1. Dr. Nora D. Volkow, MD,Director, National Institute onDrug Abuse (NIDA) National Institute of Health
2. Prescription Drug Abuse:It s Not What the Doctor Ordered April 10-12, 2012 Walt Disney World Swan Resort Nora D. Volkow, M.D. Director National Institute on Drug Abuse
3. Learning Objectives Attendance at this presentation will give participants a better understanding of:•  Recent increasing trends in the misuse and abuse of prescription drugs as well as the growing number of opioid and stimulant prescriptions being dispensed by retail pharmacies in the U.S.•  The ways in which the most commonly abused prescription drug classes affect the brain and body and the possible deleterious consequences that can result from such use and abuse.•  Strategies being developed and implemented that will increase awareness of the growing problem, and research aimed at identifying tools and interventions to most effectively prevent and treat prescription drug abuse.
4. Disclosure StatementPresenter has nothing to disclose
5.  Pharmaceutical Drug Abuse is a  Major Problem in the US Past Month Use (Among Persons Aged 12 or Older) in MillionsSource: 2010 National Survey on Drug Use and Health, SAMHSA, 2011.
6. 2011 Monitoring the Future Study Prevalence of Past Year Drug Use Among 12th graders Drug Prev. Drug Prev.Alcohol 63.5 OxyContin* 4.9Marijuana/Hashish 36.4 Sedatives* 4.3Synthetic Marijuana 11.4 Hall other than LSD 4.3Amphetamines* 8.2 Inhalants 3.2Vicodin* 8.1 Cocaine (any form) 2.9Adderall* 6.5 LSD 2.7Salvia 5.9 Ritalin* 2.6Tranquilizers* 5.6 Ketamine 1.7Cough Medicine* 5.3 Provigil 1.5MDMA (Ecstasy) 5.3 GHB 1.4Hallucinogens 5.2 Methamphetamine 1.4* Nonmedical use Categories not mutually exclusive
7. Past Year Initiates of Specific Illicit Drugs Among Persons Aged 12 or Older: 2010Numbers in Thousands Source: 2010 National Survey on Drug Use and Health, SAMHSA, 2011.
10. Eight-Fold Deaths from Drug Overdoses 1971-2007Source: CDC, Unintentional Drug Poisoning in the US, National Vital Statistics System, 2010
11. Trends in ED Visits Involving the Nonmedical Use of Narcotic Pain RelieversNumber of ED Visits Source: 2008 (8/2009 update) SAMHSA DAWN
12. Number of Stimulant Prescriptions Dispensed by U.S. Retail Pharmacies, Years 1991-2011
13. The use of stimulantmedications amonghealthy individualsfor cognitiveenhancement isincreasing,raising questionsnot only about safetybut also its efficacyacross cognitive tasksand individuals
14. Source of Prescription Drugs (how they obtained the drugs they most recently used nonmedically) Rates averaged across 2009 and 2010 Percent Source: 2010 National Survey on Drug Use and Health, SAMHSA 2011.
15. Why Do People Abuse Prescription Drugs?These prescription drugs, like other 1100 % of Basal Release 1000 AMPHETAMINEdrugs of abuse (cocaine, heroin, 900 800marijuana) raise brain dopamine levels 700 600 500 400 Dopamine 300 200 frontal Neurotransmission 100 0 0 1 2 3 4 5 hr cortex Time After Amphetamine 200 FOOD % of Basal Release nucleus VTA/SN 150 accumbens 100 Empty 50 Box Feeding 0 0 60 120 180 Time (min) Di Chiara et al. BUT dopamine is also elevated by natural reinforcers
16. Drugs of Abuse Act on the Reward & Ancillary Circuits Through Different Mechanisms…But All Lead to Similar Dopaminergic Effects in the VTA & NAc Nicotine + Opiates Alcohol Opioid Glutamate inputs - Peptides (e.g., from cortex) Opiates Alcohol VTA GABA ? Interneuron - PCP Alcohol ` - ? Stimulants + Nicotine + DA DA Glutamate + Cannabinoids - inputs (e.g., from amygdala PPT/LDT) Adapted from Nestler 2005.
17. Similarities Between Illicit & Prescription Drugs
18. Opioids Examples: OxyContin, Vicodin Activate Opiate Receptors,How They Work… which Modulate Pain & Reward Attach to opioid receptors in thebrain and spinal cord, blocking thetransmission of pain messages and Thalamus (pain)causing an increase in the activity NAc (reward)of dopamine Opiate Receptors Activate Amydala Dopamine Cells (reward)Opioids are Generally Prescribed for:•  Postsurgical pain relief•  Management of acute or chronic pain•  Relief of coughs and diarrhea
19. Similarities Between Illicit & Prescription Drugs AdderallMethamphetamine
20. Stimulants Example: Ritalin How They Work…Enhance brain activity by increasing the activity of brainexcitatory chemical messengers, such as norepinephrineand dopamine, leading to mental stimulation Stimulants Are Generally Prescribed For: •  ADHD •  Narcolepsy •  Depression that does not respond to other treatments •  Asthma that does not respond to other treatment
21. CNS Depressants Examples: Valium, XanaxHow They Work… Cause an increase in gamma-aminobutyric acid (GABA), an inhibitory chemical messenger leading to a decrease in brain activityCNS Depressants are Generally Prescribed for: •  Anxiety •  Tension •  Panic attacks •  Acute stress reactions •  Sleep disorders •  Anesthesia (at high doses)
22. Sedatives Examples: Valium, Xanax, Librium Activate the Same Receptor as Alcohol Brain areas where activity is increased by sedative drugs and by alcoholSedative Drug Alcohol
23. What is the Difference Between Therapeutic Use and Abuse?•  Dose and Frequency of Dosing Lower, fixed regimes vs higher, escalating use•  Route of Administration Oral vs injection, smoking, snorting•  Expectation of Drug Effects Expectation of clinical benefits vs euphoria high•  Context of Administration School, clinic, home vs bar, discotheque
25. Pharmacokinetics in Human Brain[11C]Cocaine [11C]Methylphenidate
26. Effects Depend on the Drug Pharmacokinetics— How fast it gets into the Brain [11C]Cocaine [11C]Methylphenidate 100 100 80 80% Peak 60 60 40 40 20 20 "High" "High" 0 0 0 10 20 30 40 50 60 70 80 0 10 20 30 40 50 60 70 80 Time (min)
27. When Used Therapeutically Drugs are Given Orally which Results in Slow Brain Uptake When Abused Drugs are Snorted or Injected which Results n Fast Brain Uptake oral Ritalin 0.0035 0.003 0.0025 0.002 0.0015 Slow!!! 0.001 0.0005 00 20 40 60 80 100 120 Time (minutes) 0.06 iv Ritalin Uptake in Striatum (nCi/cc) Uptake in Striatum (%/cc) 0.05 0.04 0.03 0.02 Fast!!! 0.01 0 0 20 40 60 80 100 120 Time (minutes)
28. What is the Difference Between Therapeutic Use and Abuse?•  Dose and Frequency of Dosing Lower, fixed regimes vs higher, escalating use•  Route of Administration Oral vs injection, smoking, snorting•  Expectation of Drug Effects Expectation of clinical benefits vs euphoria high•  Context of Administration School, clinic, home vs bar, discotheque
29. Glucose Metabolism Was Greatly Increased By the Expectation of the Drug 30 25 % Change 20 Unexpected MP 15 70 10 5 0 Expected MP Unexpected Expected MP Got Placebo Expected MP MP Increases in Metabolism Were About 0 50% Larger When MP Was µmol/100g/min Expected Than Unexpected Source: Volkow, ND et al., Journal of Neuroscience, 23, pp. 11461-11468, December 2003.
30. What is the Difference Between Therapeutic Use and Abuse?•  Dose and Frequency of Dosing Lower, fixed regimes vs higher, escalating use•  Route of Administration Oral vs injection, smoking, snorting•  Expectation of Drug Effects Expectation of clinical benefits vs euphoria high•  Context of Administration School, clinic, home vs bar, discotheque
31. MP ability to increase DA is affected by the rate of DA release; which makes its effects Context Dependent 20 P < 0.05 MP-induced change in DA 15 10 low DA cell ﬁring! high DA cell ﬁring! 5 DA" 0 MP MP Neutral Salient DAT" MP" Context ContextDA D2-R" signal! signal!
32. Four-Fold Substance Use Disorder TX Admissions Pain Relievers: 1998-2008 Source: SAMHSA Treatment Episode Data Set (TEDS), 1998 and 2008.
33. Treatment of Prescription Medications
34. Full and Partial Agonists vs Antagonists Treatment Strategies for Opioid Addiction antagonist agonist Full Agonist (Methadone) Opioid Effect no effect Partial Agonist (Buprenorphine) an antagonist drug is close effect enough in shape to bind to the receptor but not close an agonist drug has an enough to produce anactive site of similar shape effect. It also takes up Antagonist to the endogenous ligand receptor space and so (Naloxone) so binds to the receptor prevents the endogenous and produces the same ligand from binding Log Dose effect
35. Buprenorphine for the Treatment of Addiction to Opioid MedicationSubutex® -- Monotherapy productSuboxone® -- Buprenorphine/Naloxone Currently 19,000 physicians are certified to prescribe buprenorphine Related toCSAT Buprenorphine Information Center) (Source: morphine (partial agonist) Uses same receptors as morphine but does not produce the same high Can be abused, but combining with naloxone decreases abuse potential Long-lasting, less likely to cause respiratory depression
36. Medications to Treat Those Addicted Speciﬁc Binding Speciﬁc Binding [18F]cyclofoxy (µ ligand) [11C]carfentail (µ ligand) Normal Control Methadone Maintained Patient 27-47 % occupancy for 2mg Bup 30-35 % receptor occupancy for 85-92% occupancy for 16 mg Bup methadone doses > 80 mg a day 94-98% occupancy for 32 mg Bup Source: Kling et al., JPET, 2000. Greenwald, MK et al., Neuropsychoph, 2003.
37. Need for New Medications•  Develop medications with lower abuse Uptake in Striatum (nCi/cc) 0.0035 0.003 potential including drugs that don’t 0.0025 0.002 0.0015 Slow! cross BBB (i.e., CbR2 agonist) 0.001 0.0005 !! 00 20 40 60 80 100 120 Time (minutes)•  Develop slow release formulations (low dose and long duration)•  Develop novel formulations to reduce abuse liability including mixture formulations (e.g., naloxone and buprenorphine)
38. How to Minimize the Diversion andAbuse of Prescription Medications
39. Prevention Strategies - Training & Education•  Enhance clinical training for physicians, nurses, dentists and pharmacists in the areas of pain management, opioid pharmacology and abuse and addiction
40. Prevention Strategies – Public Education•  Increase patient, lay public, and policy makers’ awareness of the potential risks for abuse inherent in all opioid analgesics
41. Take Back ProgramsMaine model–  Postage paid medicine return envelopes distributed across the state–  Disposal in compliance with state and federal laws and sound environmental practices–  3850 envelopes returned (85% prescription drugs)–  Psychotherapeutics made up 31% of returns for individuals ages 50 and under
42. Prescription Monitoring Programs•  Statewide electronic database collects data on substances dispensed in the state.•  Through the database, physicians and pharmacies can identify patients who are seeking multiple prescriptions.•  As of the summer of 2010, 34 states had operational programs.
43. www.drugabuse.gov Revised Jan 2012 Revised Dec 2011 Published Dec 2011 Revised Oct 2011