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Opiates:Use, Abuse, and Detection

Dr. Leo KadehjianPalo Alto, California

Abused Prescription Drugs

StimulantsOpioids

Oxycodone (OxyContin)Buprenorphine

MethadoneFentanyl

CNS Depressants

Barbiturates

BenzodiazepinesNon-benzos Amphetamine

MethamphetamineMethylphenidate

OTCEphedrine, etc.

Morphine, codeine, etc.

DextromethorphanAntihistamines

OtherCarisoprodol

Meperidine

Ketamine

Propoxyphene

Cocaine

Steroids

United States’ Drug Consumption

4.6% of world population

Consumes 80% of global opioid supply

Consumes 99% of global hydrocodone supply

Consumes 2/3 of illicit drug supply

L. Manchikanti and A. Singh, 2008

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Prescription Opioids Cocaine Methamphetamine Heroin0

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NSDUH, 2010

Non-Medical Use of DrugsMillions

DEA 2013 Oxycodone Production Quota: 135,000 kg

2011 U.S. Population: 311,591,917

135,000 kg

311,591,917 persons= 422 mg/person!

Oxycodone per Capita

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ÅÅ

1997 20060

5

10

15

20

25

30

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Retail Sales of Opioids (millions of grams)

Oxycodone +732%

Morphine +196%

Hydrocodone +244%(#1 prescribed drug in U.S.)

Hydromorphone +274%Fentanyl +479%

Codeine -25%

Meperidine -28%Methadone +1177%

www. deadiversion.usdoj.gov

74 mg/person 329 mg/person +347%

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1992 20030

100

200

300

400

500

600

L. Manchikanti, 2006

% increase

Increase in Abuse of Controlled Drugs

+ 14% – U.S. Population

+ 81% – Adults abusing

+ 150% – Prescriptions

+ 212% – 12 to 17 yr. olds abusing

+ 542% – New teenager opioid abuse

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1995 1996 1997 1998 1999 2000 2001 2002 2003 20040

5000

10000

15000

20000

25000

30000Past Year Illicit Drug Use

Marijuana

Cocaine

Psychotherapeutic

!ousands

L. Manchikanti, 2006

Prescription Cocaine Hallucinogens Inhalants Heroin0

2

4

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8

10

12

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16Admitted Drug Abuse

CASA, “Under the Counter: …”, 2005

Millions

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Pain relievers Tranquilizers Stimulants Sedatives0

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Non-Medical Use of Prescription DrugsMillions

NSDUH, 2007

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1995 1996 1997 1998 1999 2000 2001 2002 2003 20040

500

1000

1500

2000

2500

3000

L. Manchikanti, 2006

Past Year Initiates in Illicit Drug Use

Painrelievers

Marijuana

Tranquilizers

CocaineStimulants

SedativesHeroin

!ousands

0

100000

200000

300000

400000

500000

600000 ED Visits

Drug Abuse Warning Network, 2005

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HO

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H3CO

N

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O

H3CO

N

O

O

OH

H3CO

N

O

O

HO

N

HO

O

HO

N

O

O

OH

HO

N

O

O

H3CO

N

HO

O

Hydromorphone

Codeine Oxycodone

Morphine

Hydrocodone

Oxymorphone Dihydromorphine

Dihydrocodeine

(Dilaudid) (Numorphan)

(Vicodin, Lortab) (Percodan, OxyContin) (Synalgos)

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O

O

N

O

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O

O

H3CO

N

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O

H3CO

N

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N

Morphine HeroinCodeine

DextromethorphanLevorphanol

HO

N

H3CO

O

HO

Buprenorphine

HO

O

HO

N

Morphine

HO

N

O

O

OH

NaltrexoneReVia, Vivitrol

N

Methadone

O

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Opiates: History

1803 Morphine isolated (“Morpheus”)

1530 Paracelsus mixes opium with alcohol (“laudanum”)

400 BC Pain reliever (Hippocrates, Galen, Dioscorides)

1839, 56 Opium Wars (Hong Kong ceded to British)

5000 BC Sumerians “Plant of joy"

1822 De Quincey Confessions of an English Opium Eater

1700s 1st modern anti-drug laws, China, against opium

1832 Codeine isolated

Opiates: History

1874 Diacetylmorphine synthesized

1898 Bayer markets Heroin (from “heroisch”), as non-addictive alternative to morphine!!!???

(same year as aspirin)

1853 Hypodermic syringe invented

1861-5 Civil War, 400,000 addicts (“soldier’s disease”)

1875 S.F. ban on “opium houses” (1st US drug law)

1906 U.S. Pure Food and Drug Act, labelling requirements

1909 Opium Exclusion Act, no importation International Opium Commission, Shanghai

1923 Morphine structure

1914 Harrison Narcotic Act, heroin controlled (<10 mg/g)

1924 Heroin Act, heroin illegal

Opiates: History

1950s Morphine total synthesis

1937 Methadone synthesized

1938 Meperidine (Demerol) introduced

1970s Opiate receptors discovered Enkephalins, endorphins, discovered

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Opiates: History

1993 Morphine µ-receptor sequenced, cloned

1990s Heroin trials: Switzerland, several other countries

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0 4 8 12 16 20 24 28 32 36 40 44 48M. !evis et al., 2003

poppy seeds: morphine content: 152 µg/gmorphine intake: 1.6–6.8 mg

n=9

Urine Morphine after Poppy Seed Consumption

Hr

ng/mL

codeine levels: 60–820 ng/mL

Initial

Confirmation

Morphine

Codeine

6-MAM

SAMHSA

Previous 12/98 DoD

300

300

300 2000

2000

10

4000

2000

2000

Opiate Testing Cut-offs (ng/mL)

10

2000

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Resolution of Opiate Positives: Poppy Seeds or Not?

Eliminate seeds from diet, collect another specimen after 3 days

Test for 6-monoacetylmorphine (presence proves heroin use)

Measure total morphine levels (>5000 ng/mL unlikely for seeds)

Look for evidence of opiate use (needle tracks, needles, behavior)

Measure morphine/codeine ratio (morphine > codeine for seeds)

Examine claimed consumption (positives unlikely for >1 day)R

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ON

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ON

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OH3C

H3C

O

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ON

O

HO

Heroin

H3C

O

Morphine

6–Monoacetylmorphine

t1/2: 2–8 min

t1/2: 10–20 min

t1/2: 4 hr

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0 2 4 6 8 10 12 14 16 18 20

Heroin, 12 mg i.v.

M. Smith et al., 2001Hr.

6-AMng/mL

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Lower dosing (3–7 mg)

Higher dosing (10.5–13.9 mg)

M. Smith et al., 2001

Total morphine: 1,392–9,250 ng/mL (median 3,620)

6-AM: 6.1–298 ng/mL (median 106)

Total morphine: 2,065–29,030 ng/mL (median 16,470)

6-AM: 13–568 ng/mL (median 242)

Total Morphine, 6-AM after Heroin Dosing

Detection time @ 10 ng/mL: 0–5.1 hr (median 2.3)

Detection time @ 10 ng/mL: 2.3–11.2 hr (median 4.5)

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0 2000 4000 6000 8000 10000 12000 14000

Cone et al., 1991

6-AM (ng/mL)

6-AM After Heroin Dosing (3, 6 mg)

Total morphine (ng/mL)

n = 6t = 2–8 hr

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0 100000 200000 300000 400000 500000

O’Neal and Poklis, 1998

Total morphine (ng/mL)

6-AM (ng/mL)

6-AM in Morphine Specimens >5000 ng/mL

n = 73

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435300626

102–306291498247

9,3001,500

2,1002,0006,167

660–1,9801,8725,3491,545

>100,00023,000

10100,000600,000600,000500,000500,000100,000300,00080,000

400,000

6-AcetylmorphineMorphine

Morphine-3-glucuronideMorphine-6-glucuronide

CodeineDihydrocodeineHydromorphone

HydrocodoneOxymorphone

Oxycodone

300 ng/mL 2,000 ng/mL 10 ng/mL

Opiate assay 6-AM assayCross-Reactivity

t 1/2 = 5 hr (vs. 1.5–2 hr for morphine)

High oral bioavailability: 60% (vs. 20–30% for morphine)

Oxycodone

Metabolism/Elimination: Oxycodone, oxymorphone, and noroxycodone; conjugates

E!ects: analgesia, euphoria, sedation, miosis (pupil constriction)

Adverse e!ects: nausea, constipation, respiratory depression, hypotension, tolerance, withdrawal

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OxyContin1996 Slow-release form of oxycodone (1915)

10–160 mg tablets (Purdue Pharma)

Dosing: initial 10 mg/12 hr (vs. 10–30 mg/4 hr for oxycodone)

Potency: 6x more potent than codeineequipotent to morphine and hydrocodone (Vicodin)1/4 potency of hydromorphone (Dilaudid)10x more potent than meperidine (Demerol)

Schedule II controlled substance

Street price: $1/mg = 10x prescription cost

DAWN: 3–4K mentions for oxycodone (3–5x morphine)R

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H3CO

N

O

O

OH

HO

N

O

O

OH

H3CO

NH

O

O

OH

Oxymorphone

OxycodoneNoroxycodone

13–19% free7–29% conjugated

13 –14% conjugated

major

Oxycodone Metabolism and Elimination

86–100% cross-reactivity

Urine Concentrations of Oxycodone

n = 2 5 mg oral

Oxycodone, ng/mL

700 mg/day!n = 1 12, 900

n = 9 Poyhia et al., 1992

Weinstein and Gaylord, 1979

10 mg im20 mg oral

~500–1,000 (0–24 hr)

n = 210 mg im20 mg im

2,500 and 750 (5–9 hr)2,500–10,000 ( 3–9 hr)

600–800 (2–9 hr)Smith et al., 1995

Baselt and Stewart, 1978640 and 400 (0–24 hr)

HO

O

HO

N

HO

O

O

N

OH

HO

N

H3CO

O

HO Naloxone

Morphine

Buprenorphine

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Buprenorphine (Subutex, Suboxone)

R Partial µ-opioid receptor agonist (strong binding, weake!ects

Combined with naloxone (Suboxone) to minimize abuse

Reduced physical dependence, reduced respiratory depression

Drug Addiction Treatment Act of 2000 (Pub. L. 106–310)

FDA approval 10/8/02 (Schedule III)

25–40x more potent analgesic than morphine

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!-opioid receptor antagonist

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Buprenorphine (Subutex, Suboxone)

Assay cuto!: 5 ng/mLSensitivity: 0.7 ng/mLGood recovery @ 30 ng/mL

Dosing: Addiction treatment 12–16 mg/d (sublingual) Pain: <1 mg

"erapeutic urine concentrations: Addiction treatment: few to several hundred ng/mL Pain: 4–60 ng/mL Bup, 6–26 ng/mL Nor

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Abusers: few to several hundred ng/mL or more

Fatal overdoses: 4–1,000 ng/mL 3,400 ng/mL Bup, 600 Nor

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N

H3CO

O

HO

Buprenorphine

Buprenorphine Metabolism and Elimination

HO

NH

H3CO

O

HO

Norbuprenorphineactive

10%, mostly conjugated 14%, mostly conjugated

Hydroxylation(minor)

Dealkylation

Hydroxylation(minor)

2/3 in feces1/3 in urine

Glucuronidation

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<5

5-20

20-5

0

50-7

5

75-1

00

100-

300

300-

500

500-

1,00

0

1,00

0-1,

400

1,40

0-10

,000

>10,

0000

10

20

30

40

50

60

Urine Buprenorphine in Suboxone Patients

M. Hull et al., 2008

#

70 patients, 8–24 mg/dn=216 specimens

ng/mL (LC/MS/MS)

for n=176 unadulteratedavg. 164 ng/mL

Therapeutic use

Supra-therapeutic use,misuse

Abuse

Concentration

Dose Blood Receptors Effects

Absorption

Distribution

Metabolism

Elimination

Pharmacokinetics Pharmacodynamics

Urine, sweat, oral fluid, hair, …

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E. Cone et al., 2008

AmphetamineMethamphetamine

OxycodoneOxymorphone

HydrocodoneHydromorphone

Methadone

MeperidineNormeperidine

3,0863,490

1,1381,375

195–52,216124–19,908

10,16315,674

3,9101,854

196–93,372108–329,591

4,167 2,179 104–93,322

7,599 2,690 100–341,0094,930 1,637 100–188,306

2,953 1,380 100–405,0201,062 476 100–64,526

Urine Drug Concentrations (ng/mL): 10,922 Chronic Pain Patients

Mean Median Range

Assayresponse

Cut-off

Positivesample

Estimatedconcentration

“Negative”sample

Estimatedconcentration

Cut-off

“Negative”

does NOT mean

“No drug”

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Asn40 Asp400%

10%20%30%40%50%60%70%80%90%

100%

PlaceboNaltrexone

µ-Opioid Receptor Genotype and Naltrexone Response

R. Anton et al., 2008

% With good clinical outcome

Resources on Prescription Drug Abuse

National Institute on Drug Abuse (NIDA),www. drugabuse.gov/drugpages/prescription.html

National Survey on Drug Use and Health (NSDUH),www.oas.samhsa.gov/nsduh.htm

Monitoring the Future, www.monitorthefuture.org

Drug Abuse Warning Network (DAWN)www.dawninfo.samhsa.gov/default.asp

Medline (PubMed), www.pubmed.gov

Treatment Episode Data Set (TEDS)www.oas.samhsa.gov/dasis.htm#teds2

Community Epidemiology Working Group (CEWG),www.drugabuse.gov/about/organization/CEWG/CEWGHome.html

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