Is it Heroin or Prescription Drugs?

Transcription

1 Is it Heroin or Prescription Drugs? Dr. Leo Kadehjian Palo Alto, California piates are outranked only by alcohol as humanity s oldest, most widespread, and most persistent drug problem Harvard Mental Health Letter, million chronic pain patients IDA, 211 Drug overdose: 2nd leading cause of unintentional deaths, after motor vehicle fatalities CDC, 21 pioids: 93% of prescription D deaths JAMA, 28 Prescription D deaths increased x4 since 1999 (>heroin + cocaine combined) CDC, 213 Heroin D deaths +45% SAMHSA pioid verdose Prevention Toolkit SAMHSA, 213 1

2 Terminology: piates or pioids? piates: aturally occurring in Papaver somniferum, codeine pioids: Act on opiate receptors (semi-synthetic, synthetic) xycodone, hydrocodone, buprenorphine, tramadol, meperidine, methadone, fentanyl, etc. 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 Millions 6 on-medical Use of Drugs Prescription pioids Cocaine Methamphetamine Heroin SDUH, 21 2

3 6 Millions on-medical Use of Prescription Drugs Pain relievers Tranquilizers Stimulants Sedatives SDUH, 27 6 ED Visits Drug Abuse Warning etwork, % increase Increase in Abuse of Controlled Drugs + 542% ew teenager opioid abuse % 12 to 17 yr. olds abusing + 15% Prescriptions + 81% Adults abusing + 14% U.S. Population L. Manchikanti, 26 3

4 xycodone per Capita DEA 213 xycodone Production Quota: 135, kg 211 U.S. Population: 311,591, , kg 311,591,917 persons = 422 mg/person! etail Sales of pioids (millions of grams) mg/person 329 mg/person +347% Ç HÅ J J Ç H xycodone +732% Hydrocodone +244% (#1 prescribed drug in U.S.) Codeine -25% +196% Methadone +1177% Meperidine -28% Å Hydromorphone +274% É É entanyl +479% www. deadiversion.usdoj.gov Past Year Initiates in Illicit Drug Use 3 Thousands 25 2 Pain relievers Marijuana J J É É É É É J J JH H H H H J É H J É H J J Tranquilizers J É É É Cocaine H H H Stimulants Ç Ç Ç Ç Ç Ç Ç Ç Ç Ç Sedatives Heroin L. Manchikanti, 26 4

5 H H H H H H H Hydromorphone (Dilaudid) xymorphone (umorphan, pana) Dihydromorphine H 3 C H 3 C H 3 C H 3 C H H H Codeine Hydrocodone (Vicodin, Lortab, Zohydro) xycodone (Percodan, xycontin) Dihydrocodeine (Synalgos) H H H H 3 C H uprenorphine H H altrexone evia, Vivitrol Methadone H H H Krokodil Dihydrodesoxymorphine Patented x more potent than morphine 5

6 1 pioids: elative Potencies (mg dosing) 4x 75x /1 1/5 1/3 1/1 Codeine xycodone xymorphone Hydrocodone Hydromorphone Dihydrocodeine Heroin uprenorphine Methadone Meperidine Tramadol entanyl PubMed Citations: pioids Codeine Hydromorphone Hydrocodone xymorphone xycodone Methadone uprenorphine altrexone Heroin aloxone PubMed Citations: Heroin (projected)

7 piates: History 5 C Sumerians Plant of joy" 4 C Pain reliever (Hippocrates, Galen, Dioscorides) 153 Paracelsus mixes opium with alcohol ( laudanum ) 17s 1st modern anti-drug laws, China, against opium 183 isolated ( Morpheus ) 1822 De Quincey Confessions of an English pium Eater 1832 Codeine isolated 1839, 56 pium Wars (Hong Kong ceded to ritish) piates: History 1853 Hypodermic syringe invented Civil War, 4, addicts ( soldier s disease ) 1874 Diacetylmorphine synthesized 1875 S.. ban on opium houses (1st US drug law) 1898 ayer 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 structure 1924 Heroin Act, heroin illegal 1937 Methadone synthesized 1938 Meperidine (Demerol) introduced 195s 197s total synthesis piate receptors discovered Enkephalins, endorphins, discovered 7

8 piates: History 1993 µ-receptor sequenced, cloned 199s Heroin trials: Switzerland, several other countries piate Testing Cut-offs (ng/ml) SAMHSA Previous 12/98 DoD Initial Confirmation Codeine 6-MAM H 3 C H H 3 C Heroin t 1/2 : 2 8 min H H t 1/2 : 4 hr H 3 C 6 Monoacetylmorphine t 1/2 : 1 2 min 8

9 Total, 6-AM after Heroin Dosing Lower dosing (3 7 mg) Total morphine: 1,392 9,25 ng/ml (median 3,62) 6-AM: ng/ml (median 16) Detection 1 ng/ml: 5.1 hr (median 2.3) Higher dosing ( mg) Total morphine: 2,65 29,3 ng/ml (median 16,47) 6-AM: ng/ml (median 242) Detection 1 ng/ml: hr (median 4.5) M. Smith et al., AM ng/ml Heroin, 12 mg i.v Hr. 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 Total morphine (ng/ml) Cone et al.,

10 6-AM in Specimens >5 ng/ml 14 6-AM (ng/ml) n = Total morphine (ng/ml) eal and Poklis, 1998 Cross-eactivity piate assay 6-AM assay 3 ng/ml 2, ng/ml 1 ng/ml 6-Acetylmorphine -3-glucuronide -6-glucuronide Codeine Dihydrocodeine Hydromorphone Hydrocodone xymorphone xycodone ,3 1,5 2,1 2, 6, ,98 1,872 5,349 1,545 >1, 23, 1 1, 6, 6, 5, 5, 1, 3, 8, 4, 25 2 Positive 6-AM, egative 6-AM ng/ml n = Total morphine, ng/ml. eck and M. öttcher, 26 1

11 Testing for ormetabolites of Synthetic pioids Total oth present Parent only or metabolite only % positive P P uprenorphine entanyl P P P Meperidine Methadone Propoxyphene A. DePriest et al., 21 % Missed Testing for pioid Glucuronides Codeine xymorphone Hydromorphone orbuprenorphine J. Dickerson et al., 212 Abuse Supra-therapeutic use, misuse Therapeutic use Concentration 11

12 Urine Drug Concentrations (ng/ml): 1,922 Chronic Pain Patients Mean Median ange Amphetamine 1,163 3, ,372 Methamphetamine 15,674 1, ,591 xycodone xymorphone Hydrocodone Hydromorphone Methadone 7,599 2, ,9 4,93 1, ,36 2,953 1, ,2 1, ,526 4,167 2, ,322 Meperidine ormeperidine 3,86 3,49 1, ,216 1, ,98 E. Cone et al., 28 Importance of piates Immunoassay Cutoff 1% 9% 8% 7% 6% 5% 4% 3% 2% 1% % 5 ng/ml IA cutoff n = 77,881 specimens 3 ng/ml IA cutoff 2, ng/ml IA cutoff M. Evans et al., 29 Compliance or on-compliance? 938,586 pain patients 75% test results not consistent with prescription 38% no detectable prescribed medication 29% non-prescribed medication detected 27% concentration higher than expected 15% concentration lower than expected 11% illicit drug detected J. Couto et al., 29 12

13 Urine Specimen Validity Tests Department of Health and Human Services Substance Abuse and Mental Health Services Administration Mandatory Guidelines for ederal Workplace Drug Testing Programs evised Mandatory Guidelines 4/13/ Effective 11/1/4 Creatinine, mg/dl Validity Testing Criteria: Urine 2 Inconsistent = Invalid Dilute ormal 2 Substituted Substituted Inconsistent = Invalid Specific 1.2 gravity Dilute SAMHSA creat 2 but <2 and s.g. >1.1 but <1.3 U.S. Courts creat 2 but <15 or s.g. 1.2 or 1.3 Invalid creat <2 and s.g. >1.1 but <1.2 ph 3 but <4.5 creat 2 and s.g. 1.1 ph 9 but <11 s.g. 1.1 or 1.45 Substituted Adulterated creat <2 and s.g. 1.1 or 1.2 ph <3 or 11 on-normal substance on-normal level creat <2 ph 4 or >1 on-normal substance on-normal level 13

14 C: Dilute and elow Cutoff esults Cutoff levels for drugs and drug metabolites. (a) Initial drug testing. (2) At the licensee s or other entity s discretion, as documented in the D program policies and procedures, the licensee or other entity may require the HHS-certified laboratory to conduct special analyses of dilute specimens as follows: (i) If initial validity testing indicates that a specimen is dilute, the HHS-certified laboratory shall compare the responses of the dilute specimen to the cutoff calibrator in each of the drug classes; (ii) If any response is equal to or greater than 5 percent of the cutoff, the HHS-certified laboratory shall conduct confirmatory testing of the specimen down to the LD for those drugs and/or drug metabolites; (iii) The laboratory shall report the numerical values obtained from this special analysis to the M. C, inal ule, , 3/31/8 mg/dl Urine Creatinine JA AÉ É J É A É J A É JA J A AÉ É All n= 22,245 AÉ J J J Male J emale A on-hispanic White on-hispanic lack É Mexican American Age D. arr et al., 24 Increase in Workplace Positives after Creatinine ormalization % Unadjusted (mean 119 mg/dl, ) 721 positives (16%) 12 Creatinine adjusted (mean 13 mg/dl) 1,217 positive (27%) n=4, ,949 ng/ml 2,86 ng/ml max. 4,382 ng/ml ng/ml 21,83 ng/ml ,439 ng/ml Amphetamines Cocaine Marijuana piates 478 ng/ml 2,725 ng/ml J. Price,

15 egative does T mean o drug 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), Monitoring the uture, Drug Abuse Warning etwork (DAW) Treatment Episode Data Set (TEDS) Community Epidemiology Working Group (CEWG), Medline (PubMed), 15