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UW PACC ©2017 University of Washington
UW PACC Psychiatry and Addictions Case Conference UW Medicine | Psychiatry and Behavioral Sciences
THE PATHOPHYSIOLOGY
OF ADDICTION Richard Ries MD Professor and Director Addictions Division University of Washington Dept of Psychiatry and Behavioral Sciences Seattle, WA. [email protected]
And thanks to CNS Productions for use of their Uppers Downers All-Arounders PPts
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GENERAL DISCLOSURES
The University of Washington School of Medicine also gratefully acknowledges receipt of educational grant support for this activity from the Washington State Legislature through the Safety-Net Hospital Assessment, working to
expand access to psychiatric services throughout Washington State.
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RIES CONFLICT OF INTEREST STATEMENT
Richard Ries, MD has no financial relationships with an ACCME defined commercial interests. But does grant funding around addiction and/or suicide from
• NIH ( NIDA, NIAAA) • SAMHSA • Dept of Defense • Washington State
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Psychoactive Drugs Uppers (stimulants) Downers (depressants) All Arounders (psychedelics) Other Drugs (inhalants, sports drugs, psychiatric drugs) Compulsive Behaviors (e.g., gambling, eating disorders, Internet addiction)
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Uppers (stimulants) • Cocaine (hydrochloride, crack, freebase) • Amphetamines (speed, meth, “ice”) • Amphetamine congeners (Ritalin, diet pills,
e.g., fen-phen) • Plant stimulants (khat, betel nut, yohimbe) • Caffeine (coffee, tea, soft drinks, OTC meds) • Nicotine (cigarettes, cigars, smokeless
tobacco)
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Downers (depressants) Opiates/Opioids opium, codeine, morphine, heroin, methadone, Darvon , codeine Sedative-Hypnotics benzodiazepines, e.g., Xanax , Valium , barbiturates, e.g., Seconal , others, e.g., Rohypnol , Miltown
Alcohol beer, wine, hard liquor Others antihistamines, skeletal muscle relaxants, OTC downers, lookalike downers
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All Arounders (psychedelics) • LSD, psilocybin mushrooms, & other
indole psychedelics) • Mescaline (peyote ), ecstasy, & other
phenylalkylamine psychedelics • Belladonna, mandrake, & other
anticholinergic psychedelics • Ketamine, PCP, amanita mushrooms,
nutmeg, mace, kava • Marijuana (grass, hashish) & other
cannabinols
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2001 U.S. Drug Use in Past Month
Alcohol 48.3% 108.9 million Cigarettes 24.9% 60.4 million Marijuana 5.4% 12.2 million Ecstasy 3.6% 8.1 million Cocaine 0.7% 1.7 million Heroin 0.1% 123 thousand
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10
DRUG OVERDOSE DEATHS BY MAJOR DRUG TYPE, US, 1999-2010
CDC/NCHS National Vital Statistics System, CDC Wonder. Updated with 2010 mortality.
0
2,000
4,000
6,000
8,000
10,000
12,000
14,000
16,000
18,000
1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
Num
ber o
f Dea
ths
Year
Opioids Heroin Cocaine Benzodiazepines
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NATIONAL OVERDOSE DEATHS NUMBER OF DEATHS FROM PRESCRIPTION OPIOID PAIN RELIEVERS
0
2,000
4,000
6,000
8,000
10,000
12,000
14,000
16,000
18,000
20,000 Total Female Male
Source: National Center for Health Statistics, CDC Wonder
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Death Rates for Drug Overdose by State, 2010
3.4 - 10.9* 10.9* - 13.9 14.0 - 28.9
Age-adjusted rate per 100,000 population
10.0
9.6
7.8
8.6
10.6
6.3
3.4
6.7
7.3
13.9 11.8
11.4
9.6
14.4
13.2
15.0
23.8
11.8
10.9
11.4
19.4
10.7
6.8 12.7 23.6
10.9
12.9
16.9
14.6
16.1
12.9
16.9
15.3
28.9
13.1
17.5
10.4
16.4
17.0
20.7
11.6
NH 11.8 VT 9.7 MA 11.0 RI 15.5 CT 10.1 NJ 9.8 DE 16.6 MD 11.0 DC 12.9 12.5
Footnote: *10.9 is in two ranges due to rounding. HI is 10.88 while WI is 10.94
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HOW DO DRUGS WORK ?
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Inhaling Injecting Snorting Orally Transdermal
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Inhaling: 7 to 10 seconds
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Intravenous (IV) 15 – 30 seconds Intramuscular (IM) 3 – 5 minutes Subcutaneous 3 – 5 minutes
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Snorting or Mucosal Exposure: 3 to 5 minutes
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Oral use (ingesting): 20 to 30 minutes
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Contact or Transdermal: 1 to 2 days
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WHAT ABOUT NEURO-TRANSMITTERS ?
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21
Reward System of the Brain
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Message Arrives
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Cocaine Forces Neurotransmitter Release
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Heroin Inhibits Substance “P” Pain Message
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Neurotransmitters Acetylcholine Substance “P” Norepinephrine Anandamide Epinephrine Glycine Dopamine Histamine Endorphin Nitric oxide Enkephalin Glutamic acid Serotonin Cortisone GABA
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Development of Amphetamine Tolerance Over Time
Desired effect
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Alcohol Tolerance and Withdrawal on Neurochemical Balance
Normal Acute Alcohol Intake Chronic Intake/Dependence
Acute Withdrawal
Alcohol
Source: De Witte. Addictive Behaviors. 2004;29:1325–1339.
(Glutamate) (GABA) GABA Glutamate GABA
Adaptation Alcohol
Adaptation
Excitation Inhibition
Glutamate GABA
Glutamate
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Levels of Use
Abstention
Experimental
Social/Recreational
Habitual
Abuse
Addiction
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Addiction
• Practices addiction most of the time
• Continues use despite adverse consequences
• Denies there’s a problem • After withdrawal has a
strong tendency to relapse • Has lost control • Has altered brain chemistry
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Uppers (stimulants) Cocaine (hydrochloride, crack, freebase) Amphetamines (speed, meth, “ice”) Amphetamine congeners (Ritalin, diet pills, e.g., fen-phen) Plant stimulants (khat, betel nut, yohimbe) Caffeine (coffee, tea, soft drinks, OTC meds) Nicotine (cigarettes, cigars, chewing tobacco)
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Initial Effects of Stimulants Increased energy Increased heart rate, blood pressure, breathing, & reflexes Restlessness & excessive talking Hypersensitivity Dilated pupils Little appetite or thirst Overconfidence Euphoria
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Cocaine Absorption
Intravenous Smoked Nasal Oral
Minutes After Dose
Plas
ma
Lev
els o
f Coc
aine
(n
anog
ram
s per
mill
ilite
r
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Smokable cocaine (freebase, crack, paste)
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Crack pipes
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Amphetamines d,l amphetamine (e.g., benzedrine, “crosstops,” “black beauties,” “bennies”)
Methamphetamine (e.g., methedrine, “crank,” meth, “crystal”)
Dextroamphetamine (e.g., dexedrine, “dexies,” “beans,” “Christmas trees”)
Dextromethamphetamine (“ice,” “glass,” “batu,” “snot”)
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Methamphetamines
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“Ice- a form of Meth”
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MDMA (ECSTASY)
• 3, 4-methylenedioxy-methamphetamine • Street terms: Adam, E, X, XTC, love drug, Molly • A synthetic, psychoactive drug with both
stimulant and hallucinogenic properties similar to methamphetamine and mescaline
• Adverse effects: enhanced physical activity, sweating, lack of coordination, mental confusion, jaw clenching, hyperthermia, and agitation
NIDA. (2010). NIDA InfoFacts: MDMA (Ecstasy).
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WHAT IS “MOLLY”? 1. Ecstasy pills with little MDMA and lots of caffeine, meth,
assorted drugs? OR 2. A pure crystalline form of MDMA, most often sold as a powder
filled capsule? OR 3. Methylone? Bath salts?
• Reports of desired effects of euphoria, but also increased paranoia, agitated delirium, scary hallucinations, psychotic episodes, violent or destructive self-harm behavior, including death
• Bottom line - Molly usually is not a pure form of MDMA, but may be a drug that can be very dangerous since its contents are unknown
SOURCE: Join Together Online. (2013). Story published June 24, 2013.
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• “Spice,” “Bath Salts,” main names • Chemically-based; not plant derived • Complex chemistry • Constantly changing to “stay legal” • Need to prove “intended to use” to
convict in some areas
Synthetic Drugs
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FROM THE TERM “BATH SALTS” TO…
Synthetic Cathinones Mephedrone, methylone, 4-MEC Stimulants related to methcathinone, MDMA, amphetamines
2C- Phenethylamines
Psychedelics related to mescaline Some were created in the past to imitate MDMA
Tryptamines 5-MeO-DMT & 4-AcO-DMT Psychedelics related to psilocin & bufotenin
Piperazines BZP & TFMPP Stimulants
And Dissociatives related to ketamine and PCP and Opioids related to morphine, fentanyl, and heroin.
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Downers (depressants) Opiates/Opioids Opium, codeine, morphine, heroin Vicodin , OxyContin Heroin laced fentanyl
Sedative-Hypnotics Benzodiazepines, e.g., Valium Barbiturates, e.g., Seconal Others, e.g., Rohypnol , Miltown Alcohol Beer, wine, hard liquor
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Others Downers Antihistamines Skeletal muscle relaxants Over-the-counter downers Lookalike downers
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Opiates/Opioids From Opium Semisynthetic Synthetic
opium heroin methadone morphine hydrocodone propoxyphene (Vicodin) (Darvon ) codeine hydromorphone meperidine (Dilaudid ) (Demerol ) thebaine oxycodone fentanyl (OxyContin ) (Sublimaze )
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Effects: Opiates/Opioids Pain suppression Pinpoint pupils Lowered heart rate, blood pressure, respiration Constipation Cough suppression Lax muscle tone Dryness of mouth Euphoria
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46
DRUG OVERDOSE DEATHS BY MAJOR DRUG TYPE, US, 1999-2010
CDC/NCHS National Vital Statistics System, CDC Wonder. Updated with 2010 mortality.
0
2,000
4,000
6,000
8,000
10,000
12,000
14,000
16,000
18,000
1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
Num
ber o
f Dea
ths
Year
Opioids Heroin Cocaine Benzodiazepines
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Artificial Pain Suppression
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Black Tar Heroin
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CHANGING HEROIN MARKET • 1920’s to 90’s mostly Asian White
– Low % – Concentrated in large Urban areas
• Later 90’s- now--Black Tar from Mexico – More concentrated, – Different Biz model- middle/smaller towns – Deliver via cell phone
• NOW and Future---Fentanyl/Su and Car-Fentanyl – 10-100 x stronger, synthetic, cheaper – More deadly, resists naloxone block
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Methadone (Dolophine)
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RRies 2014
-10 -9 -8 -7 -6 -5 -4 0
10
20
30
40
50
60
70
80
90
100
Intrinsic Activity Respiratory Depression
Log Dose of Opioid
Full Agonist (Methadone)
Partial Agonist (Buprenorphine)
Antagonist (Naloxone)
Intrinsic Activity: Full Agonist (Methadone), Partial Agonist (Buprenorphine), Antagonist (Naloxone)
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Treatment duration (days)
Rem
aini
ng in
trea
tmen
t (n
r)
Bup
0
5
10
15
20
0 50 100 150 200 250 300 350
Control Buprenorphine
Treatment Retention and Mortality Bup vs Placebo- all got “1-1 drug counseling”
Kakko J et al. Lancet 2003
75% retention 75% UTS negative
20% mortality in placebo group
Bup= 16 mg a day double blind with Placebo
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Sedative-Hypnotics Benzodiazepines Xanax , Valium , Halcion , Librium , Rohypnol , Klonopin , Restoril , Ativan
Barbiturates Seconal , Nembutal , Amytal , phenobarbital
Others Chloral hydrate, GHB, GBL, Placidyl , etc.
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Benzodiazepines Very Long Acting Short Acting Halazepam (Paxipam) Alprazolam (Xanax ) Prazepam (Centrax ) Temazepam (Restoril ) Flurazepam (Dalmane ) Oxazepam (Serax ) Lorazepam (Ativan )
Intermediate Acting Very Short Acting Clonazepam (Klonipin ) Triazolam (Halcion ) Chlordiazepoxide (Librium ) Diazepam (Valium )
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Effects of Benzodiazepines Anxiety control (e.g., panic attack) Relaxation Drowsiness & sleep Control seizures Reduced muscular coordination Dulled physical sensations Use with Heroin/Opioids Triples Lethality
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Original Investigation | December 17, 2014
Benzodiazepine Use in the United States Mark Olfson, MD, MPH1,2; Marissa King, PhD3; Michael Schoenbaum, PhD4 Design, Setting, and Participants A retrospective descriptive analysis of benzodiazepine prescriptions was performed with the 2008 LifeLink LRx Longitudinal Prescription database (IMS Health Inc), which includes approximately 60% of all retail pharmacies in the United States. Denominators were adjusted to generalize estimates to the US population. Results In 2008, approximately 5.2% adults 18 to 80 years used benzodiazepines. The percentage increased with age from 2.6% (18-35 years) to 5.4% (36-50 years) to 7.4% (51-64 years) to 8.7% (65-80 years). Benzodiazepine use was nearly twice as prevalent in women as men. The proportion of benzodiazepine use that was long term increased with age from 14.7% (18-35 years) to 31.4% (65-80 years).
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BMJ. 2014 Mar 19;348:g1996. doi: 10.1136/bmj.g1996.
Effect of Anxiolytic and Hypnotic drug prescriptions on Mortality Hazards: retrospective cohort study. Weich S1, Pearce HL, Croft P, Singh S, Crome I, Bashford J, Frisher M. PARTICIPANTS: 34 727 patients aged 16 years and older first prescribed anxiolytic or hypnotic drugs, or both, between 1998 and 2001, and 69 418 patients with no prescriptions for such drugs (controls) matched by age, sex, and practice. Patients were followed-up for a mean of 7.6 years (range 0.1-13.4 years). RESULTS: The age adjusted hazard ratio for mortality = 3.46 (95% confidence interval 3.34 to 3.59) and 3.32 (3.19 to 3.45) after adjusting for other potential confounders. Dose-response associations with mortality found for all three classes of study drugs (benzodiazepines, Z drugs (zaleplon, zolpidem, and zopiclone), and other drugs).
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Prescribed Benzodiazepines and Suicide Risk: A Review of the Literature. Dodds TJ1,2. DATA SOURCES: A PubMed search of English-language publications from database inception until October 11, 2016, A total of 17 studies were included in this review. RESULTS: Benzos ^ Suicide Risk ( OR’s = 3 to 5 x in most studies) CONCLUSIONS: Benzodiazepines appear to cause an overall increase in the risk of attempting or completing suicide. Possible mechanisms of prosuicidal effects
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Part I - Drug Testing: Detection Period Range Alcohol BAL/Breath 1/2 – 1 day Alcohol EtG 1-4 days Amphetamines 2 – 4 days Barbiturates (most) 2 – 4 days phenobarbital up to 30 days Benzodiazepines 3-5 days, Cups don’t show- lor, clon, alprazolam Cocaine 12 – 72 hours Codeine 1 – 3 days Darvon 6 – 48 hours
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PAIN PHYSICIAN. 2010 JAN;13(1):71-8.
COMPARISON OF CLONAZEPAM COMPLIANCE BY MEASUREMENT OF URINARY CONCENTRATION BY IMMUNOASSAY AND LC-MS/MS IN PAIN MANAGEMENT POPULATION. WEST R, PESCE A, WEST C, CREWS B, MIKEL C, ALMAZAN P, ROSENTHAL M, LATYSHEV S.
• Samples from 180 patients taking clonazepam met these medication criteria
• Positivity rates were 21% (38 samples) by immunoassay ( cups) .
• The positivity rate was 70% (126 samples) if the LC-MS/MS cutoff was set at 200 ng/mL. (chromatography)
• Positivity rate was 87% (157 samples) if the LC-MS/MS was set at 40 ng/mL.
CSAM 2017
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62
Part II - Drug Testing: Detection Period Range - Urine Testing Dilaudid 2 – 4 days Heroin 2 – 4 days Marijuana - Single use 1 – 3 days Casual use - 4 joints/wk 5 – 7 days Daily use 10 – 15 days Chronic heavy use 1 – 2 months Methadone 2 – 5 days PCP - Casual use 2 – 7 days Chronic use up to 30 days
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Meth
Treatment for Stimulant Addiction
Withdrawal 1-5 days Sedatives, antipsych. /sleep nutrition Initial- Intensive Oupt groups or Inpt Longer-term Recovery 1-1, grps, AA, CA, NA, COD? Meds ??? COD meds? Hep C/HIV Screen
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Medical Treatments for Opioid Addiction
Naloxone (short acting antag: for OD) Naltrexone (longer acting antag: helps decrease craving and use) Methadone (full synth opioid decreases use/craving/crime) Clonidine (Decrease WD Sx ) Buprenorphine (Partial opioid blocks use/OD/craving)
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Current Issues in Addiction Treatment 1. Heroin epidemic and OPIOID OD’s 2. Health Care Reform ?? 3. Expanding use of Medications for treatment 4. Developing New Meds for Addictions 5. Developing more treatment resources 6. Coerced treatment /voluntary treatment ? 7. Abstinence-oriented vs. harm reduction ? 8. Integration into Primary Care 9. And don’t forget the Anonymous programs