– route of administration: intranasal, oral, IV, rectal, k dsmoked

– “ICE”-- purified form of d-isomer, often in large crystals, not the “free base” form, which is liquid atcrystals, not the free base form, which is liquid at room temp & has very limited use (SAMSHA, 1997)bi f ll d b h ith d i f ti

38

– binges followed by crash, with depression, fatigue, hypersomnolence, craving

Methamphetamine Effects in Humans

• At low doses:– wakefulness

• At higher doses:– anxiety– wakefulness

– increased physical activity

– anxiety– irritability– insomnia

– anorexia– increased respiration

– confusion– tremor

– hyperthermia– euphoria

hypersexuality

– seizures– delusions

– hypersexuality – hallucinations– aggressiveness

(adapted from NIDA Infofax 016, 1998)

39

( p )

VII. Stimulants: Pathophysiology & Adverse Effects of Abuse

For both Cocaine and Methamphetamine:p• Medical

• CNS• CardiovascularCardiovascular• Pulmonary

• Public Health• HIVHIV• Hepatitis B & C• STDs• TB• TB

• Psychiatric• Psychosis• Mood & anxiety disorders

40

• Mood & anxiety disorders

Medical Complications of Cocaine• Complications reflect primarily:

– excessive CNS stimulation– vasoconstriction

• CardiacMyocardial ischemia/infarct– Myocardial ischemia/infarct

– Arrhythmias– Myocarditis

• Central Nervous System– Hyperpyrexia– SeizuresSeizures– Cerebral infarct– Cerebral hemorrhage

41Benowitz 1993; Boghdadi & Henning 1997

Medical Complications, 2: Pathophysiology

Benowitz 1993 42

Medical Complications: Association with pRoutes of Stimulant Administration

• Intranasal use• Intranasal use– erosion of nasal mucosa & perforated septum (especially

cocaine)– Hepatitis C (HCV)

• Injection Use– HIVHIV– HCV– endocarditis

ft ti i f ti b & ll liti– soft tissue infections: abscesses & cellulitis

• Smoking– pulmonary edema, pneumonitis, pneumothorax

43

p y , p , p

MA Psychiatric Morbidity ( 1996)(Baberg 1996)

• psychosisacute classically paranoid persecutory delusions– acute--classically paranoid, persecutory delusions, ideas of reference, heightened awareness of environment

– chronic--can persist after acute episode or recur with little or no further MA use

• pathophysiology uncertain• pathophysiology uncertain• mood disorders

– mania during intoxicationmania during intoxication– depression during withdrawal

44

MA Medical Morbidity• Chronic use: similar to cocaine

– But more dental pathology (“meth mouth”• High dose acute intoxication similar to

cocainecocaine– ventricular irritability– hypertensionhypertension– MI– hyperthermia (hyperpyrexia)– hyperthermia (hyperpyrexia)– rhabdomyolysis

seizures45

– seizures– stroke

Methamphetamine Neurotoxicity

• History– PCA-related 5HT depletion 1st shown p

in early 60s– more recently shown with MDMA, etc

• 5-HT depletion– rapid decrease in 5HT synthesisp y– persistent in animals > 110 da

• DA depletionp– decreased brain DA concentration &

decreased DA uptake sites

46

p

Amphetamine Psychosis• History

– 1st reported 1938• characteristicscharacteristics

– clear consciousness• occasionally confused

– relatively little formal thought disorder– relatively little formal thought disorder– persecutory delusions

• occasionally nonparanoid & disorganizedhallucinations all modalities– hallucinations -- all modalities

– persistent psychosis of long duration is possible• sensitization

psychosis of increased duration– psychosis of increased duration– induced by lower doses--increased vulnerability– spontaneous psychosis

Peristent s of ps chosis ma be more likel in MA than cocaine ab se

47

• Peristent sx of psychosis may be more likely in MA than cocaine abuse (Mahoney et al, 2008)

Cocaine and Pregnancy

• Irregular placental blood flow• Placental abruption• Premature rupture of membrane (PROM)• Premature labor and delivery

• In a recent meta-analysis, the only adverse event significantly associated with cocaine was PROMg y(Addis et al. 2001 Reprod Toxicol)

48

Putative Effects of Cocaine on Birth and Fetal Development

• Frequently attributed effects:– Prematurity– Low birth weight– Decreased head circumference– Lower developmental test scores– Delayed language skills

• Less frequently attributed effects• Less frequently attributed effects– Transient EEG abnormalities– Cerebral infarct– Seizures– Small brain hemorrhages

49

Meta-analysis of Effects of Cocaine on Early Childhood Developmentp

• Conclusion of 2001 JAMA review:– among children aged 6 or younger– there is no convincing evidence that prenatal cocaine

exposure is associated with developmental toxic effects• that are different in severity scope or kind from the sequelae ofthat are different in severity, scope, or kind from the sequelae of

multiple other risk factors. – many findings once thought to be specific effects of in utero

cocaine exposure are correlated with other factorscocaine exposure are correlated with other factors,• including prenatal exposure to tobacco, marijuana, or alcohol,• and the quality of the child’s environment.

“Further replication is needed of preliminary neurological findings ”– Further replication is needed of preliminary neurological findings.

(Frank et al. 2001 JAMA)

50

Developmental Effects, 2• Ackerman et al. (2010) A review of the effects of prenatal

cocaine exposure among school-aged children. Pediatrics. 2010 Mar;125(3):554-65. Epub 2010 Feb 8.

• Studies through 6 years have shown no long-term direct effects of prenatal cocaine exposure (PCE) on children's physical growth, developmental test scores, or language outcomes Little is known about the effects of PCE among school agedlanguage outcomes. Little is known about the effects of PCE among school-aged children aged 6 years and older.

• RESULTS: Associations between PCE and growth, cognitive ability, academic achievement, and language functioning were small and attenuated by environmental variables. PCE had significant negative associations with sustained attention and behavioral self-regulation, even with covariate control.

• CONCLUSIONS: Consistent with findings among preschool-aged children, environmental variables play a key role in moderating and explaining the effects of PCE on school-aged children's functioning. After controlling for these effects, PCE-related impairments are reliably reported in sustained attention and behavioral self-related impairments are reliably reported in sustained attention and behavioral selfregulation among school-aged children.

51

VIII. Treatment of Stimulant Use Disorders

• Overview:– Pharmacologic– Non-pharmacologicg

• Key variables to help determine what level of care is neededcare is needed– severity of use– stage of the use (intoxication vs. abstinence) g ( )– readiness for change (motivation)– level of social support– other psychiatric and medical comorbidity

52

– other psychiatric and medical comorbidity

Psychosocial Treatments

• Community Reinforcement• Community Reinforcement plus Vouchers• Contingency Management (Voucher based

reinforcement)• Cognitive/Behavioral Therapy (CBT)-RelapseCognitive/Behavioral Therapy (CBT) Relapse

Prevention, e.g. the Matrix Model• 12-Step facilitation

A t• Acupuncture(CSAT 1999; Knapp et al 2007)

• PLUS: Voucher-based reinforcement therapy (Contingent cash-value vouchers)

53

Community Reinforcement Approach (CRA)• CRA is an individualized treatment designed to promote lifestyle change• CRA is an individualized treatment designed to promote lifestyle change

in key areas needed for recovery(CSAT 1999)1. Marital therapy if spouse is not a user2. Vocational assistance 3. New social networks and recreational activities that promote recovery4. Self-help participation5. Relapse prevention skills training (refusal skills, mood regulation, time

management, etc.)g , )6. Disulfiram and compliance support

• Limited evidence for efficacy in cocaine dep (Roozen et al, 2004)

Community Reinforcement Approach (CRA) Plus Voucher Incentives(CRA) Plus Voucher Incentives

• Voucher-based incentives for cocaine-free urine tests added to CRA • Use of Incentives improved CRA outcomes further (Higgins et al, 1994)

* 75% vs 40% completed 24 weeks of tx

54

75% vs 40% completed 24 weeks of tx * 12 vs 6 weeks continuous cocaine abstinence

Psychosocial Treatments for Cocaine Dependence: NIDA Collaborative Cocaine Treatment StudyNIDA Collaborative Cocaine Treatment Study

• Method– Large (n=487) controlled study over a 6-month period:Large (n=487), controlled study over a 6-month period:

• Group Drug Counseling (GDC)• Individual Drug Counseling (IDC) (12-Step Facilitation) + GDC• Cognitive Behavioral psychotherapy (CBT) + GDC• Cognitive Behavioral psychotherapy (CBT) + GDC• Supportive Expressive psychotherapy (SET) + GDC

• Results– IDC + GDC provided greatest improvement on ASI and days

of cocaine use over past month– Psychotherapy was not superior to GDC for those with

severe psychiatric illness– CBT not superior for treatment of ASP

55

NIDA Collaborative Cocaine Treatment StudyCrits-Cristoph et al (1999) Arch Gen Psychiatry 56:493-502

Voucher Based IncentivesVoucher Based Incentives• Multiple positive studies: some examples

In cocaine dependence:– In cocaine dependence:• Vouchers alone: Higgins et al, 1994 & 2000; etc.• Vouchers + medication

– Levodopa/Carbidopa or placebo with or w/o voucher-based reinforcement therapy (VBRT) [Schmitz at al (2008) Drug Alcohol Dependence]:

Levodopa/carbidopa more effective than placebo, but only when combined with VBRT

– In methadone pts w cocaine dep:• Vouchers alone: Silverman et al, 1999; Petry et al 2007;

etcetc.• Vouchers + medication

– Desipramine/Pla, +/- vouchers [Kosten et al, 2003]B i /Pl / h [P li l 2006]– Bupropion/Pla, +/- vouchers [Poling et al 2006]

Review of Psychosocial Treatments f C i 1for Cocaine, 1.

• 27 randomized controlled studies; 3663 subjects • Cocaine was the psychostimulant used by

participants in all but one that studied amphetamine.amphetamine.

• Comparisons were made of psychosocial treatments but most of them did not show statistically significant differences betweenstatistically significant differences between interventions,

• Evidence currently available does not have data supporting a single psychosocial treatment approach.

Knapp WP, Soares B, Farrell M, Silva de Lima M. (2007) Psychosocial interventions for cocaine and psychostimulant amphetamines related disorders. Cochrane Database of Systematic Reviews, Issue 3.

Review of Psychosocial Treatments for Cocaine 2for Cocaine, 2.

• Overall, cognitive behavioral interventions reduced dropouts from treatment and use of cocaine when compared with drug counseling.p g g

• Behavioral interventions also performed better than clinical management (psychotherapy sessions attended), usual care (lower rates of cocaine users at 1 and 3 months), information and referral ( tt d )(non-attendance).

• A multimodal intensive intervention was more effective than non-intensive delivery

• Cognitive behavioral treatments with contingency management (voucher-based incentives) also showed benefits.

• Many of the results come from single studies which limits their• Many of the results come from single studies, which limits their generalizability.

• Simple reduction in the amount of drug used or retention in treatment is not a measure of meaningful changes in lifestylenot a measure of meaningful changes in lifestyle

Knapp et al. (2007). Cochrane Database of Systematic Reviews, Issue 3.

Treatment of Acute Cocaine Intoxication• Psychosis

– Usually resolves spontaneouslyFi t li t t t h ld b b di i– First line-treatment should be a benzodiazepine, preferably lorazepam (CSAT 1999)

– Antipsychotics are an effective backup if benzodiazepinesAntipsychotics are an effective backup if benzodiazepines alone are inadequate

• Warning -- typical antipsychotics will lower seizure threshold and increase risks of rigidity/hyperthermiaincrease risks of rigidity/hyperthermia

• inadequate data on use of atypicals in emergencies

• Hypertension, tachycardia, hyperthermia, seizures– Supportive treatment– Sedation with benzodiazepines– Lower body temp

59

Lower body temp– Treat seizures: diazepam, phenobarbital or phenytoin (CSAT 1999)

Pharmacotherapy for Cocaine Withdrawal

• Numerous medications have been tried• Dopaminergic agonists among most frequently testedp g g g q y

– e.g. Amantadine (200-400 mg/day) and Bromocriptine (BCT) (dose range: 0.625-7.5 mg/day)

– Results of clinical trials are inconsistent perhaps a bit moreResults of clinical trials are inconsistent, perhaps a bit more evidence for amantadine

– Some overdose lethality risk with amantadineAdverse effects with BCT make use inadvisable– Adverse effects with BCT make use inadvisable

– There may be a subset of patients who benefit; but characteristics of such patients not yet identified

C l i di ti ff ti t d• Conclusion: no medications proven effective to reduce cocaine withdrawal sx

(de Lima et al. 2002 Addiction)

60

( )

Cocaine Pharmacotherapy for Abstinence Initiation, Use Reduction, or Relapse Prevention, , p

• Many medications tried• Most common categories: antidepressants, g p ,

dopaminergic agents, anticonvulsants• Aim to reduce abstinence symptoms or craving• Or aim to block/reduce subjective effects of cocaine• Or aim to block/reduce subjective effects of cocaine• Promising recent RCT studies

– modafinil, topiramate, disulfiram, cocaine vaccine, pSR methamphetamine, baclofen

• Conclusion: No medication has yet shown reproducible efficacy in the treatment of cocainereproducible efficacy in the treatment of cocaine dependence

61

Medications for Cocaine Tx: Recent Meta-analyses, 1.

Dopamine agonistsLima Reisser AARL, et al. (2003) Dopamine agonists for cocaine dependence. Cochrane Database

of Systematic Reviews, Issue 2. – 17 studies, 1224 participants – Amantadine, bromocriptine, and pergolide were evaluated.– Main outcomes: urine cocaine metabolites and retention– No significant differences between interventions. – Current evidence does not support clinical use of dopamine agonists in cocaine dep.pp p g p

AnticonvulsantsMinozzi S et al (2008) Anticonvulsants for cocaine dependence Cochrane Database Syst Reviews Issue 2Minozzi S, et al. (2008) Anticonvulsants for cocaine dependence. Cochrane Database Syst Reviews, Issue 2. – 15 studies (1066 participants) – anticonvulsants studied: carbamazepine, gabapentin, lamotrigine, phenytoin,

tiagabine, topiramate, valproate. – No significant differences for any efficacy measures– No significant differences for any efficacy measures. – no current evidence supporting clinical use of anticonvulsants in cocaine dep.

Alvarez et al (2009) J Subst Abuse Treatment: similar findings; only topiramate > placebo

Medications for Cocaine Tx: R t M t l 2Recent Meta-analyses, 2.

Antipsychotics Amato L et al (2007)Antipsychotic medications for cocaine dependence Cochrane Database ofAmato L, et al. (2007)Antipsychotic medications for cocaine dependence. Cochrane Database of Systematic Reviews, Issue 3. – 7 small studies included (293 participants)– Antipsychotics: risperidone, olanzapine, haloperidol.– No significant differences for any efficacy measures comparing any g y y p g y

antipsychotic with placebo. Risperidone superior to placebo in diminishing dropouts

– no current evidence supporting clinical use of antipsychotics in cocaine dep.

DisulfiramDisulfiram– Pani et al (2010) Cochrane Database Syst Rev. 2010 Jan 20;(1):CD007024– Disulfiram vs placebo: 7 studies, 492participants,– Disulfiram vs naltrexone: 3 studies, 131 participants, – Disulfiram vsno pharmacological treatment: 1 study, 90 participants

– “There is low evidence, at the present, supporting the clinical use of disulfiram for the treatment of cocaine dependence.

63

ConclusionsPharmacotherapy of Cocaine Withdrawal, Abstinence, or Relapse Prevention in 2010

• No medication has been consistently shown to be useful

• Promising agents:– stimulants, modafinil, topiramate, buprenorphine, others – most recentmost recent

• vigabatrin (Brodie et al. 2009 Am J Psychiat)• vaccine (Martell et al. 2009 Arch Gen Psychiat)

• None are FDA-approvedpp

• Available pharmacotherapies are much less robust in effects than psychotherapeutic and psychosocial

64

effects than psychotherapeutic and psychosocial interventions

AcupunctureGates S, Smith LA, Foxcroft D. Auricular acupuncture for cocaine

dependence. Cochrane Database of Systematic Reviews 2006, Issue 1. Art. No.: CD005192.

• 7 studies with a total of 1433 people. • Most of the studies compared acupuncture with ’sham’

acupuncture: needles inserted into random places in the ear butacupuncture: needles inserted into random places in the ear but not into the specific points required for treatment.

• The authors conclude that there is no evidence that any form of auricular acupuncture is effective for treating cocaine dependencedependence.

Largest study:• Multicenter trial (Margolin et al, JAMA 2001)u t ce te t a ( a go et a , J 00 )• Randomized, controlled with sham acupuncture• n=620• Results: no differences between treatment conditions

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MA Treatment

Treatment of MA PsychosisCochrane Review

Shoptaw SJ, Kao U, Ling W. Treatment for amphetamine p g ppsychosis. Cochrane Database of SystematicReviews 2009, Issue 1. Art. No.: CD003026.

• antipsychotic medications demonstrate efficacy in providing short-term relief when a heavy user of amphetamines experiences psychosis

• equivalent efficacy between atypical anti-psychotics and conventional antipsychotics, mostly haloperidol with older drugs causing more severe side effects).

• there is no evidence to guide decisions regarding long-term t e e s o e de ce to gu de dec s o s ega d g o g teclinical care using these medications for preventing relapse to psychosis.

Management of AmphetamineIntoxicationIntoxication

• Confirm diagnosis by urine toxicology screenIf i ti i l t i l d ti t d• If ingestion is oral, use gastric lavage and activated charcoal; avoid ipecac emesis due to risk of seizure, arrhythmia, or hypertensive crisisy yp

• For seizures use diazepam acutely• For psychosis/agitation use diazepam, back up with

ti h ti if d dantipsychotic if needed • Hyperthermia: external cooling

68(Source: McCance-Katz, AAAP 1999)

Tx of MA WithdrawalTx of MA WithdrawalShoptaw SJ, Kao U, Heinzerling K, Ling W. Treatment for

amphetamine withdrawal. CochraneDatabase of Systematic Re ie s 2009 Iss e 2 Art No CD003021Reviews 2009, Issue 2. Art. No.: CD003021.

• “No medication is effective for treatment of amphetamine withdrawal. “withdrawal.

• “The benefits of mirtazapine as a withdrawal agent unclear based on findings from two randomised controlled trials:

h d i i h i i hd l– one report showed improvements in amphetamine withdrawal symptoms over placebo;

– a second report showed no differences in withdrawal symptomscompared to placebo. “

• “Further potential treatment studies should examine medications that increase central nervous system activity involving dopamine, norepinephrine and/or serotonin neurotransmitters,dopamine, norepinephrine and/or serotonin neurotransmitters, including mirtazapine.”

Pharmacotherapy for Methamphetamine Dependence, 1.p p ,

• Few clinical trials have tested pharmacotherapies for methamphetamine dependence

• Controlled trials– Negative: imipramine, sertraline, fluoxetine, amlodipine,

and flumazenil/gabapentin/hydroxyzine (“Prometa”) g p y y ( )– Promising: most recent controlled trials w positive findings:

• Bupropion (Elkashef et al 2008 Neuropsychopharm; Shoptaw et al 2008 Drug Alc Dep)

• Modafinil (Shearer et al. 2009 Addiction)

• Methylphenidate (Tiihonen 2007 Am J Psychiat)

• SR d-amphetamine (Longo et al. 2009 Addiction)

• Naltrexone (Jayaram-Lindstrom [2008] Am J Psychiat)

• Summary of pharmacotherapies for MA– No pharmacological treatments have been shown to be

effective in repeated, large-scale controlled trials

70

p , g– No treatments FDA-approved

Pharmacotherapy for Methamphetamine Dependence, 2.p p ,

• Summary of pharmacotherapies for MA– No pharmacological treatments have been shown to beNo pharmacological treatments have been shown to be

effective in repeated, large-scale controlled trials– No treatments FDA-approved– Most recent reviews:

• Cochrane Collaboration: Srisurapanont M, Jarusuraisin N, Kittirattanapaiboon P. (2001) Treatment for amphetamine dependence and b C h D t b f S t ti R i I 4 A t Nabuse. Cochrane Database of Systematic Reviews, Issue 4. Art. No.:

CD003022• Kampman KM. (2008) The search for medications to treat stimulant

dependence. Addiction Science & Clinical Practice 4(2):28-35.• Rose ME, Grant JE. (2008) Pharmacotherapy for Methamphetamine

Dependence: A Review of the Pathophysiology of Methamphetamine Addiction and the Theoretical Basis and Efficacy of Pharmacotherapeutic Interventions. Annals of Clinical Psychiatry, 20:3,145 — 155

71

y y• Elkashef et al. (2008): Pharmacothera[y of methamphetamine adddiciton:

an update. Subst Abuse 29:31-49

Methamphetamine: PsychosocialMethamphetamine: Psychosocial Therapies

• Matrix Model (Shoptaw, Rawson, et al)– DHHS Publication No. (SMA) 06-4152; Printed 2006– 16 weeks, several sessions per week

Psychoeducation Relapse prevention familyt education group support– Psychoeducation, Relapse prevention, familyt education, group support

• Possible utility of contingency managementy g y g

• Self-help groups, e.g. Crystal Meth Anonyous (CMA)

72

Caffeine 1Caffeine, 1

• Xanthine alkaloid• Sources:Sources:

– Coffee• 1 cup = 80-175 mg1 cup = 80 175 mg

– Tea– Yerba Mate– Yerba Mate– Guarana

73

Caffeine 2: Dependence & AbuseCaffeine, 2: Dependence & Abuse• Ogawa & Ueki (2007) Clinical importance of caffeine dependence

and abuse. PsychiatryClin Neurosci. Jun;61(3):263-8. – Presently, due to a paucity of clinical evidence on caffeine

dependence or abuse, no such diagnosis is included in DSM-IV

• Nehlig et al (2010)SPECT assessment of brain activation induced g ( )by caffeine: no effect on areas involved in dependence. Dialogues Clin Neurosci. 2010; 12(:255-63.– caffeine activates a few regions mainly involved in the control g y

of vigilance, anxiety, and cardiovascular regulation, but does not affect areas involved in reinforcing and reward.

74

Caffeine 3: Energy DrinksCaffeine,3: Energy Drinks• Reissig et al (2009) Caffeinated energy drinks--a growing problem.

Drug Alcohol Depend. 2009 Jan 1;99(1-3):1-10. Epub 2008 Sep 21.– increasing reports of caffeine intoxication from energy drinks, – In children and adolescents who are not habitual caffeine users,

vulnerability to caffeine intoxication may be markedly increased due tovulnerability to caffeine intoxication may be markedly increased due to absence of tolerance.

– Genetic factors may contribute to vulnerability to caffeine-related disorders including caffeine intoxication, dependence, and withdrawal.

bi d f ff i d l h l i i i h l d t di– combined use of caffeine and alcohol is increasing sharply, and studies suggest that such combined use may increase the rate of alcohol-related injury.

– Several studies suggest that energy drinks may serve as a gateway to other forms of drug dependence.

75

Summary

• Cocaine and Methamphetamine– Lower prevalence of use than alcohol,Lower prevalence of use than alcohol,

nicotine, cannabis– High cardiovascular and CNS morbidity, g y,

including psychosis– Treatment remains largely psychosocialg y y

76