piates: Use, Abuse, and Detection Dr. Leo Kadehjian Palo Alto, California Abused Prescription Drugs pioids CS Depressants Morphine, codeine, etc. xycodone (xycontin) Buprenorphine Methadone entanyl Meperidine Propoxyphene Benzodiazepines on-benzos Barbiturates TC Ephedrine, etc. Dextromethorphan Antihistamines Stimulants Cocaine Amphetamine Methamphetamine Methylphenidate ther Carisoprodol Ketamine Steroids United States Drug Consumption 4.6% of world population Consumes 2/3 of illicit drug supply Consumes 8% of global opioid supply Consumes 99% of global hydrocodone supply L. Manchikanti and A. Singh, 28 1
Millions 6 on-medical Use of Drugs 5 4 3 2 1 Prescription pioids Cocaine Methamphetamine Heroin SDUH, 21 xycodone per Capita DEA 213 xycodone Production Quota: 135, kg 211 U.S. Population: 311,591,917 135, kg 311,591,917 persons = 422 mg/person! etail Sales of pioids (millions of grams) 4 35 3 25 2 15 1 5 74 mg/person 329 mg/person +347% Ç HÅ Ç H xycodone +732% Hydrocodone +244% (#1 prescribed drug in U.S.) Codeine -25% Morphine +196% Methadone +1177% Meperidine -28% Å Hydromorphone +274% É É entanyl +479% 1997 26 www. deadiversion.usdoj.gov 2
6 5 % increase Increase in Abuse of Controlled Drugs + 542% ew teenager opioid abuse 4 3 2 1 + 212% 12 to 17 yr. olds abusing + 15% Prescriptions + 81% Adults abusing + 14% U.S. Population 1992 23 L. Manchikanti, 26 3 25 Past Year Illicit Drug Use Thousands Marijuana 2 15 Psychotherapeutic 1 5 Cocaine H H H H H H H H H H 1995 1996 1997 1998 1999 2 21 22 23 24 L. Manchikanti, 26 Admitted Drug Abuse Millions 16 14 12 1 8 6 4 2 Prescription Cocaine Hallucinogens Inhalants Heroin CASA, Under the Counter:, 25 3
6 Millions on-medical Use of Prescription Drugs 5 4 3 2 1 Pain relievers Tranquilizers Stimulants Sedatives SDUH, 27 Past Year Initiates in Illicit Drug Use 3 25 2 Thousands Pain relievers Marijuana 15 1 5 É É É É É H H H H H É H É H Tranquilizers É É É Cocaine H H H Stimulants Ç Ç Ç Ç Ç Ç Ç Ç Ç Ç 1995 1996 1997 1998 1999 2 21 22 23 24 Sedatives Heroin L. Manchikanti, 26 6 ED Visits 5 4 3 2 1 Drug Abuse Warning etwork, 25 4
H H H H H H H Morphine Hydromorphone (Dilaudid) xymorphone (umorphan) Dihydromorphine H 3 C H 3 C H 3 C H 3 C H Codeine H H Hydrocodone xycodone Dihydrocodeine (Vicodin, Lortab) (Percodan, xycontin) (Synalgos) H H 3 C H Morphine H Codeine Heroin H H 3 C Levorphanol Dextromethorphan H H H Morphine H 3 C H Buprenorphine H H altrexone evia, Vivitrol Methadone 5
piates: History 5 BC Sumerians Plant of joy" 4 BC Pain reliever (Hippocrates, Galen, Dioscorides) 153 Paracelsus mixes opium with alcohol ( laudanum ) 17s 1st modern anti-drug laws, China, against opium 183 Morphine isolated ( Morpheus ) 1822 De Quincey Confessions of an English pium Eater 1832 Codeine isolated 1839, 56 pium Wars (Hong Kong ceded to British) piates: History 1853 Hypodermic syringe invented 1861-5 Civil War, 4, addicts ( soldier s disease ) 1874 Diacetylmorphine synthesized 1875 S.. ban on opium houses (1st US drug law) 1898 Bayer markets Heroin (from heroisch ), as non-addictive alternative to morphine!!!??? (same year as aspirin) 196 U.S. Pure ood and Drug Act, labelling requirements 199 pium Exclusion Act, no importation International pium Commission, Shanghai piates: History 1914 Harrison arcotic Act, heroin controlled (<1 mg/g) 1923 Morphine structure 1924 Heroin Act, heroin illegal 1937 Methadone synthesized 1938 Meperidine (Demerol) introduced 195s 197s Morphine total synthesis piate receptors discovered Enkephalins, endorphins, discovered 6
piates: History 1993 Morphine µ-receptor sequenced, cloned 199s Heroin trials: Switzerland, several other countries ng/ml 12 1 8 Urine Morphine after Poppy Seed Consumption n=9 poppy seeds: morphine content: 152 µg/g morphine intake: 1.6 6.8 mg codeine levels: 6 82 ng/ml 6 4 2 4 8 12 16 2 24 28 32 36 4 44 48 Hr M. Thevis et al., 23 piate Testing Cut-offs (ng/ml) SAMHSA Previous 12/98 DoD Initial 3 2 2 Confirmation Morphine Codeine 6-MAM 3 2 3 2 1 4 2 1 7
esolution of piate Positives: Poppy Seeds or ot? Examine claimed consumption (positives unlikely for >1 day) Eliminate seeds from diet, collect another specimen after 3 days Test for 6-monoacetylmorphine (presence proves heroin use) Measure total morphine levels (>5 ng/ml unlikely for seeds) Measure morphine/codeine ratio (morphine > codeine for seeds) Look for evidence of opiate use (needle tracks, needles, behavior) H 3 C H H 3 C Heroin t 1/2 : 2 8 min H H Morphine t 1/2 : 4 hr H 3 C 6 Monoacetylmorphine t 1/2 : 1 2 min 6 5 4 6-AM ng/ml Heroin, 12 mg i.v. 3 2 1 2 4 6 8 1 12 14 16 18 2 Hr. M. Smith et al., 21 8
Total Morphine, 6-AM after Heroin Dosing Lower dosing (3 7 mg) Total morphine: 1,392 9,25 ng/ml (median 3,62) 6-AM: 6.1 298 ng/ml (median 16) Detection time @ 1 ng/ml: 5.1 hr (median 2.3) Higher dosing (1.5 13.9 mg) Total morphine: 2,65 29,3 ng/ml (median 16,47) 6-AM: 13 568 ng/ml (median 242) Detection time @ 1 ng/ml: 2.3 11.2 hr (median 4.5) M. Smith et al., 21 6-AM After Heroin Dosing (3, 6 mg) 6-AM (ng/ml) 25 2 n = 6 t = 2 8 hr 15 1 5 2 4 6 8 1 12 14 Total morphine (ng/ml) Cone et al., 1991 6-AM in Morphine Specimens >5 ng/ml 14 12 1 8 6-AM (ng/ml) n = 73 6 4 2 1 2 3 4 5 Total morphine (ng/ml) eal and Poklis, 1998 9
Cross-eactivity piate assay 6-AM assay 3 ng/ml 2, ng/ml 1 ng/ml 6-Acetylmorphine 435 2,1 1 Morphine 3 2, 1, Morphine-3-glucuronide 626 6,167 6, Morphine-6-glucuronide 6, Codeine 12 36 66 1,98 5, Dihydrocodeine 291 1,872 5, Hydromorphone 498 5,349 1, Hydrocodone 247 1,545 3, xymorphone 9,3 >1, 8, xycodone 1,5 23, 4, xycodone Effects: analgesia, euphoria, sedation, miosis (pupil constriction) Adverse effects: nausea, constipation, respiratory depression, hypotension, tolerance, withdrawal High oral bioavailability: 6% (vs. 2 3% for morphine) t 1/2 = 5 hr (vs. 1.5 2 hr for morphine) Metabolism/Elimination: xycodone, oxymorphone, and noroxycodone; conjugates xycontin 1996 Slow-release form of oxycodone (1915) Schedule II controlled substance 1 16 mg tablets (Purdue Pharma) Street price: $1/mg = 1x prescription cost Dosing: initial 1 mg/12 hr (vs. 1 3 mg/4 hr for oxycodone) Potency: 6x more potent than codeine equipotent to morphine and hydrocodone (Vicodin) 1/4 potency of hydromorphone (Dilaudid) 1x more potent than meperidine (Demerol) DAW: 3 4K mentions for oxycodone (3 5x morphine) 1
xycodone Metabolism and Elimination H H 3 C H H 3 C xymorphone H 13 14% conjugated 86 1% cross-reactivity xycodone 13 19% free 7 29% conjugated oroxycodone H major H Urine Concentrations of xycodone xycodone, ng/ml n = 2 5 mg oral 64 and 4 ( 24 hr) Baselt and Stewart, 1978 1 mg im n = 9 ~5 1, ( 24 hr) Poyhia et al., 1992 2 mg oral n = 2 1 mg im 2 mg im 2,5 and 75 (5 9 hr) 2,5 1, ( 3 9 hr) 6 8 (2 9 hr) Smith et al., 1995 n = 1 7 mg/day! 12, 9 Weinstein and Gaylord, 1979 H H H 3 C H H H aloxone Buprenorphine H Morphine 11
Buprenorphine (Subutex, Suboxone) Partial µ-opioid receptor agonist (strong binding, weak effects!-opioid receptor antagonist Combined with naloxone (Suboxone) to minimize abuse 25 4x more potent analgesic than morphine educed physical dependence, reduced respiratory depression Drug Addiction Treatment Act of 2 (Pub. L. 16 31) DA approval 1/8/2 (Schedule III) Buprenorphine (Subutex, Suboxone) Dosing: Addiction treatment 12 16 mg/d (sublingual) Pain: <1 mg Therapeutic urine concentrations: Addiction treatment: few to several hundred ng/ml Pain: 4 6 ng/ml Bup, 6 26 ng/ml or Abusers: few to several hundred ng/ml or more atal overdoses: 4 1, ng/ml 3,4 ng/ml Bup, 6 or Assay cutoff: 5 ng/ml Sensitivity:.7 ng/ml Good recovery @ 3 ng/ml Glucuronidation Buprenorphine Metabolism and Elimination H Hydroxylation (minor) Dealkylation H H H 3 C H Hydroxylation (minor) H 3 C Buprenorphine orbuprenorphine active 1%, mostly conjugated 14%, mostly conjugated 2/3 in feces 1/3 in urine H 12
# 6 5 4 3 Urine Buprenorphine in Suboxone Patients 7 patients, 8 24 mg/d n=216 specimens for n=176 unadulterated avg. 164 ng/ml 2 1 <5 5-2 2-5 M. Hull et al., 28 5-75 75-1 1-3 3-5 5-1, ng/ml (LC/MS/MS) 1,-1,4 1,4-1, >1, Abuse Supra-therapeutic use, misuse Therapeutic use Concentration Pharmacokinetics Pharmacodynamics Dose Blood eceptors Effects Absorption Distribution Metabolism Elimination Urine, sweat, oral fluid, hair, 13
Urine Drug Concentrations (ng/ml): 1,922 Chronic Pain Patients Mean Median ange Amphetamine 1,163 3,91 196 93,372 Methamphetamine 15,674 1,854 18 329,591 xycodone xymorphone Hydrocodone Hydromorphone Methadone 7,599 2,69 1 341,9 4,93 1,637 1 188,36 2,953 1,38 1 45,2 1,62 476 1 64,526 4,167 2,179 14 93,322 Meperidine ormeperidine 3,86 3,49 1,138 195 52,216 1,375 124 19,98 E. Cone et al., 28 Assay response Positive sample Cut-off egative sample Estimated concentration Cut-off Estimated concentration egative does T mean o drug 14
µ-pioid eceptor Genotype and altrexone esponse 1% 9% 8% 7% 6% 5% 4% 3% 2% 1% % % With good clinical outcome Placebo altrexone Asn4 Asp4. Anton et al., 28 esources on Prescription Drug Abuse ational Institute on Drug Abuse (IDA), www. drugabuse.gov/drugpages/prescription.html ational Survey on Drug Use and Health (SDUH), www.oas.samhsa.gov/nsduh.htm Monitoring the uture, www.monitorthefuture.org Drug Abuse Warning etwork (DAW) www.dawninfo.samhsa.gov/default.asp 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 Medline (PubMed), www.pubmed.gov 15