JOURNAL TRANSCRIPT

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Stimulants: Cocaine and Methamphetamine CRIT program - May 2012 Alex Walley, MD, MSc Assistant Professor of Medicine

CRIT 2012

Learning objectives At the end of this session, participants will be able to: 1. Understand how and why people use stimulants 2. Know the characteristics of stimulant intoxication and withdrawal syndromes 3. Understand the consequences of these drugs 4. Know the current options for treatment of stimulant dependence

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Roadmap 1. History 2. Epidemiology 3. Dopamine and the reward pathway 4. Acute and chronic effects 5. Treatment

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History: Cocaine • From erythroxylon coca leaves in Andes • Leaves chewed for thousands of years as stimulant • 1884 Freud published, Uber Coca, describing cocaine’s effects on Freud and its potential to treat opiate addiction • 1885 Halsted published study about anesthetic uses • 1886 Halsted raided ship medicine cabinet for fix • Used in medicines and beverages until early 1900s • Street preparations 10-50% cocaine – Hydrochloride powder is snorted or injected – Alkaline rocks (aka crack) are smoked – Crack, Rock, Base CRIT 2012

History: Methamphetamine • 1893 methamphetamine first synthesized in Japan as decongestant. • Used by German, English, American, and Japanese military in WWII for performance enhancement. • First epidemic occurred in Japan when the military dumped large quantities into the civilian market • Popular among truckers and west coast bikers in 1970s • DESOXYN to treat ADHD and obesity • Speed, Crystal, Crank, Ice, Meth, Tina CRIT 2012

Lineberry 2006

1957

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1959

Epidemiology

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Past Month Use: 2002-2008 6,000,000 5,000,000 4,000,000 3,000,000 2,000,000 1,000,000 0 2002 Pain Pills

2003 Cocaine

2004

2005

Tranquilizers CRIT 2012

2006

2007

Stimulants NSDUH 2008

2008 Heroin

2005 drug-related ED visits 160 140 120 100 80 60 40 20 0 Cocaine

Marijuana

Heroin

Methamphetamine

ED Visits per 100K people CRIT 2012

Drug Abuse Warning Network 2005 Report

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From where do these drugs come? • Methamphetamine – Super labs – Primarily Mexico and California – Local clandestine labs - 1 pound of MA creates 6 pounds of toxic waste – Holton WC. Unlawful lab leftovers. Environ Health Perspect. 2001;109:A576

• Cocaine – 75% grown in Columbia with 75% via Mexico/ Central America CRIT 2012

Cocaine processing

http://www.colombiajournal.org/cocainephotos.htm CRIT 2012

Clandestine lab incidents

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www.dea.gov

Stimulant Effects

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Why do people use drugs?

1. To feel good 2. To feel better

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Why do people use stimulants? • Euphoria - Rush – Onset and intensity depends on delivery method

• Increased energy, alertness, libido • Diminished social inhibition • Decreased appetite

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Cocaine

Methamphetamine

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Audience Response I Which statement is true about stimulants? A. B. C. D.

Methamphetamine is only used intravenously or smoked Methamphetamine has a longer half-life than cocaine Intravenous injection results in the fastest onset of action Cocaine’s peak concentration occurs in about 1 hour

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PK: Cocaine IV

Smoked

Snorted

Time to effect

10-60sec

3-5sec

1-5min

Peak concent.

3-5min

1-3min

15-20min

Half-life

20-60min

5-15min

60-90min

Lange, R. A. and L. D. Hillis (2001). "Cardiovascular complications of cocaine use." N Engl J Med 345(5): 351-8.

PK: Methamphetamine IV

Smoked

Snorted

Ingested

Time to effect

15-30 sec

Immediate

3-5 min

15-20 min

Peak concent.

2-4 h

2-4 h

2-4 h

2-4 h

Half-life

10-12 h

10-12 h

10-12 h

10-12 h

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Lineberry 2006

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Binges • 2-3 day binges are typical, called runs • Regular re-dosing to maintain rush or high in setting of acute tolerance • Ends when drug or money runs out, or paranoia/ disorganized thinking sets in

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Acute Toxicity • Elevated BP and HR

• Agitation

• Arrythmia

• Rhabdomyolysis

• Vasoconstriction

• Seizure

• Hyperthermia • Acute psychosis  prolonged psychosis –Paranoid delusions

–Visual, sensory, and auditory hallucinations (ie formications) CRIT 2012

Intoxication Treatment • Minimize sensory stimulation • Neuroleptics (ie haldol) for agitation • Benzos to control seizures • Treat hyperthermia (external cooling) • For increased BP+HR, use vasodilators and CCB or non-selective beta-blockers CRIT 2012

Is there stimulant withdrawal? • Intense craving • Depression • Fatigue • Unpleasant dreams • Hypersomnia, then insomnia • Increased appetite • Limited ability to experience pleasure >> All results of relative dopamine depletion CRIT 2012

Health Consequences

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Dental • Darkened teeth • Caries • Periodontal disease

Neuro-psychiatric • Stroke • Seizure • Depression • Anxiety • Mania • Impulsivity • Paranoia • Auditory/ visual hallucinations + formications • Violence

Pulmonary • Acute pulmonary edema • Pulmonary HTN • Inhalation injury Cardiovascular • Hypertension • DCM • Arrythmia/ Tachycardia • Acute Coronary Syndrome • Aneurysm/ dissection • Erectile dysfunction

Infectious • HIV risk • HCV/ HBV • STDs

Renal/Metabolic • Rhabdomyolisis • Dehydration • Acute Renal Failure • Acidosis • Hyperthermia

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Skin • Cellulitis/ abscess • Excoriations • Chemical burns

AHA 2008 Scientific Statement on cocaine chest pain and MI • Class I: Benefit >>> Risk – Benzodiazepines (Level B) – ASA (Level C) – NTG (Level B)

• Class IIb: Benefit ≥ Risk – CCB (Level C) – Phentolamine (Level C)

• Class III: Risk ≥ Benefit – Beta-blockers (Level C) CRIT 2012

McCord et al. Circulation. 2008: 117.

Audience Response II Studies of the treatment for cocaine-related unstable angina with beta-blockers A. include randomized controlled trials that demonstrate that they save lives B. include randomized controlled trials that demonstrate that they cause harm C. include catheter studies in humans that show worsening vasospasm with propanolol D. include observational studies that show no increased adverse events among people receiving beta-blockers in the ED CRIT 2012

Beta-Blockers in Cocaine Chest Pain 331 patients with chest pain and cocaine-positive urine test results admitted to San Francisco General Hospital between 2001-05 •

151 patients received a beta-blocker in ED – 85% received metoprolol

•

During the hospitalization – SBP decreased more in ED beta-block group – No differences in ECG results, troponin levels, intubation rates, vasopressor use, malignant ventricular arrhythmia rates, or death were found.

•

45 deaths over a median follow-up of 972 days – Discharge on a beta-blocker regimen was associated with a lower risk of cardiovascular-specific death but not all-cause mortality

Rangel C, Shu RG, Lazar LD, et al. Beta-blockers for chest pain associated with recent cocaine use. Arch Intern Med. 2010;170(10):874–9. CRIT 2012

Cocaethylene • Psychoactive substrate from EtOH+cocaine • ETOH commonly used as “landing gear”

• ETOH before cocaine inhibits cocaine metabolism, producing cocaethylene • 60-90% of cocaine abusers abuse ETOH • Greater cardiac toxicity

• Greater rates of seizures, hepatic damage CRIT 2012

Cocaine and heroin • 30-80% of heroin users use cocaine • Cocaine use results in more injections • Cocaine worsens opiate treatment success • For 50% of co-users, MMT reduces cocaine

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Leri F. Addiction 2003: 98, 7-22.

Treatment

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Pharmacologic Treatment • Antipsychotics – Amato. Cochr Database Syst Rev. 2007 Jul 18;(3):

• Anticonvulsants - GABA modulators – Carbamazepine, Phenytoin, Valproic Acid, Tigabine, Gabapentin, Lamotrigine – Alvarez. JSAT 2010: 38; 66-73. – Baclofen – Heinzerling. Drug Alcohol Depend. 2006 Dec 1;85(3):177-84. – Vigabatrin (GVG) – Brodie. Am J Psychiatry. 2009;166:1269-77.

• Stimulant replacement – Modafinil – Shearer. Addiction. 2009 Feb;104(2):224-33. – Dexamphetamine – Longo. Addiction 2009, 105, 146–154

• Vaccine – Martell. Arch Gen Psychiatry. 2009 Oct;66(10):1116-23.

• Disulfiram – Pani. Cochr Database Syst Rev. 2010 Jan 20;(1): CRIT 2012

Non-Pharma Treatment • Brief Intervention? – Bernstein et al. DAD 2005; 77: 49.

• Cognitive behavioral therapy • Self-help/ 12 step groups

• Residential Treatment • Contingency management CRIT 2012

Contingency Management RCT in 6 community methadone programs of CM among stimulant users • Usual Care vs. • Intermittent, escalating re-enforcement – 1000 chips • • • •

500 “Good job” 250 “Small” - $1 value – i.e. toiletries 209 “Large” - $20 value – i.e. kitchenware 1 “Jumbo” – $80-100 value – tv, stereo

– # of draws = # of weeks with clean urine

CRIT 2012et al. Arch Gen Psychiatry. 2006;63:201-208. Peirce

Contingency Management

The mean percentage of submitted samples testing negative for target drugs (stimulants and alcohol) is shown for abstinence incentive and usual care participants at each of 24 study visits. CRIT 2012 Peirce et al. Arch Gen Psychiatry. 2006;63:201-208

Contingency Management Methadone Maintenance Patients With Specified Weeks of Continuous Stimulant/Alcohol-Negative Samples (n=388) 25% Incentive Control

20% 15% 10% 5% 0% 4 weeks

8 weeks

12 weeks

Average cost = $1.46 per person/day Pierce CRIT 2012et al. Arch Gen Psychiatry. 2006;63:201-208.

What should we do with our stimulant-using patients? • For both inpatients and outpatients – Ask about overdose, medical complications – Harm reduction – safer use techniques – Motivational interviewing to develop a decisional balance that favors safer use, quitting and engaging in available treatment

• Consider contingency management strategies CRIT 2012

Thanks! Alex Walley, MD, MSc [email protected]

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2007 ACC/AHA guidelines UA/ NSTEMI in cocaine and methamphetamine

• Class I: Benefit >>> Risk

– For STE or STD: NTG and CCB – For persistent STE: Cath with PCI or lytics

• Class IIa: Benefit > Risk – Chest pain w/o ST changes: NTG and CCBs – STD or new TW changes: Cath

• Class IIb: Benefit ≥ Risk – Increased HR or BP: Mixed alpha/beta blocker after vasodilator

• Class III: Risk ≥ Benefit – No ST changes: Cath Note: Level of evidence is C “expert opinion” for all recommendations CRIT 2012

JACC 2007: 50(7) e1-157.

Pharmacologic Treatment • Pharmacologic treatments studied – Dopamine agonists

– Antidepressants – Opioid partial agonists and antagonist – Carbamazepine, phenytoin, lithium

• None proven effective De Lima MS. Addiction. 2001: 97, 931-949. CRIT 2012

5 things about stimulants 1. Easily available 2. Directly activate the mesolimbic pleasure center 3. Binge use often ends with dysphoria or lack of funds 4. Social and medical consequences 5. Treatment can work if you can find it CRIT 2012

Learning objectives At the end of this session, participants will be able to: 1. Understand how and why people use stimulants 2. Know the characteristics of stimulant intoxication and withdrawal syndromes 3. Understand the consequences of these drugs 4. Know the current options for treatment of stimulant dependence

CRIT 2012

Dopamine release: nucleus accumbens 1400% 1200% 1000% 800% 600% 400% 200% 0% Fo

od

Se

x

Alc oh

ol

Nic o

ti n e

Co ca ine

% basal dopamine in rat/ mouse NA after... CRIT 2012

MA

CRIT 2012 Lange, R. A. and L. D. Hillis (2001). "Cardiovascular complications of cocaine use." N Engl J Med 345(5): 351-8.

CRIT 2012

Slide from Richard Rawson

Effects of Drugs on Dopamine Release METHAMPHETAMINE 1500 % Basal Release

% of Basal Release

Accumbens

1000

500

0

0

1

2

3hr

400

Accumbens

DA DOPAC HVA

300

200 100 0 Time After Cocaine

250

NICOTINE

200

Accumbens Caudate

150 100

% of Basal Release

% of Basal Release

Time After Methamphetamine

250

COCAINE

Accumbens

ETHANOL Dose (g/kg ip) 0.25 0.5 1 2.5

200

150

100

0 0

1

2

3 hr

0

Time After Nicotine

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0

1 2 3 4hr Time After Ethanol Source: Shoblock and Sullivan; Di Chiara and Imperato

Slide from Richard Rawson

According to the Drug Enforcement Agency (DEA), crystal methamphetamine (meth) is the number one drug in rural America. And now, the crystal meth epidemic is spreading like wildfire in cities and suburbs across America. Crystal meth has become the new drug of choice for everyone from soccer moms to working moms. Even grade school students are being caught in its deadly grip.

Meth is cheap and easy to make. The recipe includes over-the-counter cold medicine, household cleaners and toxic chemicals like battery acid. This drug crisis has forced many store owners to put cold remedies under lock and key. Thousands of homemade meth labs are popping up in kitchens, garages, even inside cars. In one Iowa town officials were forced to ban children from bringing baked goods to school because so many parents are cooking meth with the same utensils. It's cheap, instantly addictive, often deadly—and it's probably already in your neighborhood. CRIT 2012

Will She Choose Life or Death? An Oprah Winfrey Show Intervention May 13, 2005 Chantel looks like an all-American 17-yearold girl. Her mother is a teacher's assistant and her father sells insurance. She works at an espresso shop. But she's addicted to crystal meth. Chantel and her family live outside Granite Falls, Washington. She says she's been addicted to meth for a year and a half, after being introduced by friends, and she says she was instantly hooked from the very first hit. Since that time, she says the longest she's gone without using meth was 40 days. In that time, Chantel says, "I was having a ball. I was going to church to see if that was the way for me. I was having fun, hanging out with sober people. And then it was just in front of me one night and I did it and I was hooked again." On one occasion, Chantel says she stayed up for 13 straight days, getting high every 20 minutes. "Meth makes you have this burst of energy," she explains. "And if you keep smoking it, you'll keep that energy burst." Was she worried about overdosing during that two-week binge? "You don't worry about anything," Chantel says. "You don't have any thought in your mind besides, 'Let's hit it again.'" CRIT 2012

Pregnancy • More common in stimulant users: – Mental illness, seizure, injury, hypertension – Premature membrane rupture and labor, placenta previa, placental abruption, intrauterine death

• 1998-2004 – Cocaine-related hosp decreased: 0.74>>0.41 per 100 – MA-related hosp increased: 0.11>>0.22 per 100

• Cocaine vs. MA related pregnancy – More common for cocaine: mental illness, poor fetal growth, and premature delivery – More common for MA: hypertension, placenta previa CRIT 2012

Cox et al. Obstet Gynecol. 2008;111:341-7.

2005 drug-related ED visits

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Drug Abuse Warning Network 2005 Report

Cardiomyopathy and Methamphetamine

• In a case-control study, researchers examined the association between methamphetamine use and cardiomyopathy (CM). • Subjects included patients aged 45 years or younger discharged from a tertiary care medical center in Honolulu. • Through medical record review, researchers identified… – 107 cases (had a discharge diagnosis of CM or congestive heart failure) and – 114 controls (ejection fraction >55% and no wall motion abnormalities).

CRIT 2012Yeo K-K, et al. Am J Med. 2007;120(2):165–171.

Cardiomyopathy and Methamphetamine • 42% of cases and 20% of controls had ever used methamphetamine. • Methamphetamine use was significantly more common in cases than in controls. • OR in analyses adjusted for age, body mass index, and renal failure, 3.7

CRIT 2012Yeo K-K, et al. Am J Med. 2007;120(2):165–171.

“No lies here folks this recipe will manufacture methamphetamine this will get you into trouble if you do this BE CAREFUL!” First of all let's talk about supplies: • 1 Case Regular Pint size Mason Jars ( Used for canning) • 2 Boxes Contact 12 hour time released tablets. • 3 Bottles of Heet. • 4 feet of surgical tubing. • 1 Bottle of Rubbing Alcohol. • 1 Gallon Muriatic Acid ( Used for cleaning concrete) • 1 Gallon of Coleman's Fuel • 1 Gallon of Aceton • 1 Pack of Coffee Filters • 1 Electric Skillet

• 4 Bottles Iodine Tincture 2%

• 2 Bottles of Hydrogen peroxide • 3 20 0z Coke Bottles (Plastic type)(with Lids/caps) • 1 Can Red Devils Lye • 1 Pair of sharp scissors • 4 Boxes Book Matches (try to get the ones with brown/red striker pads) • 1 pyrodex baking dish • 1 Box execto razor blades single sided • 1 digital scale that reads grams • 2 gallons distilled water • 1 Roll Aluminum foil tape

“That's what you would have to go buy if you wanted to make meth.” CRIT 2012 www.totse.com/en/drugs/speedy_drugs/howtomanufactu172921.html

Treating Methamphetamine Dependence Reduces Risk for HIV

Rawson RA, et al. J Subst Abuse Treat. 2008;35(3):279–284. Summary by David A. Fiellin, MD CRIT 2012 www.aodhealth.org

55

Objectives/Methods • 787 methamphetamine- dependent individuals who received 1 of 2 counseling strategies: – 16 weeks of a standardized psychosocial protocol (Matrix Model), or – 8–16 weeks of treatment-as-usual representing 8 diverse treatment approaches

• Both approaches focused on drug use, not HIV risk Rawson RA, et al. J Subst Abuse Treat. 2008;35(3):279–284.

CRIT 2012 www.aodhealth.org

56

Results 



The proportion of the sample who reported injecting methamphetamine within the previous 30 days declined significantly (14.6% to 5.4%) from baseline to discharge High-risk sexual activity also decreased: Mean times participants reported having sex without a condom Mean times participants reported having sex without a condom with a methamphetamine user Mean times participants reported having sex without a condom with an injection drug user Mean times participants reported having sex while high



Baseline

Discharge

14.7

13.2

2.3

1.4

6.5

1.4

9.1

4.9

There were significant associations between treatment retention and HIV risk outcomes

Rawson RA, et al. J Subst Abuse Treat. 2008;35(3):279–284.

CRIT 2012 www.aodhealth.org

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Results – long term follow-up

N=569 Rawson RA, et al. J Subst Abuse Treat. 2008;35(3):279–284.

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Comments • This study demonstrates the benefit of counseling for patients with methamphetamine dependence. • Treatment was associated with decreased methamphetamine use and decreased risk for HIV infection. • The association between treatment retention and reduced HIV risk supports the implementation of programs that reduce barriers for treatment entry and retention. Rawson RA, et al. J Subst Abuse Treat. 2008;35(3):279–284.

www.aodhealth.org CRIT 2012 59

Cocaine and HIV • Crack cocaine use is associated – increased number of sex partners – sex work – HIV infection, independent of IVD use

• IV cocaine leads to HIV through frequent injection Chaisson. JAMA. 1989 Jan 27;261(4):561-5.

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MA and HIV • Increased libido, social disinhibition, increased energy >> riskier sex behaviors • PDE5 inhibitors (sildenafil) can be used to mitigate MA-induced erectile dysfunction

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Methamphetamine and Trauma To assess the prevalence and impact of methamphetamine use (MU) in trauma patients, researchers surveyed the records of…

• 4932 patients who presented to – San Diego trauma center between 2003–2005 – urine toxicology screening during their visit

Swanson SM, et al. J Trauma. 2007;63(3):531 CRIT 2012

Results • The rate of MU (defined as a positive urine screen), but not other illicit drug use, increased from 2003 to 2005 (from 9% to 15%). • In adjusted analyses, patients with MU were more likely to have… – – – –

been injured in a violent way (OR, 2.0), attempted suicide (OR, 1.7), been a victim of domestic violence (OR, 2.5), required more medical care (e.g., ≥1 operations [OR, 1.5], mechanical ventilation [OR, 1.6]), and – died from their injuries (OR, 2.3). Swanson SM, et al. J Trauma. 2007;63(3):531 CRIT 2012

Cognitive Behavioral Therapy 16 week RCT of cocaine-dependent methadone patients of: CBT vs. CM vs. CBT+CM vs. TAU 30 patients per group

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Rawson et al. Arch Gen Psychiatry. 2002

Cognitive Behavioral Therapy

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Rawson et al. Arch Gen Psychiatry. 2002

Cognitive Behavioral Therapy

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Rawson et al. Arch Gen Psychiatry. 2002